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Xu X, Xu X, Cao J, Ruan L. MicroRNA-1258 suppresses oxidative stress and inflammation in septic acute lung injury through the Pknox1-regulated TGF-β1/SMAD3 cascade. Clinics (Sao Paulo) 2024; 79:100354. [PMID: 38640751 PMCID: PMC11031721 DOI: 10.1016/j.clinsp.2024.100354] [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: 10/09/2023] [Revised: 02/16/2024] [Accepted: 03/18/2024] [Indexed: 04/21/2024] Open
Abstract
AIM The study was to clarify the mechanism of miR-1258 targeting Prep1 (pKnox1) to control Transforming Growth Factor β1 (TGF-β1)/SMAD3 pathway in septic Acute Lung Injury (ALI)-induced oxidative stress and inflammation. METHODS BEAS-2B cells and C57BL/6 mice were used to make in vitro and in vivo septic ALI models, respectively. miR-1258 expression was checked by RT-qPCR. After transfection in the in vitro experimental model, inflammation, oxidative stress, viability, and apoptosis were observed through ELISA, MTT, and flow cytometry. RESULTS In the in vivo model after miR-1258 overexpression treatment, inflammation, oxidative stress, and lung injury were further investigated. The targeting relationship between miR-1258 and Pknox1 was tested. Low miR-1258 was expressed in septic ALI patients, LPS-treated BEAS-2B cells, and mice. Upregulated miR-1258 prevented inflammation, oxidative stress, and apoptosis but enhanced the viability of LPS-treated BEAS-2B cells. The impact of upregulated miR-1258 on LPS-treated BEAS-2B cells was mitigated by inhibiting Pknox1 expression. MiR-1258 overexpression had the alleviating effects on inflammation, oxidative stress, and lung injury of LPS-injured mice through suppressing Pknox1 expression and TGF-β1/SMAD3 cascade activation. CONCLUSIONS The study concludes that miR-1258 suppresses oxidative stress and inflammation in septic ALI through the Pknox1-regulated TGF-β1/SMAD3 cascade.
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Affiliation(s)
- XiaoMeng Xu
- Guangzhou Hospital of Integrated Traditional and West Medicine, Department of Anesthesiology, Guangzhou City, Guangdong Province, China
| | - XiaoHong Xu
- Guangzhou Hospital of Integrated Traditional and West Medicine, Department of Pediatrics, Guangzhou City, Guangdong Province, China
| | - JinLiang Cao
- Guangzhou Hospital of Integrated Traditional and West Medicine, Department of Anesthesiology, Guangzhou City, Guangdong Province, China
| | - LuoYang Ruan
- Guangzhou Hospital of Integrated Traditional and West Medicine, Department of Anesthesiology, Guangzhou City, Guangdong Province, China.
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Deng Z, Fan T, Xiao C, Tian H, Zheng Y, Li C, He J. TGF-β signaling in health, disease, and therapeutics. Signal Transduct Target Ther 2024; 9:61. [PMID: 38514615 PMCID: PMC10958066 DOI: 10.1038/s41392-024-01764-w] [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: 12/07/2022] [Revised: 08/31/2023] [Accepted: 01/31/2024] [Indexed: 03/23/2024] Open
Abstract
Transforming growth factor (TGF)-β is a multifunctional cytokine expressed by almost every tissue and cell type. The signal transduction of TGF-β can stimulate diverse cellular responses and is particularly critical to embryonic development, wound healing, tissue homeostasis, and immune homeostasis in health. The dysfunction of TGF-β can play key roles in many diseases, and numerous targeted therapies have been developed to rectify its pathogenic activity. In the past decades, a large number of studies on TGF-β signaling have been carried out, covering a broad spectrum of topics in health, disease, and therapeutics. Thus, a comprehensive overview of TGF-β signaling is required for a general picture of the studies in this field. In this review, we retrace the research history of TGF-β and introduce the molecular mechanisms regarding its biosynthesis, activation, and signal transduction. We also provide deep insights into the functions of TGF-β signaling in physiological conditions as well as in pathological processes. TGF-β-targeting therapies which have brought fresh hope to the treatment of relevant diseases are highlighted. Through the summary of previous knowledge and recent updates, this review aims to provide a systematic understanding of TGF-β signaling and to attract more attention and interest to this research area.
