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Xu W, Boer K, Hesselink DA, Baan CC. Extracellular Vesicles and Immune Activation in Solid Organ Transplantation: The Impact of Immunosuppression. BioDrugs 2025; 39:445-459. [PMID: 40140222 PMCID: PMC12031870 DOI: 10.1007/s40259-025-00713-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/13/2025] [Indexed: 03/28/2025]
Abstract
Recent advances in extracellular vesicle (EV) research in organ transplantation have highlighted the crucial role of donor-derived EVs in triggering alloimmune responses, ultimately contributing to transplant rejection. Following transplantation, EVs carrying donor major histocompatibility complex (MHC) molecules activate recipient antigen-presenting cells (APCs), initiating both alloreactive and regulatory T-cell responses. While immunosuppressive drugs are essential for preventing rejection, they may also influence the biogenesis and release of EVs from donor cells. This review examines the impact of maintenance immunosuppressive therapy on EV biogenesis and release post-transplantation. In addition, EV release and uptake may be influenced by specific factors such as the patient's end-stage organ disease and the transplant procedure itself. In-vitro studies using primary human parenchymal and immune cells-integrated with cutting-edge multi-omics techniques, including genomics, proteomics, lipidomics, and single-EV analysis-will offer deeper insights into EV biology and the mechanisms by which immunosuppressive agents regulate EV-initiated immune processes. A detailed understanding of how organ failure, the transplantation procedure and immunosuppressive drugs affect the biology of EVs may uncover new roles for EVs in immune activation and regulation in patients, ultimately leading to improved immunosuppressive strategies and better transplant outcomes.
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Affiliation(s)
- Weicheng Xu
- Department of Internal Medicine, Sector Nephrology and Transplantation, Erasmus MC Transplant Institute, University Medical Center Rotterdam Erasmus MC, Doctor Molewaterplein 40, Room Nc 508, 3015 GD, Rotterdam, The Netherlands.
| | - Karin Boer
- Department of Internal Medicine, Sector Nephrology and Transplantation, Erasmus MC Transplant Institute, University Medical Center Rotterdam Erasmus MC, Doctor Molewaterplein 40, Room Nc 508, 3015 GD, Rotterdam, The Netherlands
| | - Dennis A Hesselink
- Department of Internal Medicine, Sector Nephrology and Transplantation, Erasmus MC Transplant Institute, University Medical Center Rotterdam Erasmus MC, Doctor Molewaterplein 40, Room Nc 508, 3015 GD, Rotterdam, The Netherlands
| | - Carla C Baan
- Department of Internal Medicine, Sector Nephrology and Transplantation, Erasmus MC Transplant Institute, University Medical Center Rotterdam Erasmus MC, Doctor Molewaterplein 40, Room Nc 508, 3015 GD, Rotterdam, The Netherlands
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Wang M, Hao Y, He W, Jia H, Zhong Z, Xia S. Nebulized mesenchymal stem cell-derived exosomes attenuate airway inflammation in a rat model of chronic obstructive pulmonary disease. Cell Immunol 2025; 409-410:104933. [PMID: 40020434 DOI: 10.1016/j.cellimm.2025.104933] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Revised: 01/20/2025] [Accepted: 02/20/2025] [Indexed: 03/03/2025]
Abstract
Chronic Obstructive Pulmonary Disease (COPD) is one of the leading causes of death worldwide, and current treatments fail to significantly halt its progression. Exosomes derived from mesenchymal stem cells (MSCs-Exos) have demonstrated promising potential in treating COPD due to their anti-inflammatory and regenerative biological properties. In this study, we investigated the potential anti-inflammatory effects of bone marrow mesenchymal stem cell-derived exosomes (BMSCs-Exos) in a COPD rat model and the possible mechanisms by which they inhibit airway remodeling, as well as identifying the optimal dosage and administration route. Our results show that nebulized BMSC-Exos significantly improve lung function in COPD rats while reducing pulmonary inflammatory infiltration, bronchial mucus secretion, and collagen deposition. Moreover, BMSC-Exos treatment notably decreased the expression of pro-inflammatory cytokines such as TNF-α, IL-6 and IL-1β, and the pro-fibrotic factor TGF-β1 in serum, bronchoalveolar lavage fluid (BALF), and lung tissue. The most pronounced therapeutic effect was observed at a low dose of exosomes. Furthermore, quantitative real-time PCR and immunohistochemical analyses revealed that nebulized BMSC-Exos significantly inhibited airway remodeling and epithelial-mesenchymal transition (EMT) by suppressing the Wnt/β-catenin signaling pathway. In conclusion, these findings indicate that nebulized BMSC-Exos offer a noninvasive therapeutic strategy for COPD by mitigating lung inflammation and airway remodeling through the suppression of abnormal Wnt/β-catenin pathway activation induced by cigarette smoke (CS) and lipopolysaccharide (LPS) in rats.
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Affiliation(s)
- Min Wang
- Graduate School of Dalian Medical University, Dalian 116044, China
| | - Yuxin Hao
- Graduate School of Shandong First Medical University, Jinan 271016, China
| | - Wei He
- Department of Respiratory and Critical Care Medicine, Central Hospital Affiliated to Shenyang Medical College, Shenyang 110024, China
| | - Hui Jia
- Department of Respiratory and Critical Care Medicine, Central Hospital Affiliated to Shenyang Medical College, Shenyang 110024, China
| | - Zhaoshuang Zhong
- Department of Respiratory and Critical Care Medicine, Central Hospital Affiliated to Shenyang Medical College, Shenyang 110024, China
| | - Shuyue Xia
- Graduate School of Dalian Medical University, Dalian 116044, China; Department of Respiratory and Critical Care Medicine, Central Hospital Affiliated to Shenyang Medical College, Shenyang 110024, China.
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Chen XX, Qiu D, Wang Y, Ju Q, Zhao CL, Zhang YS, Wang M, Zhang Y, Zhang J. Acetate-producing bacterium Paenibacillus odorifer hampers lung cancer growth in lower respiratory tract: an in vitro study. Microbiol Spectr 2024; 12:e0071924. [PMID: 39365050 PMCID: PMC11537125 DOI: 10.1128/spectrum.00719-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Accepted: 08/20/2024] [Indexed: 10/05/2024] Open
Abstract
Lung cancer accounts for the large majority of cancer incidence and mortality worldwide for decades. The dysbiotic microbiome and its metabolite secretions in the gut have been regarded as the dominant biological factors in oncogenesis, development, and progression, adding probiotic components of which have come to be potential therapeutic regimes. However, there still exists little knowledge about whether probiotic microorganisms in lower airways inhibit lung cancer by lung microenvironment remodulation. In this study, we performed bioinformatics analysis from previous sequencing data and specific microbiome databases to identify the potent protective microbes in lower airways, followed by bacterial cultivation and morphological verifications in vitro. We found that Paenibacillus odorifer was correlated closely with the anti-tumorous by-product acetic acid in lower respiratory tract. Additionally, the enrichment of this microorganism in the health, rather than in lung neoplasms from public data sets, further confirmed its protective activity in preserving pulmonary homeostasis. Colony cultivation of this strain and targeted metabolite analysis indicated that Paenibacillus odorifer proliferation was weakened at 37°C but lasted longer than it did at the optimal temperature. And performing as a candidate origin of acetic acid, this strain was liable to inhibit the growth of lung cancer cells in time- and dose-dependent approaches which was validated by colony formation assays. These results suggested that Paenibacillus odorifer functions as a candidate probiotic in lower airways to restrict lung cancer cell growth by releasing protective molecules, indicating a potential preventive microbial strategy.IMPORTANCEVarious types of microorganisms in lower respiratory tracts protect local homeostasis against oncogenesis. Although extensive efforts engaged in gut microbiome-mediated pulmonary carcinogenesis, emerging evidence suggested the crucial role of microbial metabolites from respiratory tracts in modulating carcinogenesis-related host inflammation and DNA damage in lung cancer, which was still not fully understood in lower respiratory tract microbes and its metabolite-mediated microecological environment homeostasis in preventing or alleviating lung cancer. In this study, we analyzed the lower respiratory tract microbiome and SCFAs expression among different lung segments from the same participants, further identifying that Paenibacillus odorifer was correlated closely with anti-tumorous by-product, acetate acid in lower respiratory tract by multi-omics analysis. And previous experiments showed this strain could inhibit the growth of lung cancer cells in vitro. These findings indicated that Paenibacillus odorifer in lower respiratory tracts might perform as a candidate probiotic against lung carcinogenesis by releasing protective factor acetate, which further presented a promising diagnostic and interventional approach in clinical settings of lung cancer.
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Affiliation(s)
- Xiang-xiang Chen
- Department of Pulmonary Medicine, Affiliated Hospital of Northwest University, Xi’an Peoples’ Hospital, Xi’an, China
- Department of Pulmonary and Critical Care of Medicine, The First Affiliated Hospital of Fourth Military Medical University, Xi’an, China
| | - Dan Qiu
- Department of Pulmonary and Critical Care of Medicine, The First Affiliated Hospital of Fourth Military Medical University, Xi’an, China
| | - Yuan Wang
- Department of Microbiology, School of Basic Medicine of Fourth Military Medical University, Xi’an, China
| | - Qing Ju
- Department of Pulmonary and Critical Care of Medicine, The First Affiliated Hospital of Fourth Military Medical University, Xi’an, China
| | - Cheng-lei Zhao
- Department of Dermatology, The First Affiliated Hospital of Third Military Medical University, Chongqing, China
| | - Yong-shun Zhang
- School of Basic Medicine, Fourth Military Medical University, Xi’an, China
| | - Min Wang
- Department of Pulmonary and Critical Care of Medicine, The First Affiliated Hospital of Fourth Military Medical University, Xi’an, China
| | - Yong Zhang
- Department of Pulmonary and Critical Care of Medicine, The First Affiliated Hospital of Fourth Military Medical University, Xi’an, China
| | - Jian Zhang
- Department of Pulmonary Medicine, Affiliated Hospital of Northwest University, Xi’an Peoples’ Hospital, Xi’an, China
- Department of Pulmonary and Critical Care of Medicine, The First Affiliated Hospital of Fourth Military Medical University, Xi’an, China
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Lu W, Aarsand R, Schotte K, Han J, Lebedeva E, Tsoy E, Maglakelidze N, Soriano JB, Bill W, Halpin DMG, Rivera MP, Fong KM, Kathuria H, Yorgancıoğlu A, Gappa M, Lam DC, Rylance S, Sohal SS. Tobacco and COPD: presenting the World Health Organization (WHO) Tobacco Knowledge Summary. Respir Res 2024; 25:338. [PMID: 39261873 PMCID: PMC11391604 DOI: 10.1186/s12931-024-02961-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2024] [Accepted: 08/25/2024] [Indexed: 09/13/2024] Open
Abstract
The WHO recently published a Tobacco Knowledge Summary (TKS) synthesizing current evidence on tobacco and COPD, aiming to raise awareness among a broad audience of health care professionals. Furthermore, it can be used as an advocacy tool in the fight for tobacco control and prevention of tobacco-related disease. This article builds on the evidence presented in the TKS, with a greater level of detail intended for a lung-specialist audience. Pulmonologists have a vital role to play in advocating for the health of their patients and the wider population by sharing five key messages: (1) Smoking is the leading cause of COPD in high-income countries, contributing to approximately 70% of cases. Quitting tobacco is an essential step toward better lung health. (2) People with COPD face a significantly higher risk of developing lung cancer. Smoking cessation is a powerful measure to reduce cancer risk. (3) Cardiovascular disease, lung cancer and type-2 diabetes are common comorbidities in people with COPD. Quitting smoking not only improves COPD management, but also reduces the risk of developing these coexisting conditions. (4) Tobacco smoke also significantly impacts children's lung growth and development, increasing the risk of respiratory infections, asthma and up to ten other conditions, and COPD later in life. Governments should implement effective tobacco control measures to protect vulnerable populations. (5) The tobacco industry's aggressive strategies in the marketing of nicotine delivery systems and all tobacco products specifically target children, adolescents, and young adults. Protecting our youth from these harmful tactics is a top priority.
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Affiliation(s)
- Wenying Lu
- Respiratory Translational Research Group, Department of Laboratory Medicine, School of Health Sciences, College of Health and Medicine, University of Tasmania, Locked Bag - 1322, Newnham Drive, Launceston, TAS, 7248, Australia
| | - Rebekka Aarsand
- Department of Digital Health and Innovation, World Health Organization, Geneva, Switzerland
| | - Kerstin Schotte
- Department of Health Promotion, World Health Organization, Geneva, Switzerland
| | - Jing Han
- Department of Digital Health and Innovation, World Health Organization, Geneva, Switzerland
| | - Elizaveta Lebedeva
- Tobacco Control Unit, Special Initiative on NCDs and Innovation, World Health Organization Regional Office for Europe, Copenhagen, Denmark
| | - Elena Tsoy
- Noncommunicable Diseases Management Unit, Special Initiative on NCDs and Innovation, World Health Organization Regional Office for Europe, Copenhagen, Denmark
| | - Nino Maglakelidze
- WHO European Regional Office, Strategic Development Adviser - Tbilisi State Medical Academy, Paris, France
| | - Joan B Soriano
- Noncommunicable Diseases Management Unit, Special Initiative on NCDs and Innovation, World Health Organization Regional Office for Europe, Copenhagen, Denmark
- Servicio de Neumología, Hospital Universitario de la Princesa, Facultad de Medicina, Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Universidad Autónoma de Madrid, Instituto de Salud Carlos III, Madrid, Spain
| | - Werner Bill
- European Respiratory Society, Lausanne, Switzerland
| | - David M G Halpin
- University of Exeter College of Medicine, University of Exeter Medical School, Exeter, UK
- Royal Devon and Exeter Hospital, Exeter, UK
| | - M Patricia Rivera
- Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of Rochester, New York, USA
| | - Kwun M Fong
- Department of Thoracic Medicine, The Prince Charles Hospital, University of Queensland Thoracic Research Centre, Brisbane, Australia
| | - Hasmeena Kathuria
- Center for Tobacco Research and Intervention, School of Medicine and Public Health, University of Wisconsin, Madison, WI, USA
- Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, School of Medicine and Public Health, University of Wisconsin, Madison, WI, USA
| | - Arzu Yorgancıoğlu
- Department of Pulmonology, Celal Bayar University Medical Faculty, Manisa, Turkey
| | - Monika Gappa
- Evangelisches Krankenhaus Düsseldorf, Düsseldorf, Germany
| | - David Cl Lam
- Department of Medicine, School of Clinical Medicine, University of Hong Kong, Hong Kong SAR, China
| | - Sarah Rylance
- Department of Digital Health and Innovation, World Health Organization, Geneva, Switzerland
| | - Sukhwinder Singh Sohal
- Respiratory Translational Research Group, Department of Laboratory Medicine, School of Health Sciences, College of Health and Medicine, University of Tasmania, Locked Bag - 1322, Newnham Drive, Launceston, TAS, 7248, Australia.
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Ding Z, Chen J, Li B, Ji X. Inflammatory factors and risk of lung adenocarcinoma: a Mendelian randomization study mediated by blood metabolites. Front Endocrinol (Lausanne) 2024; 15:1446863. [PMID: 39257908 PMCID: PMC11384989 DOI: 10.3389/fendo.2024.1446863] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2024] [Accepted: 07/29/2024] [Indexed: 09/12/2024] Open
Abstract
Background Lung adenocarcinoma (LUAD) is the most common type of lung cancer, and its pathogenesis remains not fully elucidated. Inflammation and metabolic dysregulation are considered to play crucial roles in LUAD development, but their causal relationships and specific mechanisms remain unclear. Methods This study employed a two-sample Mendelian randomization (MR) approach to systematically evaluate the causal associations between 91 circulating inflammatory factors, 1,400 serum metabolites, and LUAD. We utilized LUAD genome-wide association studies (GWAS) data from the FinnGen biobank and GWAS data of metabolites and inflammatory factors from the GWAS catalog to conduct two-sample MR analyses. For the identified key metabolites, we further used mediator MR to investigate their mediating effects in the influence of IL-17A on LUAD and explored potential mechanisms through protein-protein interaction and functional enrichment analyses. Results The MR analyses revealed that IL-17A (OR 0.78, 95%CI 0.62-0.99) was negatively associated with LUAD, while 71 metabolites were significantly associated with LUAD. Among them, ferulic acid 4-sulfate may play a crucial mediating role in the suppression of LUAD by IL-17A (OR 0.87, 95%CI 0.78-0.97). IL-17A may exert its anti-LUAD effects through extensive interactions with genes related to ferulic acid 4-sulfate metabolism (such as SULT1A1, CYP1A1, etc.), inhibiting oxidative stress and inflammatory responses, as well as downstream tumor-related pathways of ferulic acid 4-sulfate (such as MAPK, NF-κB, etc.). Conclusion This study discovered causal associations between IL-17A, multiple serum metabolites, and LUAD occurrence, revealing the key role of inflammatory and metabolic dysregulation in LUAD pathogenesis. Our findings provide new evidence-based medical support for specific inflammatory factors and metabolites as early predictive and risk assessment biomarkers for LUAD, offering important clues for subsequent mechanistic studies and precision medicine applications.
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Affiliation(s)
- Zheng Ding
- Department of Cardiac Surgery, The First Affiliated Hospital of China Medical University, Liaoning, Shenyang, China
| | - Juan Chen
- Department of Medical Oncology, The First Affiliated Hospital of China Medical University, Liaoning, Shenyang, China
| | - Bohan Li
- Department of Urinary Surgery, The First Affiliated Hospital of China Medical University, Liaoning, Shenyang, China
| | - Xinyu Ji
- Department of Thoracic Surgery, The First Affiliated Hospital of China Medical University, Liaoning, Shenyang, China
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Farrell LA, O’Rourke MB, Padula MP, Souza-Fonseca-Guimaraes F, Caramori G, Wark PAB, Dharmage SC, Hansbro PM. The Current Molecular and Cellular Landscape of Chronic Obstructive Pulmonary Disease (COPD): A Review of Therapies and Efforts towards Personalized Treatment. Proteomes 2024; 12:23. [PMID: 39189263 PMCID: PMC11348234 DOI: 10.3390/proteomes12030023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Revised: 08/13/2024] [Accepted: 08/14/2024] [Indexed: 08/28/2024] Open
Abstract
Chronic obstructive pulmonary disease (COPD) ranks as the third leading cause of global illness and mortality. It is commonly triggered by exposure to respiratory irritants like cigarette smoke or biofuel pollutants. This multifaceted condition manifests through an array of symptoms and lung irregularities, characterized by chronic inflammation and reduced lung function. Present therapies primarily rely on maintenance medications to alleviate symptoms, but fall short in impeding disease advancement. COPD's diverse nature, influenced by various phenotypes, complicates diagnosis, necessitating precise molecular characterization. Omics-driven methodologies, including biomarker identification and therapeutic target exploration, offer a promising avenue for addressing COPD's complexity. This analysis underscores the critical necessity of improving molecular profiling to deepen our comprehension of COPD and identify potential therapeutic targets. Moreover, it advocates for tailoring treatment strategies to individual phenotypes. Through comprehensive exploration-based molecular characterization and the adoption of personalized methodologies, innovative treatments may emerge that are capable of altering the trajectory of COPD, instilling optimism for efficacious disease-modifying interventions.