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Affiliation(s)
- Ziqin Deng
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Tao Fan
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Chu Xiao
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - He Tian
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Yujia Zheng
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Chunxiang Li
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
| | - Jie He
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
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Kurihara C, Sakurai R, Chuang TD, Waring AJ, Walther FJ, Rehan VK. Combination of pioglitazone, a PPARγ agonist, and synthetic surfactant B-YL prevents hyperoxia-induced lung injury in adult mice lung explants. Pulm Pharmacol Ther 2023; 80:102209. [PMID: 36907545 PMCID: PMC10205668 DOI: 10.1016/j.pupt.2023.102209] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Revised: 02/24/2023] [Accepted: 03/09/2023] [Indexed: 03/13/2023]
Abstract
INTRODUCTION Hyperoxia-induced lung injury is characterized by acute alveolar injury, disrupted epithelial-mesenchymal signaling, oxidative stress, and surfactant dysfunction, yet currently, there is no effective treatment. Although a combination of aerosolized pioglitazone (PGZ) and a synthetic lung surfactant (B-YL peptide, a surfactant protein B mimic) prevents hyperoxia-induced neonatal rat lung injury, whether it is also effective in preventing hyperoxia-induced adult lung injury is unknown. METHOD Using adult mice lung explants, we characterize the effects of 24 and 72-h (h) exposure to hyperoxia on 1) perturbations in Wingless/Int (Wnt) and Transforming Growth Factor (TGF)-β signaling pathways, which are critical mediators of lung injury, 2) aberrations of lung homeostasis and injury repair pathways, and 3) whether these hyperoxia-induced aberrations can be blocked by concomitant treatment with PGZ and B-YL combination. RESULTS Our study reveals that hyperoxia exposure to adult mouse lung explants causes activation of Wnt (upregulation of key Wnt signaling intermediates β-catenin and LEF-1) and TGF-β (upregulation of key TGF-β signaling intermediates TGF-β type I receptor (ALK5) and SMAD 3) signaling pathways accompanied by an upregulation of myogenic proteins (calponin and fibronectin) and inflammatory cytokines (IL-6, IL-1β, and TNFα), and alterations in key endothelial (VEGF-A and its receptor FLT-1, and PECAM-1) markers. All of these changes were largely mitigated by the PGZ + B-YL combination. CONCLUSION The effectiveness of the PGZ + B-YL combination in blocking hyperoxia-induced adult mice lung injury ex-vivo is promising to be an effective therapeutic approach for adult lung injury in vivo.
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Affiliation(s)
- Chie Kurihara
- Harbor-UCLA Medical Center, Department of Pediatrics, Torrance, CA, USA; The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA
| | - Reiko Sakurai
- The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA
| | - Tsai-Der Chuang
- The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA
| | - Alan J Waring
- The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA
| | - Frans J Walther
- The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA
| | - Virender K Rehan
- Harbor-UCLA Medical Center, Department of Pediatrics, Torrance, CA, USA; The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.
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Zhu CJ, Yang WG, Li DJ, Song YD, Chen SY, Wang QF, Liu YN, Zhang Y, Cheng B, Wu ZW, Cui ZC. Calycosin attenuates severe acute pancreatitis-associated acute lung injury by curtailing high mobility group box 1 - induced inflammation. World J Gastroenterol 2021; 27:7669-7686. [PMID: 34908806 PMCID: PMC8641048 DOI: 10.3748/wjg.v27.i44.7669] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Revised: 07/09/2021] [Accepted: 09/10/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Acute lung injury (ALI) is a common and life-threatening complication of severe acute pancreatitis (SAP). There are currently limited effective treatment options for SAP and associated ALI. Calycosin (Cal), a bioactive constituent extracted from the medicinal herb Radix Astragali exhibits potent anti-inflammatory properties, but its effect on SAP and associated ALI has yet to be determined.
AIM To identify the roles of Cal in SAP-ALI and the underlying mechanism.
METHODS SAP was induced via two intraperitoneal injections of L-arg (4 g/kg) and Cal (25 or 50 mg/kg) were injected 1 h prior to the first L-arg challenge. Mice were sacrificed 72 h after the induction of SAP and associated ALI was examined histologically and biochemically. An in vitro model of lipopolysaccharide (LPS)-induced ALI was established using A549 cells. Immunofluorescence analysis and western blot were evaluated in cells. Molecular docking analyses were conducted to examine the interaction of Cal with HMGB1.
RESULTS Cal treatment substantially reduced the serum amylase levels and alleviated histopathological injury associated with SAP and ALI. Neutrophil infiltration and lung tissue levels of neutrophil mediator myeloperoxidase were reduced in line with protective effects of Cal against ALI in SAP. Cal treatment also attenuated the serum levels and mRNA expression of pro-inflammatory cytokines tumor necrosis factor-α, interleukin-6, IL-1β, HMGB1 and chemokine (CXC motif) ligand 1 in lung tissue. Immunofluorescence and western blot analyses showed that Cal treatment markedly suppressed the expression of HMGB1 and phosphorylated nuclear factor-kappa B (NF-κB) p65 in lung tissues and an in vitro model of LPS-induced ALI in A549 cells suggesting a role for HGMB1 in the pathogenesis of ALI. Furthermore, molecular docking analysis provided evidence for the direct interaction of Cal with HGMB1.
CONCLUSION Cal protects mice against L-arg-induced SAP and associated ALI by attenuating local and systemic neutrophil infiltration and inflammatory response via inhibition of HGMB1 and the NF-κB signaling pathway.
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Affiliation(s)
- Chang-Ju Zhu
- Henan Medical Key Laboratory of Emergency and Trauma Research, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
- Key Laboratory of Hepatobiliary and Pancreatic Surgery and Digestive Organ Transplantation of Henan Province, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Wan-Guang Yang
- Henan Medical Key Laboratory of Emergency and Trauma Research, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
- Key Laboratory of Hepatobiliary and Pancreatic Surgery and Digestive Organ Transplantation of Henan Province, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - De-Jian Li
- Henan Medical Key Laboratory of Emergency and Trauma Research, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
- Key Laboratory of Hepatobiliary and Pancreatic Surgery and Digestive Organ Transplantation of Henan Province, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Yao-Dong Song
- Henan Medical Key Laboratory of Emergency and Trauma Research, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - San-Yang Chen
- Henan Medical Key Laboratory of Emergency and Trauma Research, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
- Key Laboratory of Hepatobiliary and Pancreatic Surgery and Digestive Organ Transplantation of Henan Province, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Qiao-Fang Wang
- Henan Medical Key Laboratory of Emergency and Trauma Research, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
- Key Laboratory of Hepatobiliary and Pancreatic Surgery and Digestive Organ Transplantation of Henan Province, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Yan-Na Liu
- Henan Medical Key Laboratory of Emergency and Trauma Research, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
- Key Laboratory of Hepatobiliary and Pancreatic Surgery and Digestive Organ Transplantation of Henan Province, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Yan Zhang
- Henan Medical Key Laboratory of Emergency and Trauma Research, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Bo Cheng
- Henan Medical Key Laboratory of Emergency and Trauma Research, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Zhong-Wei Wu
- Henan Medical Key Laboratory of Emergency and Trauma Research, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Zong-Chao Cui
- Henan Medical Key Laboratory of Emergency and Trauma Research, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
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Sunkara H, Dewan SMR. Coronavirus disease-2019: A review on the disease exacerbation via cytokine storm and concurrent management. Int Immunopharmacol 2021; 99:108049. [PMID: 34426104 PMCID: PMC8343371 DOI: 10.1016/j.intimp.2021.108049] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Revised: 07/29/2021] [Accepted: 08/04/2021] [Indexed: 12/12/2022]