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Affiliation(s)
- Luke A. Farrell
- School of Life Sciences, Faculty of Science, University of Technology Sydney, Centre for Inflammation, Ultimo, NSW 2007, Australia;
| | - Matthew B. O’Rourke
- School of Life Sciences, Faculty of Science, University of Technology Sydney, Centre for Inflammation, Ultimo, NSW 2007, Australia;
| | - Matthew P. Padula
- School of Life Sciences, Faculty of Science, University of Technology Sydney, Ultimo, NSW 2007, Australia;
| | | | - Gaetano Caramori
- Pulmonology, Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy;
| | - Peter A. B. Wark
- School of Translational Medicine, Monash University, Melbourne, VIC 3000, Australia;
| | - Shymali C. Dharmage
- Centre for Epidemiology and Biostatistics, School of Population and Global Health, The University of Melbourne, Melbourne, VIC 3000, Australia;
| | - Phillip M. Hansbro
- School of Life Sciences, Faculty of Science, University of Technology Sydney, Centre for Inflammation, Ultimo, NSW 2007, Australia;
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Nucera F, Di Stefano A, Ricciardolo FLM, Gnemmi I, Pizzimenti C, Monaco F, Tuccari G, Caramori G, Ieni A. Role of ATG4 Autophagy-Related Protein Family in the Lower Airways of Patients with Stable COPD. Int J Mol Sci 2024; 25:8182. [PMID: 39125750 PMCID: PMC11311497 DOI: 10.3390/ijms25158182] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Revised: 07/18/2024] [Accepted: 07/25/2024] [Indexed: 08/12/2024] Open
Abstract
Autophagy is a complex physiological pathway mediating homeostasis and survival of cells degrading damaged organelles and regulating their recycling. Physiologic autophagy can maintain normal lung function, decrease lung cellular senescence, and inhibit myofibroblast differentiation. It is well known that autophagy is activated in several chronic inflammatory diseases; however, its role in the pathogenesis of chronic obstructive pulmonary disease (COPD) and the expression of autophagy-related genes (ATGs) in lower airways of COPD patients is still controversial. The expression and localization of all ATG proteins that represented key components of the autophagic machinery modulating elongation, closure, and maturation of autophagosome membranes were retrospectively measured in peripheral lungs of patients with stable COPD (n = 10), control smokers with normal lung function (n = 10), and control nonsmoking subjects (n = 8) using immunohistochemical analysis. These results show an increased expression of ATG4 protein in alveolar septa and bronchiolar epithelium of stable COPD patients compared to smokers with normal lung function and non-smoker subjects. In particular, the genes in the ATG4 protein family (including ATG4A, ATG4B, ATG4C, and ATG4D) that have a key role in the modulation of the physiological autophagic machinery are the most important ATGs increased in the compartment of lower airways of stable COPD patients, suggesting that the alteration shown in COPD patients can be also correlated to impaired modulation of autophagic machinery modulating elongation, closure, and maturation of autophagosomes membranes. Statistical analysis was performed by the Kruskal-Wallis test and the Mann-Whitney U test for comparison between groups. A statistically significant increased expression of ATG4A (p = 0.0047), ATG4D (p = 0.018), and ATG5 (p = 0.019) was documented in the bronchiolar epithelium as well in alveolar lining for ATG4A (p = 0.0036), ATG4B (p = 0.0054), ATG4C (p = 0.0064), ATG4D (p = 0.0084), ATG5 (p = 0.0088), and ATG7 (p = 0.018) in patients with stable COPD compared to control groups. The ATG4 isoforms may be considered as additional potential targets for the development of new drugs in COPD.
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Affiliation(s)
- Francesco Nucera
- Department of Biomedical, Dental, Morphological and Functional Imaging Sciences, Section of Pneumology, University of Messina, 98125 Messina, Italy;
| | - Antonino Di Stefano
- Istituti Clinici Scientifici Maugeri, IRCCS, Respiratory Rehabilitation Unit of Gattico-Veruno, Section of Pneumology, Laboratory of Cytoimmunopathology in Cardio Respiratory System, 28013 Gattico-Veruno, Italy; (A.D.S.); (I.G.)
| | - Fabio Luigi Massimo Ricciardolo
- Department of Clinical and Biological Sciences, Severe Asthma, Rare Lung Disease and Respiratory Pathophysiology Unit, San Luigi Gonzaga University Hospital, University of Turin, 10043 Orbassano, Italy;
| | - Isabella Gnemmi
- Istituti Clinici Scientifici Maugeri, IRCCS, Respiratory Rehabilitation Unit of Gattico-Veruno, Section of Pneumology, Laboratory of Cytoimmunopathology in Cardio Respiratory System, 28013 Gattico-Veruno, Italy; (A.D.S.); (I.G.)
| | - Cristina Pizzimenti
- Department of Human Pathology in Adult and Developmental Age ‘Gaetano Barresi’, Section of Pathology, University of Messina, 98125 Messina, Italy; (C.P.); (G.T.)
| | - Francesco Monaco
- Department of Biomedical, Dental, Morphological and Functional Imaging Sciences, Section of Toracic Surgery, University of Messina, 98125 Messina, Italy;
| | - Giovanni Tuccari
- Department of Human Pathology in Adult and Developmental Age ‘Gaetano Barresi’, Section of Pathology, University of Messina, 98125 Messina, Italy; (C.P.); (G.T.)
| | - Gaetano Caramori
- Department of Medicine and Surgery, Sections of Pneumology, University of Parma, 43126 Parma, Italy;
| | - Antonio Ieni
- Department of Human Pathology in Adult and Developmental Age ‘Gaetano Barresi’, Section of Pathology, University of Messina, 98125 Messina, Italy; (C.P.); (G.T.)
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Martin R, Nora M, Anna L, Olivia P, Leif B, Gunilla WT, Ellen T, Anna-Karin LC. Altered hypoxia-induced cellular responses and inflammatory profile in lung fibroblasts from COPD patients compared to control subjects. Respir Res 2024; 25:282. [PMID: 39014439 PMCID: PMC11253402 DOI: 10.1186/s12931-024-02907-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Accepted: 07/04/2024] [Indexed: 07/18/2024] Open
Abstract
BACKGROUND Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease characterized by chronic bronchitis, emphysema and vascular remodelling. The disease is associated with hypoxia, inflammation and oxidative stress. Lung fibroblasts are important cells in remodelling processes in COPD, as main producers of extracellular matrix proteins but also in synthesis of growth factors and inflammatory mediators. METHODS In this study we aimed to investigate if there are differences in how primary distal lung fibroblasts obtained from COPD patients and healthy subjects respond to hypoxia (1% O2) and pro-fibrotic stimuli with TGF-β1 (10 ng/mL). Genes and proteins associated with oxidative stress, endoplasmic reticulum stress, remodelling and inflammation were analysed with RT-qPCR and ELISA. RESULTS Hypoxia induced differences in expression of genes involved in oxidative stress (SOD3 and HIF-1α), ER stress (IRE1, PARK and ATF6), apoptosis (c-Jun and Bcl2) and remodelling (5HTR2B, Collagen7 and VEGFR2) in lung fibroblasts from COPD subjects compared to control subjects, where COPD fibroblasts were in general less responsive. The release of VEGF-C was increased after hypoxia, whereas TGF-β significantly reduced the VEGF response to hypoxia and the release of HGF. COPD fibroblasts had a higher release of IL-6, IL-8, MCP-1 and PGE2 compared to lung fibroblasts from control subjects. The release of inflammatory mediators was less affected by hypoxia, whereas TGFβ1 induced differences in inflammatory profile between fibroblasts from COPD and control subjects. CONCLUSION These results suggest that there is an alteration of gene regulation of various stress responses and remodelling associated mediator release that is related to COPD and hypoxia, where fibroblasts from COPD patients have a deficient response.
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Affiliation(s)
- Ryde Martin
- Lung Biology, Department of Experimental Medical Science, Faculty of Medicine, Lund University, Lund, Sweden.
- Respiratory Medicine, Allergology and Palliative Medicine, Department of Clinical Sciences Lund, Faculty of Medicine, Lund University, Lund, Sweden.
| | - Marek Nora
- Lung Biology, Department of Experimental Medical Science, Faculty of Medicine, Lund University, Lund, Sweden
| | - Löfdahl Anna
- Lung Biology, Department of Experimental Medical Science, Faculty of Medicine, Lund University, Lund, Sweden
| | - Pekny Olivia
- Lung Biology, Department of Experimental Medical Science, Faculty of Medicine, Lund University, Lund, Sweden
| | - Bjermer Leif
- Respiratory Medicine, Allergology and Palliative Medicine, Department of Clinical Sciences Lund, Faculty of Medicine, Lund University, Lund, Sweden
| | - Westergren-Thorsson Gunilla
- Lung Biology, Department of Experimental Medical Science, Faculty of Medicine, Lund University, Lund, Sweden
| | - Tufvesson Ellen
- Respiratory Medicine, Allergology and Palliative Medicine, Department of Clinical Sciences Lund, Faculty of Medicine, Lund University, Lund, Sweden
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Riondino S, Rosenfeld R, Formica V, Morelli C, Parisi G, Torino F, Mariotti S, Roselli M. Effectiveness of Immunotherapy in Non-Small Cell Lung Cancer Patients with a Diagnosis of COPD: Is This a Hidden Prognosticator for Survival and a Risk Factor for Immune-Related Adverse Events? Cancers (Basel) 2024; 16:1251. [PMID: 38610929 PMCID: PMC11011072 DOI: 10.3390/cancers16071251] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2024] [Revised: 03/18/2024] [Accepted: 03/21/2024] [Indexed: 04/14/2024] Open
Abstract
The interplay between the immune system and chronic obstructive pulmonary disease (COPD) and non-small cell lung cancer (NSCLC) is complex and multifaceted. In COPD, chronic inflammation and oxidative stress can lead to immune dysfunction that can exacerbate lung damage, further worsening the respiratory symptoms. In NSCLC, immune cells can recognise and attack the cancer cells, which, however, can evade or suppress the immune response by various mechanisms, such as expressing immune checkpoint proteins or secreting immunosuppressive cytokines, thus creating an immunosuppressive tumour microenvironment that promotes cancer progression and metastasis. The interaction between COPD and NSCLC further complicates the immune response. In patients with both diseases, COPD can impair the immune response against cancer cells by reducing or suppressing the activity of immune cells, or altering their cytokine profile. Moreover, anti-cancer treatments can also affect the immune system and worsen COPD symptoms by causing lung inflammation and fibrosis. Immunotherapy itself can also cause immune-related adverse events that could worsen the respiratory symptoms in patients with COPD-compromised lungs. In the present review, we tried to understand the interplay between the two pathologies and how the efficacy of immunotherapy in NSCLC patients with COPD is affected in these patients.
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Dong W, Yin Y, Liu B, Jiang Y, Wang L, Shi D, Qin J. Efficacy and safety of pembrolizumab as first-line treatment for advanced non-small cell lung cancer complicated with chronic obstructive pulmonary disease: protocol for a prospective, single-arm, single-center, phase II clinical trial. Front Oncol 2024; 14:1179232. [PMID: 38515570 PMCID: PMC10955356 DOI: 10.3389/fonc.2024.1179232] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Accepted: 02/27/2024] [Indexed: 03/23/2024] Open
Abstract
Background The first-line standard treatment option for patients with NSCLC complicated with Chronic obstructive pulmonary disease (COPD) is still unclear and relies on the treatment option of NSCLC alone. To date, a limited number of retrospective studies have explored the efficacy and safety of immunotherapy in patients with NSCLC complicated with COPD. We therefore designed this study to further explore the efficacy and safety of first-line immunotherapy in patients with NSCLC complicated with COPD. Methods This study was designed as a single-armed, single-center, prospective, phase II clinical study. It will include 30 advanced (stage IV) NSCLC combined with COPD primary treatment subjects. Each subject's diagnosis will be confirmed by clinical, radiographic, pathologic, and pulmonary function evaluation. A fixed dose of 200 mg pembrolizumab will be administered by intravenous infusion on day1 every 3 weeks (Q3W). The management of stable and acute exacerbations of COPD include home oxygen therapy, and the use of conventional medications are also administered. Imaging evaluation will be performed every 6 weeks for 6 months from the first pembrolizumab dose and approximately every 12 weeks thereafter until disease progression or early withdrawal. COPD status will be evaluated every 3 months by pulmonary function, GOLD grading, mMRC score, CAT score, ABCD grouping, and AECOPD severity. The primary outcome is Progression-free survival. The secondary outcome measures include objective response rate, overall survival, rate of acute exacerbations of COPD (times/year), lung function, mMRC score, CAT score, impact of treatment on patient's health-related quality of life, antibiotic use (including duration and classes), and adverse events associated with immune checkpoint inhibitors. Exploratory endpoint is to explore the association between COPD grade and the degree of immune cell (CD4+ T lymphocytes and CD8+ T lymphocytes) infiltration, as well as the association between COPD grade and the efficacy of immune checkpoint inhibitors. Clinical trial registration ClinicalTrials.gov, identifier NCT05578222.
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Affiliation(s)
| | | | | | | | | | | | - Jianwen Qin
- Department of Respiratory and Critica Care Medicine, Tianjin Chest Hospital, Affiliated Chest Hospital of Tianjin University, Tianjin, China
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Eapen MS, Lu W, Dey S, Chia C, Hardikar A, Hassan MI, Bhattarai P, Gaikwad AV, Das S, Hansbro PM, Singhera GK, Hackett TL, Sohal SS. Differential expression of mast cells in the small airways and alveolar septa of current smokers and patients with small airway disease and COPD. ERJ Open Res 2024; 10:00579-2023. [PMID: 38500797 PMCID: PMC10945381 DOI: 10.1183/23120541.00579-2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Accepted: 01/16/2024] [Indexed: 03/20/2024] Open
Abstract
Background COPD patients suffer from dysregulated and suppressed immune functionality, determined by their loss of degranulating capacity. Here we provide crucial information on the presence of degranulated mast cells (MCs) in COPD airways and demonstrate their relationship to lung physiology and airway remodelling. Methods Small airway lung resections from non-smoking controls (NC), normal lung function smokers (NLFS), small airway disease (SAD), and mild-to-moderate COPD current smokers (COPD-CS) and ex-smokers (COPD-ES) were dual immuno-stained with MC tryptase and degranulation marker lysosome-associated membrane protein (LAMP)-1. Total MCs, degranulating MCs and non-MCs were enumerated in small airway epithelium and subepithelium, and in alveolar septa. Results In the small airway wall subepithelial areas, COPD-CS and COPD-ES patients had significantly lower MCs than the NC group (p<0.05), although the numbers were considerably higher in the small airway epithelium (p<0.01). Degranulating non-MCs were higher in SAD (p<0.05) than in COPD in the small airway subepithelium. In contrast, there were significant increases in total MCs (degranulated and non-degranulated) and degranulated non-MCs in the alveolar septum of COPD patients compared with the NC group (p<001). The lower numbers of MCs in the subepithelium correlated with lower forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) and forced expiratory flow at 25-75% of FVC (FEF25-75%), higher smoking rates in COPD patients, and increased small airway wall thickness and extracellular matrix. The increase in MCs in the alveolar septum negatively correlated with FEF25-75%. Conclusions This study is the first to assess the differential pattern of MC, degranulating MC and non-MC populations in the small airways and alveoli of COPD patients. The spatial positioning of the MCs within the airways showed variable correlations with lung function.