Abstract
Setting up treatment strategies is the highest concern today to reduce the fatality of COVID-19. Due to a very new kind of virus attack, no specific treatment has been discovered to date. The most crucial way to dominate the disease severity is now the repurposing of drugs. In this review, we focused on the current treatment approaches targeting the crucial causative factors for the disease burden through cytokine storm or cytokine release syndrome. Several vaccines have been developed and have been applied already for prevention purposes, and several are on the way to be developed, although the effects and side effects are under observation. Presently, regulation of the immune response through intervention treatment methods has been adjusted on the basis of the COVID-19 severity stage and generally includes vaccines, immunotherapies including convalescent plasma and immunoglobulin treatment, monoclonal antibodies, cytokine therapy, complement inhibition, regenerative medicine, and repurposed anti-inflammatory and immune-regulatory drugs. Combination therapy is not acceptable in all respects because there is no concrete evidence in clinical trials or in vivo data. Target-specific drug therapies, such as inhibition of cytokine-producing signaling pathways, could be an excellent solution and thus reduce the severity of inflammation and disease severity. Therefore, gathering information about the mechanism of disease progression, possible goals, and drug efficacy of immune-based approaches to combat COVID-19 in the context of orderly review analysis is consequential.
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Affiliation(s)
- Haripriya Sunkara
- Pharmacology Division, Center for Life Sciences Research, Dhaka, Bangladesh; Department of Pharmacy Practice, Vijaya Institute of Pharmaceutical Sciences for Women, Vijayawada, India
| | - Syed Masudur Rahman Dewan
- Pharmacology Division, Center for Life Sciences Research, Dhaka, Bangladesh; Department of Pharmacy, Noakhali Science and Technology University, Noakhali, Chattogram, Bangladesh; Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
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Zeng Z, Chen W, Moshensky A, Shakir Z, Khan R, Crotty Alexander LE, Ware LB, Aldaz CM, Jacobson JR, Dudek SM, Natarajan V, Machado RF, Singla S. Cigarette Smoke and Nicotine-Containing Electronic-Cigarette Vapor Downregulate Lung WWOX Expression, Which Is Associated with Increased Severity of Murine Acute Respiratory Distress Syndrome. Am J Respir Cell Mol Biol 2021; 64:89-99. [PMID: 33058734 PMCID: PMC7780991 DOI: 10.1165/rcmb.2020-0145oc] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2020] [Accepted: 09/22/2020] [Indexed: 12/21/2022] Open
Abstract
A history of chronic cigarette smoking is known to increase risk for acute respiratory distress syndrome (ARDS), but the corresponding risks associated with chronic e-cigarette use are largely unknown. The chromosomal fragile site gene, WWOX, is highly susceptible to genotoxic stress from environmental exposures and thus an interesting candidate gene for the study of exposure-related lung disease. Lungs harvested from current versus former/never-smokers exhibited a 47% decrease in WWOX mRNA levels. Exposure to nicotine-containing e-cigarette vapor resulted in an average 57% decrease in WWOX mRNA levels relative to vehicle-treated controls. In separate studies, endothelial (EC)-specific WWOX knockout (KO) versus WWOX flox control mice were examined under ARDS-producing conditions. EC WWOX KO mice exhibited significantly greater levels of vascular leak and histologic lung injury. ECs were isolated from digested lungs of untreated EC WWOX KO mice using sorting by flow cytometry for CD31+ CD45-cells. These were grown in culture, confirmed to be WWOX deficient by RT-PCR and Western blotting, and analyzed by electric cell impedance sensing as well as an FITC dextran transwell assay for their barrier properties during methicillin-resistant Staphylococcus aureus or LPS exposure. WWOX KO ECs demonstrated significantly greater declines in barrier function relative to cells from WWOX flox controls during either methicillin-resistant S. aureus or LPS treatment as measured by both electric cell impedance sensing and the transwell assay. The increased risk for ARDS observed in chronic smokers may be mechanistically linked, at least in part, to lung WWOX downregulation, and this phenomenon may also manifest in the near future in chronic users of e-cigarettes.
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Affiliation(s)
- Zhenguo Zeng
- Department of Critical Care Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People’s Republic of China
| | - Weiguo Chen
- Division of Pulmonary, Critical Care, Sleep and Allergy Medicine, University of Illinois, Chicago, Illinois
| | | | - Zaid Shakir
- Division of Pulmonary, Critical Care, Sleep and Allergy Medicine, University of Illinois, Chicago, Illinois
| | - Raheel Khan
- Division of Pulmonary, Critical Care, Sleep and Allergy Medicine, University of Illinois, Chicago, Illinois
| | | | | | - C. M. Aldaz
- MD Anderson Cancer Center, University of Texas, Houston, Texas; and
| | - Jeffrey R. Jacobson
- Division of Pulmonary, Critical Care, Sleep and Allergy Medicine, University of Illinois, Chicago, Illinois
| | - Steven M. Dudek
- Division of Pulmonary, Critical Care, Sleep and Allergy Medicine, University of Illinois, Chicago, Illinois
| | - Viswanathan Natarajan
- Division of Pulmonary, Critical Care, Sleep and Allergy Medicine, University of Illinois, Chicago, Illinois
| | - Roberto F. Machado
- Division of Pulmonary, Critical Care, Sleep, and Occupational Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | - Sunit Singla
- Division of Pulmonary, Critical Care, Sleep and Allergy Medicine, University of Illinois, Chicago, Illinois
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Zhu HP, Huang HY, Wu DM, Dong N, Dong L, Chen CS, Chen CL, Chen YG. Regulatory mechanism of NOV/CCN3 in the inflammation and apoptosis of lung epithelial alveolar cells upon lipopolysaccharide stimulation. Mol Med Rep 2019; 21:1872-1880. [PMID: 31545412 PMCID: PMC7057825 DOI: 10.3892/mmr.2019.10655] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2019] [Accepted: 08/20/2019] [Indexed: 01/11/2023] Open
Abstract
Lipopolysaccharide (LPS) induces inflammatory stress and apoptosis. Pulmonary epithelial cell apoptosis has been shown to accelerate the progression of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS), and is the leading cause of mortality in patients with ALI/ARDS. Nephroblastoma overexpressed (NOV; also known as CCN3), an inflammatory modulator, is reported to be a biomarker in ALI. Using an LPS-induced ALI model, we investigated the expression of CCN3 and its possible molecular mechanism involved in lung alveolar epithelial cell inflammation and apoptosis. Our data revealed that LPS treatment greatly increased the level of CCN3 in human lung alveolar type II epithelial cells (A549 cell line). The A549 cells were also transfected with a specific CCN3 small interfering RNA (siRNA). CCN3 knockdown not only largely attenuated the expression of inflammatory cytokines, interleukin (IL)-1β and transforming growth factor (TGF)-β1, but also reduced the apoptotic rate of the A549 cells and altered the expression of apoptosis-associated proteins (Bcl-2 and caspase-3). Furthermore, CCN3 knockdown greatly inhibited the activation of nuclear factor (NF)-κB p65 in the A549 cells, and TGF-β/p-Smad and NF-κB inhibitors significantly decreased the expression level of CCN3 in A549 cells. In conclusion, our data indicate that CCN3 knockdown affects the expression of downstream genes through the TGF-β/p-Smad or NF-κB pathways, leading to the inhibition of cell inflammation and apoptosis in human alveolar epithelial cells.