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Affiliation(s)
- Mathew Suji Eapen
- Respiratory Translational Research Group, Department of Laboratory Medicine, School of Health Sciences, College of Health and Medicine, University of Tasmania, Launceston, Australia
| | - Wenying Lu
- Respiratory Translational Research Group, Department of Laboratory Medicine, School of Health Sciences, College of Health and Medicine, University of Tasmania, Launceston, Australia
- Launceston Respiratory and Sleep Centre, Launceston, Australia
| | - Surajit Dey
- Respiratory Translational Research Group, Department of Laboratory Medicine, School of Health Sciences, College of Health and Medicine, University of Tasmania, Launceston, Australia
| | - Collin Chia
- Respiratory Translational Research Group, Department of Laboratory Medicine, School of Health Sciences, College of Health and Medicine, University of Tasmania, Launceston, Australia
- Launceston Respiratory and Sleep Centre, Launceston, Australia
- Department of Respiratory Medicine, Launceston General Hospital, Launceston, Australia
| | - Ashutosh Hardikar
- Department of Cardiothoracic Surgery, Royal Hobart Hospital, Hobart, Australia
| | - Md Imtaiyaz Hassan
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, India
| | - Prem Bhattarai
- Respiratory Translational Research Group, Department of Laboratory Medicine, School of Health Sciences, College of Health and Medicine, University of Tasmania, Launceston, Australia
| | - Archana Vijay Gaikwad
- Respiratory Translational Research Group, Department of Laboratory Medicine, School of Health Sciences, College of Health and Medicine, University of Tasmania, Launceston, Australia
| | - Shatarupa Das
- Faculty of Science, Centre for Inflammation, Centenary Institute and University of Technology Sydney School of Life Sciences, Sydney, Australia
| | - Philip M. Hansbro
- Faculty of Science, Centre for Inflammation, Centenary Institute and University of Technology Sydney School of Life Sciences, Sydney, Australia
| | - Gurpreet Kaur Singhera
- Department of Anaesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, BC, Canada
- Centre for Heart Lung Innovation, St Paul's Hospital, Vancouver, BC, Canada
| | - Tillie-Louise Hackett
- Department of Anaesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, BC, Canada
- Centre for Heart Lung Innovation, St Paul's Hospital, Vancouver, BC, Canada
| | - Sukhwinder Singh Sohal
- Respiratory Translational Research Group, Department of Laboratory Medicine, School of Health Sciences, College of Health and Medicine, University of Tasmania, Launceston, Australia
- Launceston Respiratory and Sleep Centre, Launceston, Australia
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Bhattarai P, Lu W, Hardikar A, Dey S, Gaikwad AV, Shahzad AM, Chia C, Williams A, Singhera GK, Hackett TL, Eapen MS, Sohal SS. Endothelial to mesenchymal transition is an active process in smokers and patients with early COPD contributing to pulmonary arterial pathology. ERJ Open Res 2024; 10:00767-2023. [PMID: 38348240 PMCID: PMC10860200 DOI: 10.1183/23120541.00767-2023] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2023] [Accepted: 11/21/2023] [Indexed: 02/15/2024] Open
Abstract
Background We have previously reported pulmonary arterial remodelling in smokers and patients with early COPD, which can be attributed to endothelial to mesenchymal transition (EndMT). In this study, we aimed to evaluate if EndMT is an active mechanism in smokers and COPD. Methods Immunohistochemical staining for the EndMT biomarkers CD31, N-cadherin, vimentin and S100A4 was done on lung resection tissue from 49 subjects. These comprised 15 nonsmoker controls (NC), six normal lung function smokers (NLFS), nine patients with small airway disease (SAD), nine current smokers with mild-moderate COPD (COPD-CS) and 10 ex-smokers with COPD (COPD-ES). Pulmonary arteries were analysed using Image ProPlus software v7.0. Results We noted reduced junctional CD31+ endothelial cells (p<0.05) in the intimal layer of all smoking groups compared to NC. We also observed increased abundance of the mesenchymal markers N-cadherin (p<0.05) and vimentin (p<0.001) in all smoking groups and across all arterial sizes versus NC, except for N-cadherin in large arteries in COPD-CS. The abundance of S100A4 correlated with arterial thickness (small: r=0.29, p=0.05; medium: r=0.33, p=0.03; large: r=0.35, p=0.02). Vimentin in the small arterial wall negatively correlated with forced expiratory volume in 1 s/forced vital capacity (r= -0.35, p=0.02) and forced expiratory flow rate at 25-75% of forced vital capacity (r= -0.34, p=0.03), while increased cytoplasmic CD31 abundance in the intimal layer of medium and large arteries negatively correlated with predicted diffusing capacity of the lung for carbon monoxide (medium: r= -0.35, p=0.04; large: r= -0.39, p=0.03). Conclusion This is the first study showing the acquisition of mesenchymal traits by pulmonary endothelial cells from NLFS, SAD and mild-moderate COPD patients through EndMT. This informs on the potential early origins of pulmonary hypertension in smokers and patients with early COPD.
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Affiliation(s)
- Prem Bhattarai
- Respiratory Translational Research Group, Department of Laboratory Medicine, School of Health Sciences, College of Health and Medicine, University of Tasmania, Launceston, TAS, Australia
- Launceston Respiratory and Sleep Centre, Launceston, TAS, Australia
| | - Wenying Lu
- Respiratory Translational Research Group, Department of Laboratory Medicine, School of Health Sciences, College of Health and Medicine, University of Tasmania, Launceston, TAS, Australia
- Launceston Respiratory and Sleep Centre, Launceston, TAS, Australia
| | - Ashutosh Hardikar
- Department of Cardiothoracic Surgery, Royal Hobart Hospital, Hobart, TAS, Australia
- Department of Cardiothoracic Surgery, The Royal Adelaide Hospital, Adelaide, SA, Australia
| | - Surajit Dey
- Respiratory Translational Research Group, Department of Laboratory Medicine, School of Health Sciences, College of Health and Medicine, University of Tasmania, Launceston, TAS, Australia
| | - Archana Vijay Gaikwad
- Respiratory Translational Research Group, Department of Laboratory Medicine, School of Health Sciences, College of Health and Medicine, University of Tasmania, Launceston, TAS, Australia
| | - Affan Mahmood Shahzad
- Respiratory Translational Research Group, Department of Laboratory Medicine, School of Health Sciences, College of Health and Medicine, University of Tasmania, Launceston, TAS, Australia
| | - Collin Chia
- Respiratory Translational Research Group, Department of Laboratory Medicine, School of Health Sciences, College of Health and Medicine, University of Tasmania, Launceston, TAS, Australia
- Launceston Respiratory and Sleep Centre, Launceston, TAS, Australia
- Department of Respiratory Medicine, Launceston General Hospital, Launceston, TAS, Australia
| | - Andrew Williams
- Respiratory Translational Research Group, Department of Laboratory Medicine, School of Health Sciences, College of Health and Medicine, University of Tasmania, Launceston, TAS, Australia
| | - Gurpreet Kaur Singhera
- Department of Anaesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, BC, Canada
- Centre for Heart Lung Innovation, St Paul's Hospital, Vancouver, BC, Canada
| | - Tillie-Louise Hackett
- Department of Anaesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, BC, Canada
- Centre for Heart Lung Innovation, St Paul's Hospital, Vancouver, BC, Canada
| | - Mathew Suji Eapen
- Respiratory Translational Research Group, Department of Laboratory Medicine, School of Health Sciences, College of Health and Medicine, University of Tasmania, Launceston, TAS, Australia
| | - Sukhwinder Singh Sohal
- Respiratory Translational Research Group, Department of Laboratory Medicine, School of Health Sciences, College of Health and Medicine, University of Tasmania, Launceston, TAS, Australia
- Launceston Respiratory and Sleep Centre, Launceston, TAS, Australia
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Fang H, Dong T, Li S, Zhang Y, Han Z, Liu M, Dong W, Hong Z, Fu M, Zhang H. A Bibliometric Analysis of Comorbidity of COPD and Lung Cancer: Research Status and Future Directions. Int J Chron Obstruct Pulmon Dis 2023; 18:3049-3065. [PMID: 38149238 PMCID: PMC10750778 DOI: 10.2147/copd.s425735] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2023] [Accepted: 12/15/2023] [Indexed: 12/28/2023] Open
Abstract
Objective Although studies on the association between COPD and lung cancer are of great significance, no bibliometric analysis has been conducted in the field of their comorbidity. This bibliometric analysis explores the current situation and frontier trends in the field of COPD and lung cancer comorbidity, and to lay a new direction for subsequent research. Methods Articles in the field of COPD and cancer comorbidity were retrieved from Web of Science Core Collections (WoSCC) from 2004 to 2023, and analyzed by VOSviewer, CiteSpace, Biblimatrix and WPS Office. Results In total, 3330 publications were included. The USA was the leading country with the most publications and great influence. The University of Groningen was the most productive institution. Edwin Kepner Silverman was the most influential scholar in this field. PLOS One was found to be the most prolific journal. Mechanisms and risk factors were of vital importance in this research field. Environmental pollution and pulmonary fibrosis may be future research prospects. Conclusion This bibliometric analysis provided new guidance for the development of the field of COPD and lung cancer comorbidity by visualizing current research hotspots, and predicting possible hot research directions in the future.
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Affiliation(s)
- Hanyu Fang
- Graduate School, Beijing University of Chinese Medicine, Beijing, People’s Republic of China, 100029
- Department of Traditional Chinese Medicine for Pulmonary Diseases, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, 100029, People’s Republic of China
| | - Tairan Dong
- Graduate School, Beijing University of Chinese Medicine, Beijing, People’s Republic of China, 100029
| | - Shanlin Li
- Graduate School, Beijing University of Chinese Medicine, Beijing, People’s Republic of China, 100029
| | - Yihan Zhang
- Graduate School, Beijing University of Chinese Medicine, Beijing, People’s Republic of China, 100029
| | - Zhuojun Han
- Graduate School, Beijing University of Chinese Medicine, Beijing, People’s Republic of China, 100029
| | - Mingfei Liu
- Graduate School, Beijing University of Chinese Medicine, Beijing, People’s Republic of China, 100029
- Department of Traditional Chinese Medicine for Pulmonary Diseases, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, 100029, People’s Republic of China
| | - Wenjun Dong
- Graduate School, Beijing University of Chinese Medicine, Beijing, People’s Republic of China, 100029
- Department of Traditional Chinese Medicine for Pulmonary Diseases, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, 100029, People’s Republic of China
| | - Zheng Hong
- Graduate School, Beijing University of Chinese Medicine, Beijing, People’s Republic of China, 100029
- Department of Traditional Chinese Medicine for Pulmonary Diseases, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, 100029, People’s Republic of China
| | - Min Fu
- Department of Infectious Diseases, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, 100029, People’s Republic of China
| | - Hongchun Zhang
- Graduate School, Beijing University of Chinese Medicine, Beijing, People’s Republic of China, 100029
- Department of Traditional Chinese Medicine for Pulmonary Diseases, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, 100029, People’s Republic of China
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Lu W, Eapen MS, Hardikar A, Chia C, Robertson I, Singhera GK, Hackett TL, Sohal SS. Epithelial-mesenchymal transition changes in nonsmall cell lung cancer patients with early COPD. ERJ Open Res 2023; 9:00581-2023. [PMID: 38152085 PMCID: PMC10752287 DOI: 10.1183/23120541.00581-2023] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2023] [Accepted: 10/06/2023] [Indexed: 12/29/2023] Open
Abstract
Background Epithelial-mesenchymal transition (EMT) might be central to lung cancer development in smokers and COPD. We illustrate EMT changes in a broader demographic of patient groups who were diagnosed with nonsmall cell lung cancer (adenocarcinoma and squamous cell carcinoma). These included COPD current and ex-smokers, patients with small airway disease and normal lung function smokers compared to normal controls. Methods We had access to surgically resected small airway tissue from 46 subjects and assessed for airway wall thickness and immunohistochemically for the EMT biomarkers E-cadherin, N-cadherin, S100A4, vimentin and epidermal growth factor receptor (EGFR). All tissue analysis was done with a computer and microscope-assisted Image-Pro Plus 7.0 software. Results Airway wall thickness significantly increased across all pathological groups (p<0.05) compared to normal controls. Small airway epithelial E-cadherin expression markedly decreased (p<0.01), and increases in N-cadherin, vimentin, S100A4 and EGFR expression were observed in all pathological groups compared to normal controls (p<0.01). Vimentin-positive cells in the reticular basement membrane, lamina propria and adventitia showed a similar trend to epithelium across all pathological groups (p<0.05); however, such changes were only observed in reticular basement membrane for S100A4 (p<0.05). Vimentin was higher in adenocarcinoma versus squamous cell carcinoma; in contrast, S100A4 was higher in the squamous cell carcinoma group. EGFR and N-cadherin expression in both phenotypes was markedly higher than E-cadherin, vimentin and S100A4 (p<0.0001). Conclusion EMT is an active process in the small airway of smokers and COPD diagnosed with nonsmall cell lung cancer, contributing to small airway remodelling and cancer development as seen in these patients.
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Affiliation(s)
- Wenying Lu
- Respiratory Translational Research Group, School of Health Sciences, University of Tasmania, Newnham, TAS, Australia
- Launceston Respiratory and Sleep Centre, Launceston, TAS, Australia
| | - Mathew Suji Eapen
- Respiratory Translational Research Group, School of Health Sciences, University of Tasmania, Newnham, TAS, Australia
| | - Ashutosh Hardikar
- Department of Cardiothoracic Surgery, Royal Hobart Hospital, Hobart, TAS, Australia
| | - Collin Chia
- Respiratory Translational Research Group, School of Health Sciences, University of Tasmania, Newnham, TAS, Australia
- Launceston Respiratory and Sleep Centre, Launceston, TAS, Australia
- Department of Respiratory Medicine, Launceston General Hospital, Launceston, TAS, Australia
| | - Iain Robertson
- Respiratory Translational Research Group, School of Health Sciences, University of Tasmania, Newnham, TAS, Australia
| | - Gurpreet Kaur Singhera
- Department of Anesthesiology, Pharmacology and Therapeutics, Department of Medicine, University of British Columbia, Vancouver, BC, Canada
- UBC Centre for Heart Lung Innovation, St Paul's Hospital, Vancouver, BC, Canada
| | - Tillie L. Hackett
- Department of Anesthesiology, Pharmacology and Therapeutics, Department of Medicine, University of British Columbia, Vancouver, BC, Canada
- UBC Centre for Heart Lung Innovation, St Paul's Hospital, Vancouver, BC, Canada
| | - Sukhwinder Singh Sohal
- Respiratory Translational Research Group, School of Health Sciences, University of Tasmania, Newnham, TAS, Australia
- Launceston Respiratory and Sleep Centre, Launceston, TAS, Australia
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15
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Wang JJ, Zhou Z, Zhang LY. Clinical evaluation of ventilation mode on acute exacerbation of chronic obstructive pulmonary disease with respiratory failure. World J Clin Cases 2023; 11:6040-6050. [PMID: 37731551 PMCID: PMC10507537 DOI: 10.12998/wjcc.v11.i26.6040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Revised: 07/19/2023] [Accepted: 08/18/2023] [Indexed: 09/08/2023] Open
Abstract
BACKGROUND At present, understanding of the most effective ventilation methods for treating chronic obstructive pulmonary disease (COPD) patients experiencing acute worsening symptoms and respiratory failure remains relatively limited. This report analyzed the efficiency and side effects of various ventilation techniques used for individuals experiencing an acute COPD exacerbation. AIM To determine whether pressure-controlled ventilation (PCV) can lower peak airway pressures (PAPs) and reduce the incidence of barotrauma compared to volume-controlled ventilation (VCV), without compromising clinical outcomes and oxygenation parameters. METHODS We have evaluated 600 patients who were hospitalized due to a severe COPD exacerbation, with 400 receiving mechanical ventilation for the respiratory failure. The participants were divided into two different groups, who were administered either VCV or PCV, along with appropriate management. We thereafter observed patients' attributes, clinical factors, and laboratory, radiographic, and arterial blood gas evaluations at the start and during their stay in the intensive care unit (ICU). We have also employed appropriate statistical methods for the data analysis. RESULTS Both the VCV and PCV groups experienced significant enhancements in the respiratory rate, tidal volume, and arterial blood gas values during their time in the ICU. However, no significant distinctions were detected between the groups in terms of oxygenation indices (partial pressures of oxygen/raction of inspired oxygen ratio) and partial pressures of carbon dioxide improvements. There was no considerable disparity observed between the VCV and PCV groups in the hospital mortality (32% vs 28%, P = 0.53), the number of days of ICU stay [median interquartile range (IQR): 9 (6-14) d vs 8 (5-13) d, P = 0.41], or the duration of the mechanical ventilation [median (IQR): 6 (4-10) d vs 5 (3-9) d, P = 0.47]. The PCV group displayed lower PAPs compared to the VCV group (P < 0.05) from the beginning of mechanical ventilation until extubation or ICU departure. The occurrence of barotrauma was considerably lower in the PCV group in comparison to the VCV group (6% vs 16%, P = 0.03). CONCLUSION Both VCV and PCV were found to be effective in treating patients with acute COPD exacerbation. However, PCV was associated with lower PAPs and a significant decrease in barotrauma, thus indicating that it might be a safer ventilation method for this group of patients. However, further large-scale study is necessary to confirm these findings and to identify the best ventilation approach for patients experiencing an acute COPD exacerbation.
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Affiliation(s)
- Jun-Jun Wang
- Department of Respiratory and Critical Care Medicine, The First People's Hospital of Yangquan City, Yangquan 045000, Shanxi Province, China
| | - Zhong Zhou
- Department of Respiratory and Critical Care Medicine, Guiyang Public Health Treatment Center, Guiyang 550001, Guizhou Province, China
| | - Li-Ying Zhang
- Department of Respiratory and Critical Care Medicine, The Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200023, China
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O’Shaughnessy M, Sheils O, Baird AM. The Lung Microbiome in COPD and Lung Cancer: Exploring the Potential of Metal-Based Drugs. Int J Mol Sci 2023; 24:12296. [PMID: 37569672 PMCID: PMC10419288 DOI: 10.3390/ijms241512296] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Revised: 07/28/2023] [Accepted: 07/29/2023] [Indexed: 08/13/2023] Open
Abstract
Chronic obstructive pulmonary disease (COPD) and lung cancer 17 are two of the most prevalent and debilitating respiratory diseases worldwide, both associated with high morbidity and mortality rates. As major global health concerns, they impose a substantial burden on patients, healthcare systems, and society at large. Despite their distinct aetiologies, lung cancer and COPD share common risk factors, clinical features, and pathological pathways, which have spurred increasing research interest in their co-occurrence. One area of particular interest is the role of the lung microbiome in the development and progression of these diseases, including the transition from COPD to lung cancer. Exploring novel therapeutic strategies, such as metal-based drugs, offers a potential avenue for targeting the microbiome in these diseases to improve patient outcomes. This review aims to provide an overview of the current understanding of the lung microbiome, with a particular emphasis on COPD and lung cancer, and to discuss the potential of metal-based drugs as a therapeutic strategy for these conditions, specifically concerning targeting the microbiome.
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Affiliation(s)
- Megan O’Shaughnessy
- School of Medicine, Trinity Translational Medicine Institute, Trinity College Dublin, D08 W9RT Dublin, Ireland
| | - Orla Sheils
- School of Medicine, Trinity Translational Medicine Institute, Trinity College Dublin, D08 W9RT Dublin, Ireland
- Department of Histopathology and Morbid Anatomy, Trinity Translational Medicine Institute, St. James’s Hospital, D08 RX0X Dublin, Ireland
| | - Anne-Marie Baird
- School of Medicine, Trinity Translational Medicine Institute, Trinity College Dublin, D08 W9RT Dublin, Ireland
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17
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Chase CB, Mhaskar R, Fiedler C, West WJ, Varadhan A, Cobb J, Cool S, Fishberger G, Dolorit M, Weeden EE, Strang HE, Nguyen D, Garrett JR, Moodie CC, Fontaine JP, Tew JR, Baldonado JJAR, Toloza EM. Effects of preoperative pulmonary function on perioperative outcomes after robotic-assisted pulmonary lobectomy. Am J Surg 2023; 226:128-132. [PMID: 37121787 DOI: 10.1016/j.amjsurg.2023.02.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2022] [Revised: 02/07/2023] [Accepted: 02/22/2023] [Indexed: 03/06/2023]
Abstract
INTRODUCTION Effects of pulmonary function test (PFT) results on perioperative outcomes were investigated after robotic-assisted video-thoracoscopic (RAVT) pulmonary lobectomy. METHODS We retrospectively analyzed 706 consecutive patients who underwent RAVT lobectomy by one surgeon over 10.8 years. Preoperative (preop) forced expiratory volume in 1 s as a percent of predicted (FEV1%) was used to group patients as having normal FEV1% (≥80%) versus reduced FEV1% (<80%). Demographics, preop comorbidities, intraoperative (intraop) and postoperative (postop) complications, perioperative outcomes, and median survival time (MST) were compared across patients with normal vs. reduced FEV1% using Chi-Square (X2), Fisher's Exact test, Student's t-test, Kruskal-Wallis test, or Kaplan-Meier analysis respectively, with significance at p ≤ 0.05. Multivariable analysis was performed for perioperative outcomes to investigate the differences across patients in the FEV1% groups. RESULTS There were 470 patients with normal FEV1% and 236 patients with reduced FEV1%. The two FEV1% groups did not differ in intraop or postop complication rates, except for higher postop other arrhythmia requiring intervention (p = 0.004), prolonged air leak >5 days (p = 0.002), mucous plug formation (p = 0.009), hypoxia (p < 0.001), and pneumonia (p = 0.002), and total postop complications (p < 0.001) in reduced-FEV1% patients. Reduced FEV1% correlated with increased intraop estimated blood loss (p < 0.0001) and skin-to-skin operative time (p < 0.0001). Median overall survival in patients with normal FEV1% was 93.20 months (95% CI: 76.5-126.0) versus 58.9 months (95% CI: 50.4-68.4) in patients with reduced FEV1% (p = 0.0004). CONCLUSION Patients should have PFTs conducted before surgery to determine at-risk patients. However, RAVT pulmonary lobectomy is feasible and safe even in patients with reduced FEV1%.
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Affiliation(s)
- Collin B Chase
- Department of Medical Education, University of South Florida Health Morsani College of Medicine, Tampa, FL, USA.
| | - Rahul Mhaskar
- Department of Medical Education, University of South Florida Health Morsani College of Medicine, Tampa, FL, USA; Department of Internal Medicine, University of South Florida Health Morsani College of Medicine, Tampa, FL, USA.
| | - Cole Fiedler
- Department of Medical Education, University of South Florida Health Morsani College of Medicine, Tampa, FL, USA.
| | - William J West
- Department of Medical Education, University of South Florida Health Morsani College of Medicine, Tampa, FL, USA.
| | - Ajay Varadhan
- Department of Medical Education, University of South Florida Health Morsani College of Medicine, Tampa, FL, USA.
| | - Jessica Cobb
- Department of Medical Education, University of South Florida Health Morsani College of Medicine, Tampa, FL, USA.
| | - Sarah Cool
- Department of Medical Education, University of South Florida Health Morsani College of Medicine, Tampa, FL, USA.
| | - Gregory Fishberger
- Department of Medical Education, University of South Florida Health Morsani College of Medicine, Tampa, FL, USA.
| | - Maykel Dolorit
- Department of Medical Education, University of South Florida Health Morsani College of Medicine, Tampa, FL, USA.
| | - Emily E Weeden
- Department of Medical Education, University of South Florida Health Morsani College of Medicine, Tampa, FL, USA.
| | - Harrison E Strang
- Department of Medical Education, University of South Florida Health Morsani College of Medicine, Tampa, FL, USA.
| | - Diep Nguyen
- Department of Medical Education, University of South Florida Health Morsani College of Medicine, Tampa, FL, USA.
| | - Joseph R Garrett
- Department of Thoracic Oncology, Moffitt Cancer Center, Tampa, FL, USA.
| | - Carla C Moodie
- Department of Thoracic Oncology, Moffitt Cancer Center, Tampa, FL, USA.
| | - Jacques P Fontaine
- Department of Thoracic Oncology, Moffitt Cancer Center, Tampa, FL, USA; Department of Surgery, University of South Florida Health Morsani College of Medicine, Tampa, FL, USA; Department of Oncologic Sciences, University of South Florida Health Morsani College of Medicine, Tampa, FL, USA.
| | - Jenna R Tew
- Department of Thoracic Oncology, Moffitt Cancer Center, Tampa, FL, USA.
| | - Jobelle J A R Baldonado
- Department of Thoracic Oncology, Moffitt Cancer Center, Tampa, FL, USA; Department of Surgery, University of South Florida Health Morsani College of Medicine, Tampa, FL, USA; Department of Oncologic Sciences, University of South Florida Health Morsani College of Medicine, Tampa, FL, USA.
| | - Eric M Toloza
- Department of Thoracic Oncology, Moffitt Cancer Center, Tampa, FL, USA; Department of Surgery, University of South Florida Health Morsani College of Medicine, Tampa, FL, USA; Department of Oncologic Sciences, University of South Florida Health Morsani College of Medicine, Tampa, FL, USA.
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18
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Berggren-Nylund R, Ryde M, Löfdahl A, Ibáñez-Fonseca A, Kåredal M, Westergren-Thorsson G, Tufvesson E, Larsson-Callerfelt AK. Effects of hypoxia on bronchial and alveolar epithelial cells linked to pathogenesis in chronic lung disorders. Front Physiol 2023; 14:1094245. [PMID: 36994416 PMCID: PMC10040785 DOI: 10.3389/fphys.2023.1094245] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Accepted: 03/02/2023] [Indexed: 03/15/2023] Open
Abstract
Introduction: Chronic lung disorders involve pathological alterations in the lung tissue with hypoxia as a consequence. Hypoxia may influence the release of inflammatory mediators and growth factors including vascular endothelial growth factor (VEGF) and prostaglandin (PG)E2. The aim of this work was to investigate how hypoxia affects human lung epithelial cells in combination with profibrotic stimuli and its correlation to pathogenesis.Methods: Human bronchial (BEAS-2B) and alveolar (hAELVi) epithelial cells were exposed to either hypoxia (1% O2) or normoxia (21% O2) during 24 h, with or without transforming growth factor (TGF)-β1. mRNA expression of genes and proteins related to disease pathology were analysed with qPCR, ELISA or immunocytochemistry. Alterations in cell viability and metabolic activity were determined.Results: In BEAS-2B and hAELVi, hypoxia significantly dowregulated genes related to fibrosis, mitochondrial stress, oxidative stress, apoptosis and inflammation whereas VEGF receptor 2 increased. Hypoxia increased the expression of Tenascin-C, whereas both hypoxia and TGF-β1 stimuli increased the release of VEGF, IL-6, IL-8 and MCP-1 in BEAS-2B. In hAELVi, hypoxia reduced the release of fibroblast growth factor, epidermal growth factor, PGE2, IL-6 and IL-8, whereas TGF-β1 stimulus significantly increased the release of PGE2 and IL-6. TGF-β1 stimulated BEAS-2B cells showed a decreased release of VEGF-A and IL-8, while TGF-β1 stimulated hAELVi cells showed a decreased release of PGE2 and IL-8 during hypoxia compared to normoxia. Metabolic activity was significantly increased by hypoxia in both epithelial cell types.Discussion: In conclusion, our data indicate that bronchial and alveolar epithelial cells respond differently to hypoxia and profibrotic stimuli. The bronchial epithelium appears more responsive to changes in oxygen levels and remodelling processes compared to the alveoli, suggesting that hypoxia may be a driver of pathogenesis in chronic lung disorders.
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Affiliation(s)
| | - Martin Ryde
- Respiratory Medicine, Allergology and Palliative Medicine, Department of Clinical Sciences Lund, Lund University, Lund, Sweden
| | - Anna Löfdahl
- Lung Biology, Department of Experimental Medical Science, Lund University, Lund, Sweden
| | - Arturo Ibáñez-Fonseca
- Lung Biology, Department of Experimental Medical Science, Lund University, Lund, Sweden
| | - Monica Kåredal
- Division of Occupational and Environmental Medicine, Lund University, Lund, Sweden
| | | | - Ellen Tufvesson
- Respiratory Medicine, Allergology and Palliative Medicine, Department of Clinical Sciences Lund, Lund University, Lund, Sweden
| | - Anna-Karin Larsson-Callerfelt
- Lung Biology, Department of Experimental Medical Science, Lund University, Lund, Sweden
- *Correspondence: Anna-Karin Larsson-Callerfelt,
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19
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Sharma A, Sharma L, Nandy SK, Payal N, Yadav S, Vargas-De-La-Cruz C, Anwer MK, Khan H, Behl T, Bungau SG. Molecular Aspects and Therapeutic Implications of Herbal Compounds Targeting Different Types of Cancer. Molecules 2023; 28:750. [PMID: 36677808 PMCID: PMC9867434 DOI: 10.3390/molecules28020750] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Revised: 01/05/2023] [Accepted: 01/08/2023] [Indexed: 01/15/2023] Open
Abstract
Due to genetic changes in DNA (deoxyribonucleic acid) sequences, cancer continues to be the second most prevalent cause of death. The traditional target-directed approach, which is confronted with the importance of target function in healthy cells, is one of the most significant challenges in anticancer research. Another problem with cancer cells is that they experience various mutations, changes in gene duplication, and chromosomal abnormalities, all of which have a direct influence on the potency of anticancer drugs at different developmental stages. All of these factors combine to make cancer medication development difficult, with low clinical licensure success rates when compared to other therapy categories. The current review focuses on the pathophysiology and molecular aspects of common cancer types. Currently, the available chemotherapeutic drugs, also known as combination chemotherapy, are associated with numerous adverse effects, resulting in the search for herbal-based alternatives that attenuate resistance due to cancer therapy and exert chemo-protective actions. To provide new insights, this review updated the list of key compounds that may enhance the efficacy of cancer treatment.
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Affiliation(s)
- Aditi Sharma
- Department of Pharmacology, School of Pharmaceutical Sciences, Shoolini University, Solan 173229, Himachal Pradesh, India
| | - Lalit Sharma
- Department of Pharmacology, School of Pharmaceutical Sciences, Shoolini University, Solan 173229, Himachal Pradesh, India
| | - Shouvik Kumar Nandy
- Department of Pharmacology, School of Pharmaceutical Sciences, Shoolini University, Solan 173229, Himachal Pradesh, India
| | - Nazrana Payal
- School of Biotechnology, Shoolini University of Biotechnology and Management Sciences, Solan 173229, Himachal Pradesh, India
| | - Shivam Yadav
- Department of Pharmaceutical Sciences, School of Pharmaceutical Sciences, Chhatrapati Shahu ji Maharaj University, Kanpur 208024, Uttar Pradesh, India
| | - Celia Vargas-De-La-Cruz
- Department of Pharmacology, Faculty of Pharmacy and Biochemistry, Bromatology and Toxicology, Universidad Nacional Mayor de San Marcos, Lima 150001, Peru
- E-Health Research Center, Universidad de Ciencias y Humanidades, Lima 15001, Peru
| | - Md. Khalid Anwer
- Department of Pharmaceutics, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia
| | - Haroon Khan
- Department of Pharmacy, Abdul Wali Khan University, Mardan 23200, Pakistan
| | - Tapan Behl
- School of Health Science and Technology, University of Petroleum and Energy Studies, Dehradun 248007, Uttarakhand, India
| | - Simona Gabriela Bungau
- Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, 410028 Oradea, Romania
- Doctoral School of Biomedical Sciences, University of Oradea, 410028 Oradea, Romania
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20
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Liu Y, Han J, Kong T, Xiao N, Mei Q, Liu J. DriverMP enables improved identification of cancer driver genes. Gigascience 2022; 12:giad106. [PMID: 38091511 PMCID: PMC10716827 DOI: 10.1093/gigascience/giad106] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Revised: 10/30/2023] [Accepted: 11/22/2023] [Indexed: 12/18/2023] Open
Abstract
BACKGROUND Cancer is widely regarded as a complex disease primarily driven by genetic mutations. A critical concern and significant obstacle lies in discerning driver genes amid an extensive array of passenger genes. FINDINGS We present a new method termed DriverMP for effectively prioritizing altered genes on a cancer-type level by considering mutated gene pairs. It is designed to first apply nonsilent somatic mutation data, protein‒protein interaction network data, and differential gene expression data to prioritize mutated gene pairs, and then individual mutated genes are prioritized based on prioritized mutated gene pairs. Application of this method in 10 cancer datasets from The Cancer Genome Atlas demonstrated its great improvements over all the compared state-of-the-art methods in identifying known driver genes. Then, a comprehensive analysis demonstrated the reliability of the novel driver genes that are strongly supported by clinical experiments, disease enrichment, or biological pathway analysis. CONCLUSIONS The new method, DriverMP, which is able to identify driver genes by effectively integrating the advantages of multiple kinds of cancer data, is available at https://github.com/LiuYangyangSDU/DriverMP. In addition, we have developed a novel driver gene database for 10 cancer types and an online service that can be freely accessed without registration for users. The DriverMP method, the database of novel drivers, and the user-friendly online server are expected to contribute to new diagnostic and therapeutic opportunities for cancers.
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Affiliation(s)
- Yangyang Liu
- School of Mathematics and Statistics, Shandong University (Weihai), Weihai 264209, China
| | - Jiyun Han
- School of Mathematics and Statistics, Shandong University (Weihai), Weihai 264209, China
| | - Tongxin Kong
- School of Mathematics and Statistics, Shandong University (Weihai), Weihai 264209, China
| | - Nannan Xiao
- School of Mathematics and Statistics, Shandong University (Weihai), Weihai 264209, China
| | - Qinglin Mei
- MOE Key Laboratory of Bioinformatics, BNRIST Bioinformatics Division, Department of Automation, Tsinghua University, Beijing 100084, China
| | - Juntao Liu
- School of Mathematics and Statistics, Shandong University (Weihai), Weihai 264209, China
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21
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dos Santos CF, Braz MG, de Arruda NM, Caram L, Nogueira DL, Tanni SE, de Godoy I, Ferrari R. DNA damage and antioxidant capacity in COPD patients with and without lung cancer. PLoS One 2022; 17:e0275873. [PMID: 36327269 PMCID: PMC9632772 DOI: 10.1371/journal.pone.0275873] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2022] [Accepted: 09/23/2022] [Indexed: 11/06/2022] Open
Abstract
Background and objective Chronic obstructive pulmonary disease (COPD) is characterized by chronic inflammation of the lower airways, and COPD patients show two to five times higher risk of lung cancer than smokers with normal lung function. COPD is associated with increased oxidative stress, which may cause DNA damage and lung carcinogenesis. Our aim was to evaluate DNA damage and oxidative stress (lipid peroxidation and antioxidant status) and their relationship in patients with COPD with and without lung cancer. Methods We evaluated 18 patients with COPD, 18 with COPD with lung cancer, and 18 controls (former or current smokers). DNA damage was evaluated in peripheral blood lymphocytes using a comet assay; the concentration of malondialdehyde (MDA) and hydrophilic antioxidant performance (HAP) were measured in the plasma. Results DNA damage was higher in patients with COPD with cancer than in the controls (p = 0.003). HAP was significantly lower in patients with COPD with cancer than in those without cancer and controls. The presence of lung cancer and COPD showed a positive association with DNA strand breaks and the concentration of MDA. Conclusion COPD with lung cancer was associated with elevated DNA damage in peripheral lymphocytes, and cancer and COPD showed a positive correlation with DNA damage. The antioxidant capacity showed a negative association with the interaction COPD and cancer and presence of COPD. The mechanisms underlying the increased incidence of lung cancer in COPD are unknown; DNA damage may be involved. Further research may provide insights into their development and treatment.
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Affiliation(s)
| | - Mariana Gobbo Braz
- Botucatu Medical School, GENOTOX Laboratory, São Paulo State University—UNESP, São Paulo, Brazil
| | | | - Laura Caram
- Department of Internal Medicine, Botucatu Medical School, São Paulo State University—UNESP, São Paulo, Brazil
| | - Duelene Ludimila Nogueira
- Department of Internal Medicine, Botucatu Medical School, São Paulo State University—UNESP, São Paulo, Brazil
| | - Suzana Erico Tanni
- Department of Internal Medicine, Botucatu Medical School, São Paulo State University—UNESP, São Paulo, Brazil
| | - Irma de Godoy
- Department of Internal Medicine, Botucatu Medical School, São Paulo State University—UNESP, São Paulo, Brazil
| | - Renata Ferrari
- Department of Internal Medicine, Botucatu Medical School, São Paulo State University—UNESP, São Paulo, Brazil
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22
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Xu YR, Wang AL, Li YQ. Hypoxia-inducible factor 1-alpha is a driving mechanism linking chronic obstructive pulmonary disease to lung cancer. Front Oncol 2022; 12:984525. [PMID: 36338690 PMCID: PMC9634253 DOI: 10.3389/fonc.2022.984525] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2022] [Accepted: 10/10/2022] [Indexed: 11/27/2022] Open
Abstract
Patients with chronic obstructive pulmonary disease (COPD), irrespective of their smoking history, are more likely to develop lung cancer than the general population. This is mainly because COPD is characterized by chronic persistent inflammation and hypoxia, which are the risk factors for lung cancer. However, the mechanisms underlying this observation are still unknown. Hypoxia-inducible factor 1-alpha (HIF-1α) plays an important role in the crosstalk that exists between inflammation and hypoxia. Furthermore, HIF-1α is the main regulator of somatic adaptation to hypoxia and is highly expressed in hypoxic environments. In this review, we discuss the molecular aspects of the crosstalk between hypoxia and inflammation, showing that HIF-1α is an important signaling pathway that drives COPD progression to lung cancer. Here, we also provide an overview of HIF-1α and its principal regulatory mechanisms, briefly describe HIF-1α-targeted therapy in lung cancer, and summarize substances that may be used to target HIF-1α at the level of COPD-induced inflammation.
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Affiliation(s)
- Yuan-rui Xu
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
- Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, Zhejiang, China
| | - An-long Wang
- Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, Zhejiang, China
| | - Ya-qing Li
- Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, Zhejiang, China
- *Correspondence: Ya-qing Li,
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23
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Qi C, Sun SW, Xiong XZ. From COPD to Lung Cancer: Mechanisms Linking, Diagnosis, Treatment, and Prognosis. Int J Chron Obstruct Pulmon Dis 2022; 17:2603-2621. [PMID: 36274992 PMCID: PMC9586171 DOI: 10.2147/copd.s380732] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Accepted: 09/30/2022] [Indexed: 11/23/2022] Open
Abstract
Many studies have proved that the pathogenesis of the chronic obstructive pulmonary disease (COPD) and lung cancer is related, and may cause and affect each other to a certain extent. In fact, the change of chronic airway obstruction will continue to have an impact on the screening, treatment, and prognosis of lung cancer.In this comprehensive review, we outlined the links and heterogeneity between COPD and lung cancer and finds that factors such as gene expression and genetic susceptibility, epigenetics, smoking, epithelial mesenchymal transformation (EMT), chronic inflammation, and oxidative stress injury may all play a role in the process. Although the relationship between these two diseases have been largely determined, the methods to prevent lung cancer in COPD patients are still limited. Early diagnosis is still the key to a better prognosis. Thus, it is necessary to establish more intuitive screening evaluation criteria and find suitable biomarkers for lung cancer screening in high-risk populations with COPD. Some studies have indicated that COPD may change the efficacy of anti-tumor therapy by affecting the response of lung cancer patients to immune checkpoint inhibitors (ICIs). And for lung cancer patients with COPD, the standardized management of COPD can improve the prognosis. The treatment of lung cancer patients with COPD is an individualized, comprehensive, and precise process. The development of new targets and new strategies of molecular targeted therapy may be the breakthrough for disease treatment in the future.
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Affiliation(s)
- Chang Qi
- Department of Respiratory and Critical Care Medicine, NHC Key Laboratory of Pulmonary Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People’s Republic of China
| | - Sheng-Wen Sun
- Department of Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People’s Republic of China
| | - Xian-Zhi Xiong
- Department of Respiratory and Critical Care Medicine, NHC Key Laboratory of Pulmonary Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People’s Republic of China,Correspondence: Xian-Zhi Xiong, Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, People’s Republic of China, Tel/Fax +86 27-85726705, Email
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24
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Yuan L, Guo T, Hu C, Yang W, Tang X, Cheng H, Xiang Y, Qu X, Liu H, Qin X, Qin L, Liu C. Clinical characteristics and gene mutation profiles of chronic obstructive pulmonary disease in non-small cell lung cancer. Front Oncol 2022; 12:946881. [PMID: 36267961 PMCID: PMC9576924 DOI: 10.3389/fonc.2022.946881] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Accepted: 06/27/2022] [Indexed: 12/03/2022] Open
Abstract
Purpose The coexistence of chronic obstructive pulmonary disease (COPD) often leads to a worse prognosis in patients with non-small cell lung cancer (NSCLC). Meanwhile, approaches targeting specific genetic alterations have been shown to significantly improve the diagnosis and treatment outcomes of patients with NSCLC. Herein, we sought to evaluate the impact of COPD on the clinical manifestations and gene mutation profiles of NSCLC patients with both circulating tumor (ctDNA) and tumor DNA (tDNA). Materials and methods The influence of COPD on clinical features was observed in 285 NSCLC cohorts suffering from NSCLC alone, NSCLC coexisting with COPD, or NSCLC coexisting with prodromal changes in COPD (with emphysema, bullae, or chronic bronchitis). The gene mutation profiles of specific 168 NSCLC-related genes were further analyzed in the NSCLC sub-cohorts with formalin-fixed and paraffin-embedded tumor DNA (FFPE tDNA) samples and plasma circulating tumor DNA (PLA ctDNA) samples. Moreover, mutation concordance was assessed in tDNA and paired ctDNA of 110 NSCLC patients. Results Relative to patients with NSCLC alone, patients with NSCLC coexisting with COPD and prodromal changes presented with worse lung functions, more clinical symptoms, signs and comorbidities, and inconsistent gene mutation profiles. In addition, patients in the latter two groups exhibited a higher average frequency of gene mutation. Lastly, mutation concordance between tDNA and ctDNA samples was significantly reduced in NSCLC patients coexisting with COPD. Conclusions Collectively, our findings revealed that coexistence of COPD leads to worse clinical manifestations and altered gene mutation profiles in patients with NSCLC. Additionally, for NSCLC patients with COPD, the use of ctDNA instead of tDNA may not be the most efficient approach to identifying gene mutations.
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Affiliation(s)
- Lin Yuan
- Department of Respiratory Medicine, National Key Clinical Specialty, Branch of National Clinical Research Center for Respiratory Disease, Xiangya Hospital, Central South University, Changsha, China
- Department of Physiology, School of Basic Medicine Science, Central South University, Changsha, China
- Basic and Clinical Research Laboratory of Major Respiratory Diseases, Central South University, Changsha, China
| | - Ting Guo
- Department of Respiratory Medicine, The First Hospital of Changsha, Changsha, China
| | - Chengping Hu
- Department of Respiratory Medicine, National Key Clinical Specialty, Branch of National Clinical Research Center for Respiratory Disease, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, China
| | - Wei Yang
- Department of Respiratory Medicine, National Key Clinical Specialty, Branch of National Clinical Research Center for Respiratory Disease, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, China
| | - Xiaoli Tang
- Pulmonary and Critical Care Medicine, Huaihua Tumor Hospital, Huaihua, China
| | - Hao Cheng
- Department of Radiotherapy, The Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, China
- Department of Nasopharyngeal Carcinoma, The First People’s Hospital of Chenzhou, Chenzhou, China
| | - Yang Xiang
- Department of Physiology, School of Basic Medicine Science, Central South University, Changsha, China
| | - Xiangping Qu
- Department of Physiology, School of Basic Medicine Science, Central South University, Changsha, China
| | - Huijun Liu
- Department of Physiology, School of Basic Medicine Science, Central South University, Changsha, China
| | - Xiaoqun Qin
- Department of Physiology, School of Basic Medicine Science, Central South University, Changsha, China
| | - Ling Qin
- Department of Respiratory Medicine, National Key Clinical Specialty, Branch of National Clinical Research Center for Respiratory Disease, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, China
- *Correspondence: Ling Qin, ; Chi Liu,
| | - Chi Liu
- Department of Respiratory Medicine, National Key Clinical Specialty, Branch of National Clinical Research Center for Respiratory Disease, Xiangya Hospital, Central South University, Changsha, China
- Department of Physiology, School of Basic Medicine Science, Central South University, Changsha, China
- Basic and Clinical Research Laboratory of Major Respiratory Diseases, Central South University, Changsha, China
- *Correspondence: Ling Qin, ; Chi Liu,
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25
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Ma A, Wang G, Du Y, Guo W, Guo J, Hu Y, Bai D, Huang H, Zhuang L, Chen J, Liu Q. The clinical relevance of neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio in chronic obstructive pulmonary disease with lung cancer. Front Oncol 2022; 12:902955. [PMID: 36237340 PMCID: PMC9552820 DOI: 10.3389/fonc.2022.902955] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Accepted: 08/31/2022] [Indexed: 11/13/2022] Open
Abstract
BackgroundChronic obstructive pulmonary disease (COPD) coexisting with lung cancer is associated with severe mortality and a worse prognosis. Inflammation plays an important role in common pathogenic pathways and disease progression. However, a few studies have identified the clinical value of the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) in COPD with lung cancer, which are systemic inflammatory response markers in the blood. This study aimed to determine the association of the NLR or PLR with clinical characteristics and whether NLR or PLR can be diagnostic markers for COPD with lung cancer.MethodsBetween 2015 and 2021, we conducted a retrospective analysis of 236 COPD patients with lung cancer and 500 patients without lung cancer (control group). Clinical information, blood routine examination, and spirometry results were collected and analyzed. The receiver operating characteristic (ROC) curve was used to identify the best cutoff point of NLR or PLR. Multivariate logistic regression analysis was performed to evaluate the association of NLR or PLR with the diagnosis and prognosis of COPD with lung cancer.ResultsCompared to patients in the COPD-only group, patients in the lung cancer group had a higher percentage of current smoking and emphysema, and it was found that NLR or PLR was significantly higher in the lung cancer group. Multivariate analysis showed that age, smoking status, FEV1%pred, emphysema, NLR, and PLR were independent risk factors for lung cancer development in COPD. Furthermore, the high level of NLR or PLR was associated with age over 70 years old, current smoking status, and ineligible surgery treatment. The level of PLR or NLR markedly increased with hypercoagulation status, the severity of airflow limitation, and advanced progression of lung cancer. Additionally, the ROC analysis also revealed that elevated NLR or PLR was an independent predictor of COPD in lung cancer patients, TNM stages IIIB–IV at first diagnosis in lung cancer, and ineligible surgery in lung cancer patients.ConclusionIncreased NLR or PLR values might be an important and easily measurable inflammation biomarker to predict the diagnosis and severity of lung cancer with COPD.
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Affiliation(s)
- Aiping Ma
- Department of Respiratory and Critical Medicine, The First Affiliated Hospital, School of Medicine, Xiamen University, Xiamen, China
| | - Guangdong Wang
- Department of Respiratory and Critical Medicine, The First Affiliated Hospital, School of Medicine, Xiamen University, Xiamen, China
| | - Yan Du
- Department of Respiratory and Critical Medicine, The First Affiliated Hospital, School of Medicine, Xiamen University, Xiamen, China
| | - Weixi Guo
- Department of Thoracic Surgery, The First Affiliated Hospital, School of Medicine, Xiamen University, Xiamen, China
| | - Jiaxi Guo
- Department of Respiratory and Critical Medicine, The First Affiliated Hospital, School of Medicine, Xiamen University, Xiamen, China
| | - Yi Hu
- Department of Clinical Laboratory, The First Affiliated Hospital, School of Medicine, Xiamen University, Xiamen, China
| | - Dongyu Bai
- Department of Pathology, The First Affiliated Hospital, School of Medicine, Xiamen University, Xiamen, China
| | - Huiping Huang
- Department of Infection Control, The First Affiliated Hospital, School of Medicine, Xiamen University, Xiamen, China
| | - Lianjin Zhuang
- Division of Quality Management, The First Affiliated Hospital, School of Medicine, Xiamen University, Xiamen, China
| | - Jinhan Chen
- Department of Geriatrics, The First Affiliated Hospital, School of Medicine, Xiamen University, Xiamen, China
- *Correspondence: Qun Liu, ; Jinhan Chen,
| | - Qun Liu
- Department of Respiratory and Critical Medicine, The First Affiliated Hospital, School of Medicine, Xiamen University, Xiamen, China
- *Correspondence: Qun Liu, ; Jinhan Chen,
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Su X, Wu W, Zhu Z, Lin X, Zeng Y. The effects of epithelial-mesenchymal transitions in COPD induced by cigarette smoke: an update. Respir Res 2022; 23:225. [PMID: 36045410 PMCID: PMC9429334 DOI: 10.1186/s12931-022-02153-z] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Accepted: 08/25/2022] [Indexed: 12/15/2022] Open
Abstract
Cigarette smoke is a complex aerosol containing a large number of compounds with a variety of toxicity and carcinogenicity. Long-term exposure to cigarette smoke significantly increases the risk of a variety of diseases, including chronic obstructive pulmonary disease (COPD) and lung cancer. Epithelial–mesenchymal transition (EMT) is a unique biological process, that refers to epithelial cells losing their polarity and transforming into mobile mesenchymal cells, playing a crucial role in organ development, fibrosis, and cancer progression. Numerous recent studies have shown that EMT is an important pathophysiological process involved in airway fibrosis, airway remodeling, and malignant transformation of COPD. In this review, we summarized the effects of cigarette smoke on the development and progression of COPD and focus on the specific changes and underlying mechanisms of EMT in COPD induced by cigarette smoke. We spotlighted the signaling pathways involved in EMT induced by cigarette smoke and summarize the current research and treatment approaches for EMT in COPD, aiming to provide ideas for potential new treatment and research directions.
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Affiliation(s)
- Xiaoshan Su
- Department of Pulmonary and Critical Care Medicine, The Second Affiliated Hospital of Fujian Medical University, Respirology Medicine Centre of Fujian Province, Quanzhou, China
| | - Weijing Wu
- Department of Pulmonary and Critical Care Medicine, The Second Affiliated Hospital of Fujian Medical University, Respirology Medicine Centre of Fujian Province, Quanzhou, China
| | - Zhixing Zhu
- Department of Pulmonary and Critical Care Medicine, The Second Affiliated Hospital of Fujian Medical University, Respirology Medicine Centre of Fujian Province, Quanzhou, China
| | - Xiaoping Lin
- Department of Pulmonary and Critical Care Medicine, The Second Affiliated Hospital of Fujian Medical University, Respirology Medicine Centre of Fujian Province, Quanzhou, China
| | - Yiming Zeng
- Department of Pulmonary and Critical Care Medicine, The Second Affiliated Hospital of Fujian Medical University, Respirology Medicine Centre of Fujian Province, Quanzhou, China.
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27
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Identification and Validation of Prognostic Markers for Lung Squamous Cell Carcinoma Associated with Chronic Obstructive Pulmonary Disease. JOURNAL OF ONCOLOGY 2022; 2022:4254195. [PMID: 36035311 PMCID: PMC9402374 DOI: 10.1155/2022/4254195] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Revised: 06/28/2022] [Accepted: 07/03/2022] [Indexed: 12/04/2022]
Abstract
Background Globally, the incidence and associated mortality of chronic obstructive pulmonary disease (COPD) and lung carcinoma are showing a worsening trend. There is increasing evidence that COPD is an independent risk factor for the occurrence and progression of lung carcinoma. This study aimed to identify and validate the gene signatures associated with COPD, which may serve as potential new biomarkers for the prediction of prognosis in patients with lung carcinoma. Methods A total of 111 COPD patient samples and 40 control samples were obtained from the GSE76925 cohort, and a total of 4933 genes were included in the study. The weighted gene coexpression network analysis (WGCNA) was performed to identify the modular genes that were significantly associated with COPD. The KEGG pathway and GO functional enrichment analyses were also performed. The RNAseq and clinicopathological data of 490 lung squamous cell carcinoma patients were obtained from the TCGA database. Further, univariate Cox regression and Lasso analyses were performed to screen for marker genes and construct a survival analysis model. Finally, the Human Protein Atlas (HPA) database was used to assess the gene expression in normal and tumor tissues of the lungs. Results A 6-gene signature (DVL1, MRPL4, NRTN, NSUN3, RPH3A, and SNX32) was identified based on the Cox proportional risk analysis to construct the prognostic RiskScore survival model associated with COPD. Kaplan–Meier survival analysis indicated that the model could significantly differentiate between the prognoses of patients with lung carcinoma, wherein higher RiskScore samples were associated with a worse prognosis. Additionally, the model had a good predictive performance and reliability, as indicated by a high AUC, and these were validated in both internal and external sets. The 6-gene signature had a good predictive ability across clinical signs and could be considered an independent factor of prognostic risk. Finally, the protein expressions of the six genes were analyzed based on the HPA database. The expressions of DVL1, MRPL4, and NSUN3 were relatively higher, while that of RPH3A was relatively lower in the tumor tissues. The expression of SNX32 was high in both the tumor and paracarcinoma tissues. Results of the analyses using TCGA and GSE31446 databases were consistent with the expressions reported in the HPA database. Conclusion Novel COPD-associated gene markers for lung carcinoma were identified and validated in this study. The genes may be considered potential biomarkers to evaluate the prognostic risk of patients with lung carcinoma. Furthermore, some of these genes may have implications as new therapeutic targets and can be used to guide clinical applications.
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Sohal SS. Therapeutic Modalities for Asthma, COPD, and Pathogenesis of COVID-19: Insights from the Special Issue. J Clin Med 2022; 11:jcm11154525. [PMID: 35956140 PMCID: PMC9369734 DOI: 10.3390/jcm11154525] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Accepted: 08/02/2022] [Indexed: 12/10/2022] Open
Affiliation(s)
- Sukhwinder Singh Sohal
- Respiratory Translational Research Group, Department of Laboratory Medicine, School of Health Sciences, College of Health and Medicine, University of Tasmania, Launceston, TAS 7248, Australia
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Sharma P, Dhanjal DS, Chopra C, Tambuwala MM, Sohal SS, van der Spek PJ, Sharma HS, Satija S. Targeting eosinophils in chronic respiratory diseases using nanotechnology-based drug delivery. Chem Biol Interact 2022; 365:110050. [DOI: 10.1016/j.cbi.2022.110050] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Revised: 07/09/2022] [Accepted: 07/13/2022] [Indexed: 11/03/2022]
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Jeganathan V, Knight S, Bricknell M, Ridgers A, Wong R, Brazzale DJ, Ruehland WR, Rahman MA, Leong TL, McDonald CF. Impact of smoking status and chronic obstructive pulmonary disease on pulmonary complications post lung cancer surgery. PLoS One 2022; 17:e0266052. [PMID: 35349598 PMCID: PMC8963579 DOI: 10.1371/journal.pone.0266052] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Accepted: 03/11/2022] [Indexed: 11/19/2022] Open
Abstract
Introduction Smoking and chronic obstructive pulmonary disease (COPD) are associated with an increased risk of post-operative pulmonary complications (PPCs) following lung cancer resection. It remains unclear whether smoking cessation reduces this risk. Methods Retrospective review of a large, prospectively collected database of over 1000 consecutive resections for lung cancer in a quaternary lung cancer centre over a 23-year period. Results One thousand and thirteen patients underwent curative-intent lobectomy or pneumonectomy between 1995 and 2018. Three hundred and sixty-two patients (36%) were ex-smokers, 314 (31%) were current smokers and 111 (11%) were never smokers. A pre-operative diagnosis of COPD was present in 57% of current smokers, 57% of ex-smokers and 20% of never smokers. Just over 25% of patients experienced a PPC. PPCs were more frequent in current smokers compared to never smokers (27% vs 17%, p = 0.036), however, no difference was seen between current and ex-smokers (p = 0.412) or between never and ex-smokers (p = 0.113). Those with a diagnosis of COPD, independent of smoking status, had a higher frequency of both PPCs (65% vs 35%, p<0.01) and overall complications (60% vs 40%, p<0.01) as well as a longer length of hospital stay (10 vs 9 days, p<0.01). Conclusion Smoking and COPD are both associated with a higher rate of PPCs post lung cancer resection. COPD, independent of smoking status, is also associated with an increased overall post-operative complication rate and length of hospital stay. An emphasis on COPD treatment optimisation, rather than smoking cessation in isolation, may help improve post-operative outcomes.
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Affiliation(s)
- Vishnu Jeganathan
- Department of Respiratory and Sleep Medicine, Austin Health, Heidelberg, Victoria, Australia
- Institute for Breathing and Sleep, Heidelberg, Victoria, Australia
- * E-mail:
| | - Simon Knight
- Department of Thoracic Surgery, Austin Health, Heidelberg, Victoria, Australia
| | - Matthew Bricknell
- Institute for Breathing and Sleep, Heidelberg, Victoria, Australia
- Faculty of Medicine, University of Melbourne, Parkville, Victoria, Australia
| | - Anna Ridgers
- Department of Respiratory and Sleep Medicine, Austin Health, Heidelberg, Victoria, Australia
- Institute for Breathing and Sleep, Heidelberg, Victoria, Australia
- Faculty of Medicine, University of Melbourne, Parkville, Victoria, Australia
| | - Raymond Wong
- Department of Respiratory and Sleep Medicine, Austin Health, Heidelberg, Victoria, Australia
- Institute for Breathing and Sleep, Heidelberg, Victoria, Australia
| | - Danny J. Brazzale
- Department of Respiratory and Sleep Medicine, Austin Health, Heidelberg, Victoria, Australia
- Institute for Breathing and Sleep, Heidelberg, Victoria, Australia
| | - Warren R. Ruehland
- Department of Respiratory and Sleep Medicine, Austin Health, Heidelberg, Victoria, Australia
- Institute for Breathing and Sleep, Heidelberg, Victoria, Australia
| | - Muhammad Aziz Rahman
- Institute for Breathing and Sleep, Heidelberg, Victoria, Australia
- School of Health, Federation University Australia, Berwick, Victoria, Australia
| | - Tracy L. Leong
- Department of Respiratory and Sleep Medicine, Austin Health, Heidelberg, Victoria, Australia
- Institute for Breathing and Sleep, Heidelberg, Victoria, Australia
- Faculty of Medicine, University of Melbourne, Parkville, Victoria, Australia
| | - Christine F. McDonald
- Department of Respiratory and Sleep Medicine, Austin Health, Heidelberg, Victoria, Australia
- Institute for Breathing and Sleep, Heidelberg, Victoria, Australia
- Faculty of Medicine, University of Melbourne, Parkville, Victoria, Australia
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Feng Z, Yin Y, Liu B, Wang L, Chen M, Zhu Y, Zhang H, Sun D, Qin J. ZNF143 Expression is Associated with COPD and Tumor Microenvironment in Non-Small Cell Lung Cancer. Int J Chron Obstruct Pulmon Dis 2022; 17:685-700. [PMID: 35400998 PMCID: PMC8986213 DOI: 10.2147/copd.s352392] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Accepted: 03/24/2022] [Indexed: 11/23/2022] Open
Abstract
Background Chronic obstructive pulmonary disease (COPD) is an inflammatory-related disease highly associated with increased lung cancer risk. Studies have explored the tumor promoting roles for zinc finger protein 143 (ZNF143). However, the role of ZNF143 in COPD and tumor microenvironment of non-small cell lung cancer (NSCLC) has not been fully elucidated. Methods COPD-related key genes were identified by differential gene expression evaluation, WGCNA and SVM-RFE analysis using mRNA expression data retrieved from public databases. ROC analysis was conducted to evaluate the diagnostic value of ZNF143. Correlation between ZNF143 and clinic-pathological features, associations with tumor-infiltrating immune cells (TICs) and the relationship with predictors of immunotherapy efficacy were explored. ZNF143 gene expression was validated by qRT-PCR using an independent cohort. Results Bioinformatic and machine learning analysis showed that ZNF143 was a COPD-related gene. ZNF143 expression was significantly upregulated in COPD and is a potential diagnostic biomarker in COPD with AUC > 0.85. ZNF143 expression was significantly upregulated in lung squamous cell carcinoma (LUSC) and lung adenocarcinoma (LUAD). ZNF143 expression levels were significantly higher in LUAD patients with COPD relative to the levels in patients only with LUAD. Upregulation of ZNF143 in patients with comorbidity of NSCLC and COPD was further confirmed by qRT-PCR analysis. High expression of ZNF143 was significantly correlated with advanced TNM stage in LUSC. High ZNF143 expression was associated with activated TICs in both LUAD and LUSC samples. Moreover, ZNF143 expression was significantly correlated with the levels of several known predictors of immunotherapy efficacy, including PD-L1, PD-L2, TMB and TIDE in NSCLC. Conclusion ZNF143 is a novel COPD biomarker. High expression level of ZNF143 is associated with immune microenvironment and high risk of progression of COPD to NSCLC.
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Affiliation(s)
- Zhenxing Feng
- Department of Radiology, Tianjin Chest Hospital, Tianjin, 300222, People’s Republic of China
| | - Yan Yin
- Respiratory and Critical Care Medicine, Tianjin Chest Hospital, Tianjin, 300222, People’s Republic of China
| | - Bin Liu
- Respiratory and Critical Care Medicine, Tianjin Chest Hospital, Tianjin, 300222, People’s Republic of China
| | - Lei Wang
- Respiratory and Critical Care Medicine, Tianjin Chest Hospital, Tianjin, 300222, People’s Republic of China
| | - Miaomiao Chen
- Respiratory and Critical Care Medicine, Tianjin Chest Hospital, Tianjin, 300222, People’s Republic of China
| | - Yue Zhu
- Respiratory and Critical Care Medicine, Tianjin Chest Hospital, Tianjin, 300222, People’s Republic of China
| | - Hong Zhang
- Department of Radiology, Tianjin Chest Hospital, Tianjin, 300222, People’s Republic of China
| | - Daqiang Sun
- Department of Thoracic Surgery, Tianjin Chest Hospital, Tianjin, 300222, People’s Republic of China
- Daqiang Sun, Department of Thoracic Surgery, Tianjin Chest Hospital, Tianjin, 300222, People’s Republic of China, Email
| | - Jianwen Qin
- Respiratory and Critical Care Medicine, Tianjin Chest Hospital, Tianjin, 300222, People’s Republic of China
- Correspondence: Jianwen Qin, Respiratory and Critical Care Medicine, Tianjin Chest Hospital, Tianjin, 300222, People’s Republic of China, Email
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Zeng W, Zhao C, Yu M, Chen H, Pan Y, Wang Y, Bao H, Ma H, Ma S. Alterations of lung microbiota in patients with non-small cell lung cancer. Bioengineered 2022; 13:6665-6677. [PMID: 35254206 PMCID: PMC8973753 DOI: 10.1080/21655979.2022.2045843] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
The role of lung microbiota in non-small cell lung cancer remains unclear. We investigated the characteristics and functional roles of lung microbiota in non-small cell lung cancer. Bronchoalveolar lavage fluid samples were obtained from patients with non-small cell lung cancer (n = 46) and with benign lung disease (n = 29). The differences in composition and gene expression in the microbiota between the samples were analyzed using 16s rRNA sequencing. The oncogenic genus (Veillonella) was then evaluated in the progression of lung cancer in C57 BL/6 mice. Compared to benign lung disease, the lung microbiota in non-small cell lung cancer was significantly altered, both in terms of α- and β-diversity. In terms of bacterial composition, the non-small cell lung cancer group was enriched with two Phyla (Firmicutes, Bacteroidetes) and three genera (Streptococcus, Prevotella, Veillonella). Prevotella and Veillonella were most strongly associated with non-small cell lung cancer, and Veillonella significantly promoted the progression of lung cancer in vivo. Moreover, metabolic prediction revealed that ribosomes, biosynthesis of secondary metabolites, and pyrimidine metabolism were among the enriched pathways that may be involved in the progression of non-small cell lung cancer. Overall, results suggest that the progression of non-small cell lung cancer is followed by significant changes in the composition and function of the lung microbiota. These differing genera may be potential diagnostic markers and therapeutic targets.
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Affiliation(s)
- Wen Zeng
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.,Department of Oncology, Ganzhou Cancer Hospital, Gannan Medical University,Ganzhou, Jiangxi, China
| | - ChengZhu Zhao
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Mengge Yu
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Hailong Chen
- Department of Oncology, Ganzhou Cancer Hospital, Gannan Medical University,Ganzhou, Jiangxi, China
| | - Yiyun Pan
- Department of Oncology, Ganzhou Cancer Hospital, Gannan Medical University,Ganzhou, Jiangxi, China
| | - Yuhuan Wang
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Hejing Bao
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | | | - Shudong Ma
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
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Zheng W, Wang T, Wu P, Yan Q, Liu C, Wu H, Zhan S, Liu X, Jiang Y, Zhuang H. Host Factor Interaction Networks Identified by Integrative Bioinformatics Analysis Reveals Therapeutic Implications in COPD Patients With COVID-19. Front Pharmacol 2021; 12:718874. [PMID: 35002688 PMCID: PMC8733735 DOI: 10.3389/fphar.2021.718874] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Accepted: 11/11/2021] [Indexed: 01/08/2023] Open
Abstract
Background: The COVID-19 pandemic poses an imminent threat to humanity, especially for those who have comorbidities. Evidence of COVID-19 and COPD comorbidities is accumulating. However, data revealing the molecular mechanism of COVID-19 and COPD comorbid diseases is limited. Methods: We got COVID-19/COPD -related genes from different databases by restricted screening conditions (top500), respectively, and then supplemented with COVID-19/COPD-associated genes (FDR<0.05, |LogFC|≥1) from clinical sample data sets. By taking the intersection, 42 co-morbid host factors for COVID-19 and COPD were finally obtained. On the basis of shared host factors, we conducted a series of bioinformatics analysis, including protein-protein interaction analysis, gene ontology and pathway enrichment analysis, transcription factor-gene interaction network analysis, gene-microRNA co-regulatory network analysis, tissue-specific enrichment analysis and candidate drug prediction. Results: We revealed the comorbidity mechanism of COVID-19 and COPD from the perspective of host factor interaction, obtained the top ten gene and 3 modules with different biological functions. Furthermore, we have obtained the signaling pathways and concluded that dexamethasone, estradiol, progesterone, and nitric oxide shows effective interventions. Conclusion: This study revealed host factor interaction networks for COVID-19 and COPD, which could confirm the potential drugs for treating the comorbidity, ultimately, enhancing the management of the respiratory disease.
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Affiliation(s)
- Wenjiang Zheng
- The First Clinical Medical School, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Ting Wang
- The First Clinical Medical School, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Peng Wu
- The First Clinical Medical School, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Qian Yan
- The First Clinical Medical School, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Chengxin Liu
- The First Clinical Medical School, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Hui Wu
- The First Clinical Medical School, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Shaofeng Zhan
- The First Affiliated Hospital of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xiaohong Liu
- The First Affiliated Hospital of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yong Jiang
- Shenzhen Hospital of Integrated Traditional Chinese and Western Medicine, Shenzhen, China
| | - Hongfa Zhuang
- The First Affiliated Hospital of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
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Su X, Chen J, Lin X, Chen X, Zhu Z, Wu W, Lin H, Wang J, Ye X, Zeng Y. FERMT3 mediates cigarette smoke-induced epithelial-mesenchymal transition through Wnt/β-catenin signaling. Respir Res 2021; 22:286. [PMID: 34742298 PMCID: PMC8571878 DOI: 10.1186/s12931-021-01881-y] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Accepted: 10/28/2021] [Indexed: 02/06/2023] Open
Abstract
Background Cigarette smoking is a major risk factor for chronic obstructive pulmonary disease (COPD) and lung cancer. Epithelial–mesenchymal transition (EMT) is an essential pathophysiological process in COPD and plays an important role in airway remodeling, fibrosis, and malignant transformation of COPD. Previous studies have indicated FERMT3 is downregulated and plays a tumor-suppressive role in lung cancer. However, the role of FERMT3 in COPD, including EMT, has not yet been investigated. Methods The present study aimed to explore the potential role of FERMT3 in COPD and its underlying molecular mechanisms. Three GEO datasets were utilized to analyse FERMT3 gene expression profiles in COPD. We then established EMT animal models and cell models through cigarette smoke (CS) or cigarette smoke extract (CSE) exposure to detect the expression of FERMT3 and EMT markers. RT-PCR, western blot, immunohistochemical, cell migration, and cell cycle were employed to investigate the potential regulatory effect of FERMT3 in CSE-induced EMT. Results Based on Gene Expression Omnibus (GEO) data set analysis, FERMT3 expression in bronchoalveolar lavage fluid was lower in COPD smokers than in non-smokers or smokers. Moreover, FERMT3 expression was significantly down-regulated in lung tissues of COPD GOLD 4 patients compared with the control group. Cigarette smoke exposure reduced the FERMT3 expression and induces EMT both in vivo and in vitro. The results showed that overexpression of FERMT3 could inhibit EMT induced by CSE in A549 cells. Furthermore, the CSE-induced cell migration and cell cycle progression were reversed by FERMT3 overexpression. Mechanistically, our study showed that overexpression of FERMT3 inhibited CSE-induced EMT through the Wnt/β-catenin signaling. Conclusions In summary, these data suggest FERMT3 regulates cigarette smoke-induced epithelial–mesenchymal transition through Wnt/β-catenin signaling. These findings indicated that FERMT3 was correlated with the development of COPD and may serve as a potential target for both COPD and lung cancer. Supplementary Information The online version contains supplementary material available at 10.1186/s12931-021-01881-y.
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Affiliation(s)
- Xiaoshan Su
- Department of Pulmonary and Critical Care Medicine, The Second Affiliated Hospital of Fujian Medical University, Respirology Medicine Centre of Fujian Province, Quanzhou, China
| | - Junjie Chen
- Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Xiaoping Lin
- Department of Pulmonary and Critical Care Medicine, The Second Affiliated Hospital of Fujian Medical University, Respirology Medicine Centre of Fujian Province, Quanzhou, China
| | - Xiaoyang Chen
- Department of Pulmonary and Critical Care Medicine, The Second Affiliated Hospital of Fujian Medical University, Respirology Medicine Centre of Fujian Province, Quanzhou, China
| | - Zhixing Zhu
- Department of Pulmonary and Critical Care Medicine, The Second Affiliated Hospital of Fujian Medical University, Respirology Medicine Centre of Fujian Province, Quanzhou, China
| | - Weijing Wu
- Department of Pulmonary and Critical Care Medicine, The Second Affiliated Hospital of Fujian Medical University, Respirology Medicine Centre of Fujian Province, Quanzhou, China
| | - Hai Lin
- Department of Pulmonary and Critical Care Medicine, The Second Affiliated Hospital of Fujian Medical University, Respirology Medicine Centre of Fujian Province, Quanzhou, China
| | - Jianming Wang
- Department of Critical Care Medicine, Quanzhou First Hospital Affiliated to Fujian Medical University, Quanzhou, China
| | - Xiangjia Ye
- Department of Pulmonary and Critical Care Medicine, The Second Affiliated Hospital of Fujian Medical University, Respirology Medicine Centre of Fujian Province, Quanzhou, China
| | - Yiming Zeng
- Department of Pulmonary and Critical Care Medicine, The Second Affiliated Hospital of Fujian Medical University, Respirology Medicine Centre of Fujian Province, Quanzhou, China.
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Dey S, Eapen MS, Chia C, Gaikwad AV, Wark PAB, Sohal SS. Pathogenesis, clinical features of asthma COPD overlap (ACO), and therapeutic modalities. Am J Physiol Lung Cell Mol Physiol 2021; 322:L64-L83. [PMID: 34668439 DOI: 10.1152/ajplung.00121.2021] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Both asthma and COPD are heterogeneous diseases identified by characteristic symptoms and functional abnormalities, with airway obstruction common in both diseases. Asthma COPD overlap (ACO) does not define a single disease but is a descriptive term for clinical use that includes several overlapping clinical phenotypes of chronic airways disease with different underlying mechanisms. This literature review was initiated to describe published studies, identify gaps in knowledge, and propose future research goals regarding the disease pathology of ACO, especially the airway remodelling changes and inflammation aspects. Airway remodelling occurs in asthma and COPD, but there are differences in the structures affected and the prime anatomic site at which they occur. Reticular basement membrane thickening and cellular infiltration with eosinophils and T-helper (CD4+) lymphocytes are prominent features of asthma. Epithelial squamous metaplasia, airway wall fibrosis, emphysema, bronchoalveolar lavage (BAL) neutrophilia and (CD8+) T-cytotoxic lymphocyte infiltrations in the airway wall are features of COPD. There is no universally accepted definition of ACO, nor are there clearly defined pathological characteristics to differentiate from asthma and COPD. Understanding etiological concepts within the purview of inflammation and airway remodelling changes in ACO would allow better management of these patients.
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Affiliation(s)
- Surajit Dey
- Respiratory Translational Research Group, Department of Laboratory Medicine, School of Health Sciences, College of Health and Medicine, University of Tasmania, Launceston, Tasmania, Australia
| | - Mathew Suji Eapen
- Respiratory Translational Research Group, Department of Laboratory Medicine, School of Health Sciences, College of Health and Medicine, University of Tasmania, Launceston, Tasmania, Australia
| | - Collin Chia
- Respiratory Translational Research Group, Department of Laboratory Medicine, School of Health Sciences, College of Health and Medicine, University of Tasmania, Launceston, Tasmania, Australia.,Department of Respiratory Medicine, Launceston General Hospital, Launceston, Tasmania, Australia
| | - Archana Vijay Gaikwad
- Respiratory Translational Research Group, Department of Laboratory Medicine, School of Health Sciences, College of Health and Medicine, University of Tasmania, Launceston, Tasmania, Australia
| | - Peter A B Wark
- Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute, University of Newcastle, New Lambton Heights, Australia.,Department of Respiratory and Sleep Medicine John Hunter Hospital, New Lambton Heights, Australia
| | - Sukhwinder Singh Sohal
- Respiratory Translational Research Group, Department of Laboratory Medicine, School of Health Sciences, College of Health and Medicine, University of Tasmania, Launceston, Tasmania, Australia
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Ge H, Liu X, Gu W, Feng X, Zhang F, Han F, Qian Y, Jin X, Gao B, Yu L, Bao H, Zhou M, Li S, Jie Z, Wang J, Chen Z, Hang J, Zhang J, Zhu H. Distribution of COPD Comorbidities and Creation of Acute Exacerbation Risk Score: Results from SCICP. J Inflamm Res 2021; 14:3335-3348. [PMID: 34290518 PMCID: PMC8289369 DOI: 10.2147/jir.s315600] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Accepted: 06/17/2021] [Indexed: 12/13/2022] Open
Abstract
Background Chronic obstructive pulmonary disease (COPD) often coexists with multiple comorbidities which may have a significant impact on acute exacerbations of patients. At present, what kind of comorbidities affects acute exacerbations and how comorbidities lead to poor prognosis are still controversial. The purpose of our study is to determine the impact of comorbidities on COPD exacerbation and establish an acute exacerbation risk assessment system related to comorbidities. Methods A total of 742 COPD patients participated in the Shanghai COPD Investigation on Comorbidity Program (SCICP, ChiCTR2000030911). Finally, the baseline information of 415 participants and one-year follow-up data were involved in the analysis. We collected hemogram indices, pulmonary function tests and acute exacerbation of COPD with regular medical follow-up. Q-type cluster analysis was used to determine the clusters of participants. Receiver operating characteristic (ROC) analysis was constructed to assess the ability of indicators in predicting acute exacerbations. Results Almost 65% of the population we investigated had at least one comorbidity. The distribution and incidence of comorbidities differed between exacerbation group and non-exacerbation group. Three comorbidity clusters were identified: (1) respiratory, metabolic, immune and psychologic disease (non-severe cases); (2) cardiovascular and neoplastic disease (severe cases); (3) less comorbidity. Different sub-phenotypes of COPD patients showed significant distinction in health status. Anxiety (OR=5.936, P=0.001), angina (OR=10.155, P=0.025) and hypertension (OR=3.142, P=0.001) were found to be independent risk factors of exacerbation in a year. The novel risk score containing BODEx and four diseases showed great prognostic value of COPD exacerbation in developing sample. Conclusion Our study detailed the major interaction between comorbidities and exacerbation in COPD. Noteworthily, a novel risk score using comprehensive index – BODEx – and comorbidity parameters can identify patients at high risk of acute exacerbation.
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Affiliation(s)
- Haiyan Ge
- Department of Respiratory and Critical Care Medicine, Huadong Hospital, Fudan University, Shanghai, People's Republic of China
| | - Xuanqi Liu
- Department of Respiratory and Critical Care Medicine, Huadong Hospital, Fudan University, Shanghai, People's Republic of China
| | - Wenchao Gu
- Department of Respiratory Medicine, Pudong New District People's Hospital, Shanghai, People's Republic of China
| | - Xiumin Feng
- Department of Respiratory and Critical Care Medicine, Changhai Hospital Affiliated to Navy Military Medical University, Shanghai, People's Republic of China.,Department of Respiratory and Critical Care Medicine, Changji Branch of First Affiliated Hospital of Xinjiang Medical University, Xinjiang, People's Republic of China
| | - Fengying Zhang
- Department of Respiratory Medicine, Putuo District People's Hospital, Shanghai, People's Republic of China
| | - Fengfeng Han
- Department of Respiratory Medicine, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China
| | - Yechang Qian
- Baoshan District Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai, People's Republic of China
| | - Xiaoyan Jin
- Department of Respiratory Medicine, Tongren Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China
| | - Beilan Gao
- Department of Respiratory Medicine, Shanghai Pulmonary Hospital, Tongji University, Shanghai, People's Republic of China
| | - Li Yu
- Department of Pulmonary and Critical Care Medicine, Tongji Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China
| | - Hong Bao
- Department of Respiratory Medicine Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, People's Republic of China
| | - Min Zhou
- Department of Respiratory and Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Shengqing Li
- Department of Respiratory and Critical Care Medicine, Huashan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Zhijun Jie
- Department of Respiratory Medicine, Shanghai Fifth's Hospital, Fudan University, Shanghai, People's Republic of China
| | - Jian Wang
- Department of Respiratory Medicine, Shanghai Ninth's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China
| | - Zhihong Chen
- Department of Respiratory and Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Jingqing Hang
- Department of Respiratory Medicine, Putuo District People's Hospital, Shanghai, People's Republic of China
| | - Jingxi Zhang
- Department of Respiratory and Critical Care Medicine, Changhai Hospital Affiliated to Navy Military Medical University, Shanghai, People's Republic of China
| | - Huili Zhu
- Department of Respiratory and Critical Care Medicine, Huadong Hospital, Fudan University, Shanghai, People's Republic of China
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Chen P, Jiang P, Chen J, Yang Y, Guo X. XIST promotes apoptosis and the inflammatory response in CSE-stimulated cells via the miR-200c-3p/EGR3 axis. BMC Pulm Med 2021; 21:215. [PMID: 34243729 PMCID: PMC8268373 DOI: 10.1186/s12890-021-01582-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Accepted: 07/01/2021] [Indexed: 01/27/2023] Open
Abstract
Background Chronic obstructive pulmonary disease (COPD) is a disease that causes obstructed airways and abnormal inflammatory responses in the lungs. Early growth response 3 (EGR3) has been revealed to play a vital role in the regulation of the inflammatory response in certain diseases. We aimed to explore the role of EGR3 and its upstream mechanism in COPD. Methods and result In the present study, 16HBE cells were treated with cigarette smoke extract (CSE) to mimic the inflammatory response in vitro. RT-qPCR revealed that the expression of EGR3 was upregulated in lungs from COPD patients. EGR3 expression in 16HBE cells was increased by CSE treatment. Moreover, flow cytometry analysis and western blot analysis showed that EGR3 downregulation inhibited 16HBE cell apoptosis. EGR3 silencing decreased the protein levels of IL-6, TNF-α, IL-1β and COX2 in CSE-stimulated 16HBE cells. In addition, EGR3 was targeted by microRNA-200c-3p (miR-200c-3p) in 16HBE cells. MiR-200c-3p expression was significantly decreased in lung tissues from COPD patients compared to that in healthy controls. Furthermore, miR-200c-3p bound to lncRNA X-inactive specific transcript (XIST) in 16HBE cells. Additionally, XIST expression was elevated in lung tissues from COPD patients. Rescue assays indicated that EGR3 overexpression counteracted the effects of XIST downregulation on apoptosis and inflammation in CSE-stimulated 16HBE cells. Conclusion The XIST/miR-200c-3p/EGR3 axis facilitated apoptosis and inflammation in CSE-stimulated 16HBE cells. These findings may provide novel insight for treating COPD by alleviating lung inflammation. Supplementary Information The online version contains supplementary material available at 10.1186/s12890-021-01582-8.
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Affiliation(s)
- Panfeng Chen
- Department of Respiratory and Critical Care Medicine, Tianjin First Central Hospital, No. 24 Fukang Road, Nankai District, Tianjin, 300192, China.
| | - Ping Jiang
- Department of Respiratory and Critical Care Medicine, Tianjin First Central Hospital, No. 24 Fukang Road, Nankai District, Tianjin, 300192, China
| | - Jianing Chen
- Department of Respiratory and Critical Care Medicine, Tianjin First Central Hospital, No. 24 Fukang Road, Nankai District, Tianjin, 300192, China
| | - Yang Yang
- Department of Respiratory and Critical Care Medicine, Haihe Hospital, Tianjin, 300222, China
| | - Xiumei Guo
- Department of Orthopaedics, Baoding Second Central Hospital, Baoding, 072750, Hebei, China
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Electronic cigarettes: Modern instruments for toxic lung delivery and posing risk for the development of chronic disease. Int J Biochem Cell Biol 2021; 137:106039. [PMID: 34242684 DOI: 10.1016/j.biocel.2021.106039] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 06/18/2021] [Accepted: 07/04/2021] [Indexed: 02/07/2023]
Abstract
Following the emergence of electronic cigarette, or vaping product use associated lung injury (EVALI) in 2019 in the US, regulation of e-cigarettes has become globally tighter and the collective evidence of the detrimental effects of vaping has grown. The danger of cellular distress and altered homeostasis is heavily associated with the modifiable nature of electronic cigarette devices. An array of harmful chemicals and elevated concentrations of metals have been detected in e-cigarette aerosols which have been linked to various pathogeneses. Vaping is linked to increased inflammation, altered lipid homeostasis and mitochondrial dysfunction whilst also increasing microbial susceptibility whilst the long-term damage is yet to be observed. The scientific evidence is mounting and highlighting that, along with traditional tobacco cigarette smoking, electronic cigarette vaping is not a safe practice.
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39
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Zhao Y, Zhang J, Sun H, Brasier AR. Crosstalk of the IκB Kinase with Spliced X-Box Binding Protein 1 Couples Inflammation with Glucose Metabolic Reprogramming in Epithelial-Mesenchymal Transition. J Proteome Res 2021; 20:3475-3488. [PMID: 34124911 DOI: 10.1021/acs.jproteome.1c00093] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
Epithelial-mesenchymal transition (EMT) plays a critical role in airway injury, repair, and structural remodeling. IκB kinase (IKK)-NFκB signaling regulates late EMT-associated gene expression. However, IKK-mediated mesenchymal transition occurs earlier than NFκB/RelA subunit-dependent EMT gene expression, leading us to investigate the hypothesis that IKK plays an independent mechanism in transforming growth factor-β (TGFβ)-induced EMT. Time-resolved dissection of early proteome and phosphoproteome changes in response to TGFβ and a specific IKK inhibitor, BMS-345541, revealed that IKK regulates cascades of 23 signaling pathways essential in EMT, including TGFβ signaling, p38 mitogen associate protein kinase (MAPK), Toll receptor signaling, and integrin pathways. We identified early IKK-dependent phosphorylation of core regulatory proteins in essential EMT signaling cassettes, including ATF2, JUN, NFKB1/p105, and others. Interestingly, we found that IKKβ directly complexes with and phosphorylates the spliced X-box-binding protein 1 (XBP1s). XBP1s is an arm of the unfolded protein response (UPR) that activates the hexosamine biosynthetic pathway (HBP), a pathway that mediates protein N-glycosylation and survival from ER stress-induced apoptosis in EMT. We found that inhibition of IKK activity abolishes the phosphorylation of XBP1-T48, blocks XBP1s nuclear translocation, and inhibits the activation of HBP. Our study elucidates a previously unrecognized IKKβ-XBP1s-HBP crosstalk pathway that couples inflammation and glucose metabolic reprogramming in ETM. Because XBP1-HBP controls N-glycosylation of the extracellular matrix (ECM) in EMT, this novel IKKβ-XBP1-HBP pathway may contain therapeutic targets whose inhibition could prevent ECM remodeling in lung fibrosis or other airway remodeling diseases.
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Affiliation(s)
- Yingxin Zhao
- Department of Internal Medicine, University of Texas Medical Branch (UTMB), Galveston, Texas 77555-1060, United States.,Institute for Translational Sciences, UTMB, Galveston, Texas 77555-0342, United States.,Sealy Center for Molecular Medicine, UTMB, Galveston, Texas 77555-0129, United States
| | - Jing Zhang
- Department of Internal Medicine, University of Texas Medical Branch (UTMB), Galveston, Texas 77555-1060, United States
| | - Hong Sun
- Department of Internal Medicine, University of Texas Medical Branch (UTMB), Galveston, Texas 77555-1060, United States
| | - Allan R Brasier
- Institute for Clinical and Translational Research, University of Wisconsin-Madison School of Public Health, Madison, Wisconsin 53705, United States
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40
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Liu G, Philp AM, Corte T, Travis MA, Schilter H, Hansbro NG, Burns CJ, Eapen MS, Sohal SS, Burgess JK, Hansbro PM. Therapeutic targets in lung tissue remodelling and fibrosis. Pharmacol Ther 2021; 225:107839. [PMID: 33774068 DOI: 10.1016/j.pharmthera.2021.107839] [Citation(s) in RCA: 150] [Impact Index Per Article: 37.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Accepted: 03/03/2021] [Indexed: 02/07/2023]
Abstract
Structural changes involving tissue remodelling and fibrosis are major features of many pulmonary diseases, including asthma, chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). Abnormal deposition of extracellular matrix (ECM) proteins is a key factor in the development of tissue remodelling that results in symptoms and impaired lung function in these diseases. Tissue remodelling in the lungs is complex and differs between compartments. Some pathways are common but tissue remodelling around the airways and in the parenchyma have different morphologies. Hence it is critical to evaluate both common fibrotic pathways and those that are specific to different compartments; thereby expanding the understanding of the pathogenesis of fibrosis and remodelling in the airways and parenchyma in asthma, COPD and IPF with a view to developing therapeutic strategies for each. Here we review the current understanding of remodelling features and underlying mechanisms in these major respiratory diseases. The differences and similarities of remodelling are used to highlight potential common therapeutic targets and strategies. One central pathway in remodelling processes involves transforming growth factor (TGF)-β induced fibroblast activation and myofibroblast differentiation that increases ECM production. The current treatments and clinical trials targeting remodelling are described, as well as potential future directions. These endeavours are indicative of the renewed effort and optimism for drug discovery targeting tissue remodelling and fibrosis.
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Affiliation(s)
- Gang Liu
- Centre for Inflammation, Centenary Institute and University of Technology Sydney, Sydney, NSW, Australia
| | - Ashleigh M Philp
- Centre for Inflammation, Centenary Institute and University of Technology Sydney, Sydney, NSW, Australia; St Vincent's Medical School, UNSW Medicine, UNSW, Sydney, NSW, Australia
| | - Tamera Corte
- Royal Prince Alfred Hospital, Camperdown, NSW, Australia; Sydney Medical School, University of Sydney, Sydney, NSW, Australia
| | - Mark A Travis
- The Lydia Becker Institute of Immunology and Inflammation, Faculty of Biology, Medicine and Health, Manchester Academic Health Sciences Centre and Wellcome Trust Centre for Cell-Matrix Research, University of Manchester, Manchester, United Kingdom
| | - Heidi Schilter
- Pharmaxis Ltd, 20 Rodborough Road, Frenchs Forest, Sydney, NSW, Australia
| | - Nicole G Hansbro
- Centre for Inflammation, Centenary Institute and University of Technology Sydney, Sydney, NSW, Australia
| | - Chris J Burns
- Walter and Eliza Hall Institute of Medical Research, Department of Medical Biology, The University of Melbourne, Melbourne, VIC 3010, Australia
| | - Mathew S Eapen
- Respiratory Translational Research Group, Department of Laboratory Medicine, School of Health Sciences, University of Tasmania, Launceston, TAS, Australia
| | - Sukhwinder S Sohal
- Respiratory Translational Research Group, Department of Laboratory Medicine, School of Health Sciences, University of Tasmania, Launceston, TAS, Australia
| | - Janette K Burgess
- University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD (GRIAC), Department of Pathology and Medical Biology, Groningen, The Netherlands; Woolcock Institute of Medical Research, Discipline of Pharmacology, The University of Sydney, Sydney, NSW, Australia
| | - Philip M Hansbro
- Centre for Inflammation, Centenary Institute and University of Technology Sydney, Sydney, NSW, Australia.
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41
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Montaño M, Pérez-Bautista O, Velasco-Torres Y, González-Ávila G, Ramos C. Women with COPD from biomass smoke have reduced serum levels of biomarkers of angiogenesis and cancer, with EGFR predominating, compared to women with COPD from smoking. Chron Respir Dis 2021; 18:14799731211005023. [PMID: 33787367 PMCID: PMC8020220 DOI: 10.1177/14799731211005023] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 02/22/2021] [Accepted: 03/01/2021] [Indexed: 12/23/2022] Open
Abstract
The main causes of COPD are smoking (COPD-TS) and exposure to biomass smoke (COPD-BS), considered as different phenotypes. The association of COPD-TS with lung cancer (LC) is well established, but not in COPD-BS. Thus, we studied the serum concentration of cytokines that participate in inflammation, angiogenesis, and tumor progression, used frequently as LC biomarkers, in women with COPD-BS compared with COPD-TS (n = 70). Clinical and physiological characteristics and the serum concentration (multiplex immunoassay) of 16 cytokines were evaluated. The analysis revealed that women with COPD-BS were shorter and older, and had lower concentrations of 12 serum cytokines: 6 proinflammatory and angiogenic IL-6Rα, PECAM-1, leptin, osteopontin, prolactin, and follistatin; and 6 that participate in angiogenesis and in tumor progression FGF-2, HGF, sVEGFR-2, sHER2/neu, sTIE-2, G-CSF, and SCF. Notably, there was a significant increase in sEGFR in women with COPD-BS compared to women with COPD-TS. PDGF-AA/BB and sTIE-2 did not change. These findings suggest that women with COPD-BS have markedly decreased proinflammatory, angiogenic, and tumor progression potential, compared to women with COPD-TS, with sEGFR as the predominant mediator, which might reflect a differential pattern of inflammation in women exposed to BS, favoring the development of chronic bronchitis.
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Affiliation(s)
- Martha Montaño
- Laboratorio de Biología Celular, Departamento de Investigación en Fibrosis Pulmonar, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas (INER), Ciudad de México, México
| | - Oliver Pérez-Bautista
- Departamento de Investigación en Tabaquismo y EPOC, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, (INER), Ciudad de México, México
| | - Yadira Velasco-Torres
- Laboratorio de Biología Celular, Departamento de Investigación en Fibrosis Pulmonar, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas (INER), Ciudad de México, México
| | - Georgina González-Ávila
- Laboratoro de Oncología Biomédica, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas (INER), Ciudad de México, México
| | - Carlos Ramos
- Laboratorio de Biología Celular, Departamento de Investigación en Fibrosis Pulmonar, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas (INER), Ciudad de México, México
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42
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Eapen MS, Sohal SS. WNT/β-catenin pathway: A novel therapeutic target for attenuating airway remodelling and EMT in COPD. EBioMedicine 2020; 62:103095. [PMID: 33161229 PMCID: PMC7656136 DOI: 10.1016/j.ebiom.2020.103095] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2020] [Accepted: 10/12/2020] [Indexed: 12/24/2022] Open
Affiliation(s)
- Mathew Suji Eapen
- Respiratory Translational Research Group, Department of Laboratory Medicine, School of Health Sciences, College of Health and Medicine, University of Tasmania, Locked Bag - 1322, Newnham Drive, Launceston, Tasmania 7248, Australia
| | - Sukhwinder Singh Sohal
- Respiratory Translational Research Group, Department of Laboratory Medicine, School of Health Sciences, College of Health and Medicine, University of Tasmania, Locked Bag - 1322, Newnham Drive, Launceston, Tasmania 7248, Australia.
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43
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Paudel KR, Dharwal V, Patel VK, Galvao I, Wadhwa R, Malyla V, Shen SS, Budden KF, Hansbro NG, Vaughan A, Yang IA, Kohonen-Corish MRJ, Bebawy M, Dua K, Hansbro PM. Role of Lung Microbiome in Innate Immune Response Associated With Chronic Lung Diseases. Front Med (Lausanne) 2020; 7:554. [PMID: 33043031 PMCID: PMC7530186 DOI: 10.3389/fmed.2020.00554] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Accepted: 08/03/2020] [Indexed: 12/13/2022] Open
Abstract
Respiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD), lung fibrosis, and lung cancer, pose a huge socio-economic burden on society and are one of the leading causes of death worldwide. In the past, culture-dependent techniques could not detect bacteria in the lungs, therefore the lungs were considered a sterile environment. However, the development of culture-independent techniques, particularly 16S rRNA sequencing, allowed for the detection of commensal microbes in the lung and with further investigation, their roles in disease have since emerged. In healthy individuals, the predominant commensal microbes are of phylum Firmicutes and Bacteroidetes, including those of the genera Veillonella and Prevotella. In contrast, pathogenic microbes (Haemophilus, Streptococcus, Klebsiella, Pseudomonas) are often associated with lung diseases. There is growing evidence that microbial metabolites, structural components, and toxins from pathogenic and opportunistic bacteria have the capacity to stimulate both innate and adaptive immune responses, and therefore can contribute to the pathogenesis of lung diseases. Here we review the multiple mechanisms that are altered by pathogenic microbiomes in asthma, COPD, lung cancer, and lung fibrosis. Furthermore, we focus on the recent exciting advancements in therapies that can be used to restore altered microbiomes in the lungs.
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Affiliation(s)
- Keshav Raj Paudel
- Centre for Inflammation, Centenary Institute, Sydney, NSW, Australia.,Faculty of Science, University of Technology Sydney, Sydney, NSW, Australia
| | - Vivek Dharwal
- Centre for Inflammation, Centenary Institute, Sydney, NSW, Australia.,Faculty of Science, University of Technology Sydney, Sydney, NSW, Australia
| | - Vyoma K Patel
- Centre for Inflammation, Centenary Institute, Sydney, NSW, Australia.,Faculty of Science, University of Technology Sydney, Sydney, NSW, Australia
| | - Izabela Galvao
- Centre for Inflammation, Centenary Institute, Sydney, NSW, Australia.,Faculty of Science, University of Technology Sydney, Sydney, NSW, Australia
| | - Ridhima Wadhwa
- Centre for Inflammation, Centenary Institute, Sydney, NSW, Australia.,Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, Sydney, NSW, Australia
| | - Vamshikrishna Malyla
- Centre for Inflammation, Centenary Institute, Sydney, NSW, Australia.,Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, Sydney, NSW, Australia
| | - Sj Sijie Shen
- Centre for Inflammation, Centenary Institute, Sydney, NSW, Australia.,Faculty of Science, University of Technology Sydney, Sydney, NSW, Australia
| | - Kurtis F Budden
- Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute, The University of Newcastle, Newcastle, NSW, Australia
| | - Nicole G Hansbro
- Centre for Inflammation, Centenary Institute, Sydney, NSW, Australia.,Faculty of Science, University of Technology Sydney, Sydney, NSW, Australia
| | - Annalicia Vaughan
- Faculty of Medicine, Thoracic Research Centre, The University of Queensland, Brisbane, QLD, Australia.,Department of Thoracic Medicine, The Prince Charles Hospital, Brisbane, QLD, Australia
| | - Ian A Yang
- Faculty of Medicine, Thoracic Research Centre, The University of Queensland, Brisbane, QLD, Australia.,Department of Thoracic Medicine, The Prince Charles Hospital, Brisbane, QLD, Australia
| | - Maija R J Kohonen-Corish
- Faculty of Science, University of Technology Sydney, Sydney, NSW, Australia.,Woolcock Institute of Medical Research, University of Sydney, Sydney, NSW, Australia.,School of Medicine, Western Sydney University, Sydney, NSW, Australia.,St George and Sutherland Clinical School, University of New South Wales, Sydney, NSW, Australia
| | - Mary Bebawy
- Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, Sydney, NSW, Australia
| | - Kamal Dua
- Centre for Inflammation, Centenary Institute, Sydney, NSW, Australia.,Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, Sydney, NSW, Australia.,Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute, The University of Newcastle, Newcastle, NSW, Australia
| | - Philip M Hansbro
- Centre for Inflammation, Centenary Institute, Sydney, NSW, Australia.,Faculty of Science, University of Technology Sydney, Sydney, NSW, Australia.,Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute, The University of Newcastle, Newcastle, NSW, Australia
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44
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Brzecka A, Sarul K, Dyła T, Avila-Rodriguez M, Cabezas-Perez R, Chubarev VN, Minyaeva NN, Klochkov SG, Neganova ME, Mikhaleva LM, Somasundaram SG, Kirkland CE, Tarasov VV, Aliev G. The Association of Sleep Disorders, Obesity and Sleep-Related Hypoxia with Cancer. Curr Genomics 2020; 21:444-453. [PMID: 33093806 PMCID: PMC7536792 DOI: 10.2174/1389202921999200403151720] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2019] [Revised: 07/31/2019] [Accepted: 03/16/2020] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Sleep disorders have emerged as potential cancer risk factors. OBJECTIVE This review discusses the relationships between sleep, obesity, and breathing disorders with concomitant risks of developing cancer. RESULTS Sleep disorders result in abnormal expression of clock genes, decreased immunity, and melatonin release disruption. Therefore, these disorders may contribute to cancer development. Moreover, in sleep breathing disorder, which is frequently experienced by obese persons, the sufferer experiences intermittent hypoxia that may stimulate cancer cell proliferation. DISCUSSION During short- or long- duration sleep, sleep-wake rhythm disruption may occur. Insomnia and obstructive sleep apnea increase cancer risks. In short sleepers, an increased risk of stomach cancer, esophageal squamous cell cancer, and breast cancer was observed. Among long sleepers (>9 hours), the risk of some hematologic malignancies is elevated. CONCLUSION Several factors including insomnia, circadian disruption, obesity, and intermittent hypoxia in obstructive sleep apnea are contributing risk factors for increased risk of several types of cancers. However, further studies are needed to determine the more significant of these risk factors and their interactions.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | | | - Gjumrakch Aliev
- Address correspondence to this author at the GALLY International Research Institute, 7733 Louis Pasteur Drive, #330, San Antonio, TX, 78229, USA; Tel: +1(440) 263-7461; +7-964-493-1515; E-mails: and
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45
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Clinical Application of Forced Oscillation Technique (FOT) in Early Detection of Airway Changes in Smokers. J Clin Med 2020; 9:jcm9092778. [PMID: 32867314 PMCID: PMC7565456 DOI: 10.3390/jcm9092778] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Revised: 08/24/2020] [Accepted: 08/24/2020] [Indexed: 01/31/2023] Open
Abstract
The forced oscillation technique (FOT) is a non-invasive method to assess airway function by emitting oscillatory signals into the respiratory tract during tidal ventilation. This opinion piece discusses the current use, trialled modification and future directions in utilizing FOT as a novel diagnostic tool for early detection of small airway changes in smokers. The published evidence to date has shown that FOT parameters could be a sensitive diagnostic tool to detect early respiratory changes in smokers. Multiple frequencies and the frequency dependence of resistance and reactance can provide the most valuable and early information regarding smoking induced changes in airways. Considering its non-invasiveness, lower level of discomfort to patients than spirometry, feasibility, and cost effectiveness, it could be the first-choice diagnostic technique for detection of early respiratory changes in smokers. The finding of FOT could further be supported and correlated with inflammatory markers.
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46
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Yang S, Liu T, Liang G. The benefits of smoking cessation on survival in cancer patients by integrative analysis of multi-omics data. Mol Oncol 2020; 14:2069-2080. [PMID: 32580248 PMCID: PMC7463331 DOI: 10.1002/1878-0261.12755] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Revised: 06/10/2020] [Accepted: 06/18/2020] [Indexed: 12/12/2022] Open
Abstract
Few studies have examined the association between smoking status (including former smokers) at diagnosis and overall survival among cancer patients. We aimed to assess the benefits of quitting smoking on cancer prognosis in cohorts of cancer patient smokers obtained from the Cancer Genome Atlas (TCGA) database. Hazard ratios (HR) were calculated to evaluate smoking behavior at cancer diagnosis (reformed smokers vs. current smokers) in association with overall survival using multivariate‐adjusted Cox regressions analysis. According to our analyses, quitting smoking was the independent protective factor for overall survival in lung squamous cell carcinoma (LUSC) (HR = 0.67, 95% CI = 0.48–0.94). Comprehensive analysis of multicomponent data across reformed and current smokers identified a total of 85 differential expressed genes (DEGs) affected by different modes of genetic and epigenetic regulation, potentially representing cancer drivers in smokers. Moreover, we provided a smoking‐associated gene expression signature, which could evaluate the true effect on prognosis with high power (HR = 1.70, 95% CI = 1.19–2.43, AUC = 0.65, 0.67, and 0.70 for 2‐, 3‐, and 5‐year survival, respectively). This signature was also applicable in other smoking‐related cancers, including bladder urothelial carcinoma (HR = 1.70, 95% CI = 1.01–2.88), cervical carcinoma (HR = 5.69, 95% CI = 1.37–23.69), head and neck squamous cell carcinoma (HR = 1.97, 95% CI = 1.41–2.76), lung adenocarcinoma (HR = 1.73, 95% CI = 1.16–2.57), and pancreatic adenocarcinoma (HR = 4.28, 95% CI = 1.47–12.47). In conclusion, this study demonstrates that quitting smoking at diagnosis decreases risk of death in cancer patients. We also provide a smoking‐associated gene expression signature to evaluate the effect of smoking on survival. Lastly, we suggest that smoking cessation could comprise a part of cancer treatment to improve survival rates of cancer patients.
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Affiliation(s)
- Sheng Yang
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, China
| | - Tong Liu
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, China
| | - Geyu Liang
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, China
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47
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Liu YN, Guan Y, Shen J, Jia YL, Zhou JC, Sun Y, Jiang JX, Shen HJ, Shu Q, Xie QM, Xie Y. Shp2 positively regulates cigarette smoke-induced epithelial mesenchymal transition by mediating MMP-9 production. Respir Res 2020; 21:161. [PMID: 32586329 PMCID: PMC7318404 DOI: 10.1186/s12931-020-01426-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Accepted: 06/17/2020] [Indexed: 01/09/2023] Open
Abstract
Cigarette smoke (CS) is a major risk factor for the development of lung cancer and chronic obstructive pulmonary disease (COPD). Epithelial-mesenchymal transition (EMT) commonly coexists in lung cancer and COPD. CS triggers many factors including matrix metalloproteinases (MMPs) production, contributing to EMT progression in the lungs. Here, how Shp2 signaling regulates the CS-induced MMP-9 production and EMT progression were investigated in mouse lungs and in pulmonary epithelial cell cultures (NCI-H292) found CS induced MMP-9 production, EMT progression (increased vimentin and α-SMA; decreased E-cadherin) and collagen deposition in lung tissues; cigarette smoke extract (CSE) induced MMP-9 production and EMT-related phenotypes in NCI-H292 cells, which were partially prevented by Shp2 KO/KD or Shp2 inhibition. The CSE exposure induced EMT phenotypes were suppressed by MMP-9 inhibition. Recombinant MMP-9 induced EMT, which was prevented by MMP-9 inhibition or Shp2 KD/inhibition. Mechanistically, CS and CSE exposure resulted in ERK1/2, JNK and Smad2/3 phosphorylation, which were suppressed by Shp2 KO/KD/inhibition. Consequentially, the CSE exposure-induced MMP-9 production and EMT progression were suppressed by ERK1/2, JNK and Smad2/3 inhibitors. Thus, CS induced MMP-9 production and EMT resulted from activation of Shp2/ERK1/2/JNK/Smad2/3 signaling pathways. Our study contributes to the underlying mechanisms of pulmonary epithelial structural changes in response to CS, which may provide novel therapeutic solutions for treating associated diseases, such as COPD and lung cancer.
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Affiliation(s)
- Ya-Nan Liu
- The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Zhejiang, 310052, Hangzhou, China
- Zhejiang Respiratory Drugs Research Laboratory of Food and Drug Administration of China, Zhejiang University School of Medicine, Zhejiang, 310058, Hangzhou, China
- The First People's Hospital of Yancheng, Yancheng, 224001, Jiangsu, China
- Medical College of Yangzhou University, 11 Huaihai Road, Yangzhou, 225001, Jiangsu, China
| | - Yan Guan
- Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Zhejiang, 310000, Hangzhou, China
| | - Jian Shen
- Zhejiang Respiratory Drugs Research Laboratory of Food and Drug Administration of China, Zhejiang University School of Medicine, Zhejiang, 310058, Hangzhou, China
- Breath Smooth Biotech Hangzhou Co, LTD., Zhejiang, 310012, Hangzhou, China
| | - Yong-Liang Jia
- Zhejiang Respiratory Drugs Research Laboratory of Food and Drug Administration of China, Zhejiang University School of Medicine, Zhejiang, 310058, Hangzhou, China
- Breath Smooth Biotech Hangzhou Co, LTD., Zhejiang, 310012, Hangzhou, China
| | - Jian-Cang Zhou
- Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Zhejiang, 310000, Hangzhou, China
| | - Yun Sun
- The First People's Hospital of Yancheng, Yancheng, 224001, Jiangsu, China
- Medical College of Yangzhou University, 11 Huaihai Road, Yangzhou, 225001, Jiangsu, China
| | - Jun-Xia Jiang
- Zhejiang Respiratory Drugs Research Laboratory of Food and Drug Administration of China, Zhejiang University School of Medicine, Zhejiang, 310058, Hangzhou, China
| | - Hui-Juan Shen
- Zhejiang Respiratory Drugs Research Laboratory of Food and Drug Administration of China, Zhejiang University School of Medicine, Zhejiang, 310058, Hangzhou, China
| | - Qiang Shu
- The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Zhejiang, 310052, Hangzhou, China
| | - Qiang-Min Xie
- The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Zhejiang, 310052, Hangzhou, China.
- Zhejiang Respiratory Drugs Research Laboratory of Food and Drug Administration of China, Zhejiang University School of Medicine, Zhejiang, 310058, Hangzhou, China.
| | - Yicheng Xie
- The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Zhejiang, 310052, Hangzhou, China.
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Papoutsopoulou S, Satsangi J, Campbell BJ, Probert CS. Review article: impact of cigarette smoking on intestinal inflammation-direct and indirect mechanisms. Aliment Pharmacol Ther 2020; 51:1268-1285. [PMID: 32372449 DOI: 10.1111/apt.15774] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2020] [Revised: 04/13/2020] [Accepted: 04/16/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND The inflammatory bowel diseases, Crohn's disease and ulcerative colitis are related multifactorial diseases. Their pathogenesis is influenced by each individual's immune system, the environmental factors within exposome and genetic predisposition. Smoking habit is the single best-established environmental factor that influences disease phenotype, behaviour and response to therapy. AIM To assess current epidemiological, experimental and clinical evidence that may explain how smoking impacts on the pathogenesis of inflammatory bowel disease. METHODS A Medline search for 'cigarette smoking', in combination with terms including 'passive', 'second-hand', 'intestinal inflammation', 'Crohn's disease', 'ulcerative colitis', 'colitis'; 'intestinal epithelium', 'immune system', 'intestinal microbiota', 'tight junctions', 'mucus', 'goblet cells', 'Paneth cells', 'autophagy'; 'epigenetics', 'genes', 'DNA methylation', 'histones', 'short noncoding/long noncoding RNAs'; 'carbon monoxide/CO' and 'nitric oxide/NO' was performed. RESULTS Studies found evidence of direct and indirect effects of smoking on various parameters, including oxidative damage, impairment of intestinal barrier and immune cell function, epigenetic and microbiota composition changes, that contribute to the pathogenesis of inflammatory bowel disease. CONCLUSIONS Cigarette smoking promotes intestinal inflammation by affecting the function and interactions among intestinal epithelium, immune system and microbiota/microbiome.
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Affiliation(s)
- Stamatia Papoutsopoulou
- Gastroenterology Research Unit, Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK
| | - Jack Satsangi
- Translational Gastroenterology Unit, Nuffield Department of Medicine, Experimental Medicine Division, University of Oxford, John Radcliffe Hospital, Oxford, UK
| | - Barry J Campbell
- Gastroenterology Research Unit, Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK
| | - Chris S Probert
- Gastroenterology Research Unit, Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK
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CUL1-Mediated Organelle Fission Pathway Inhibits the Development of Chronic Obstructive Pulmonary Disease. COMPUTATIONAL AND MATHEMATICAL METHODS IN MEDICINE 2020; 2020:5390107. [PMID: 32565880 PMCID: PMC7271281 DOI: 10.1155/2020/5390107] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Accepted: 05/04/2020] [Indexed: 12/20/2022]
Abstract
Chronic obstructive pulmonary disease (COPD) is a global high-incidence chronic airway inflammation disease. Its deterioration will lead to more serious lung lesions and even lung cancer. Therefore, it is urgent to determine the pathogenesis of COPD and find potential therapeutic targets. The purpose of this study is to reveal the molecular mechanism of COPD disease development through in-depth analysis of transcription factors and ncRNA-driven pathogenic modules of COPD. We obtained the expression profile of COPD-related microRNAs from the NCBI-GEO database and analyzed the differences among groups to identify the microRNAs significantly associated with COPD. Then, their target genes are predicted and mapped to a protein-protein interaction (PPI) network. Finally, key transcription factors and the ncRNA of the regulatory module were identified based on the hypergeometric test. The results showed that CUL1 was the most interactive gene in the highly interactive module, so it was recognized as a dysfunctional molecule of COPD. Enrichment analysis also showed that it was much involved in the biological process of organelle fission, the highest number of regulatory modules. In addition, ncRNAs, mainly composed of miR-590-3p, miR-495-3p, miR-186-5p, and transcription factors such as MYC, BRCA1, and CDX2, significantly regulate COPD dysfunction blocks. In summary, we revealed that the COPD-related target gene CUL1 plays a key role in the potential dysfunction of the disease. It promotes the proliferation of fibroblast cells in COPD patients by mediating functional signals of organelle fission and thus participates in the progress of the disease. Our research helps biologists to further understand the etiology and development trend of COPD.
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Liang C, Cao H, Cao X. Tetrandrine can alleviate inflammation and delay the growth of lung cancer during low-dose radiotherapy of non-small cell lung cancer. BIOTECHNOL BIOTEC EQ 2020. [DOI: 10.1080/13102818.2020.1736951] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022] Open
Affiliation(s)
- Chenglei Liang
- Department of Pharmacy, Xuyi County Hospital of Traditional Chinese Medicine, Xuyi, Jiangsu, P.R. China
| | - Hu Cao
- Department of Pharmacy, Xuyi County Hospital of Traditional Chinese Medicine, Xuyi, Jiangsu, P.R. China
| | - Xiaopin Cao
- Department of Pharmacy, Xuyi County Hospital of Traditional Chinese Medicine, Xuyi, Jiangsu, P.R. China
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