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Affiliation(s)
- Hai-Ping Zhu
- Department of Emergency Medicine and Chest Pain Center, Clinical Research Center for Emergency and Critical Care Medicine of Shandong, Key Laboratory of Emergency and Critical Care Medicine, Key Laboratory of Cardiopulmonary‑Cerebral Resuscitation Research, Qilu Hospital, Shandong University, Jinan, Shandong 250012, P.R. China
| | - Hui-Ya Huang
- Department of Intensive Care Unit, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Deng-Min Wu
- Department of Rehabilitation Medicine, Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Nian Dong
- Department of Respiratory and Critical Care Medicine, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Li Dong
- Department of Respiratory and Critical Care Medicine, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Cheng-Shui Chen
- Department of Respiratory and Critical Care Medicine, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Chao-Lei Chen
- Department of Respiratory and Critical Care Medicine, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Yu-Guo Chen
- Department of Emergency Medicine and Chest Pain Center, Clinical Research Center for Emergency and Critical Care Medicine of Shandong, Key Laboratory of Emergency and Critical Care Medicine, Key Laboratory of Cardiopulmonary‑Cerebral Resuscitation Research, Qilu Hospital, Shandong University, Jinan, Shandong 250012, P.R. China
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Wang F, Wen Q, Zhang S, Fu Z, Liu F, Cui J, Liu J, Tian H. Sustained bile drainage decreases the organs injuries via inflammation-associated factors modulation in a severe acute pancreatitis rat model. Exp Ther Med 2019; 17:4628-4634. [PMID: 31086593 PMCID: PMC6489021 DOI: 10.3892/etm.2019.7478] [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: 07/11/2018] [Accepted: 03/07/2019] [Indexed: 11/06/2022] Open
Abstract
The timely and effective treatment for severe acute pancreatitis (SAP) is favorable to prognosis. Decompression of the bile duct might be a feasible way to decrease the progression of SAP. The present study investigated the effects of sustained bile external drainage on organs injury caused by SAP in Sprague-Dawley (SD) rats and the mechanisms involved. A total of 72 female SD rats weighting 190-230 g were randomly divided into four groups (n=18): Sham operation group (SOG), SOG + bile drainage group (BDG), SAP group, and SAP + BDG. Sodium taurocholate solution (4%; 1 mg/kg body weight) was used to set up SAP model via injection of retrograde puncture of biliopancreatic duct through the duodenum. A cannula was inserted into the bile duct and fixed externally to establish BDG model. At each time points (t=3, 6, 12; n=6), tissues from the liver, lung, and pancreas, and blood samples were collected. Serum amylase (AMY) was analyzed in all the samples. The levels of tumor necrosis factor-α (TNF-α), heme oxygenase-1 (HO-1), interleukin-10 (IL-10) and high mobility group box 1 (HMGB1) were detected by ELISA. Hematoxylin-eosin staining was performed to observe the histopathological changes, and nuclear transcription factor (NF)-κB-p65 levels in the pancreas were analyzed by western blotting. The data indicated that BDG alleviated the SAP progression and multiple organs injuries. Meanwhile, the histopathological changes of the pancreas, liver, and lungs were improved by BDG. BDG decreased the pathological scores of pancreas significantly (P<0.05). The levels of AMY, TNF-α, HMGB1, and NF-κB-p65 were significantly downregulated by BDG (P<0.05), while the level of HO-1 was upregulated and IL-10 was unchanged. In summary, BDG may attenuate the multiple organs injuries caused by SAP via downregulation of TNF-α, HMGB1, NF-κB-p65 and upregulation of HO-1.
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Affiliation(s)
- Fuhai Wang
- Department of General Surgery, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong 250014, P.R. China
| | - Qingbin Wen
- Department of Surgery, Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250014, P.R. China
| | - Sai Zhang
- Department of Surgery, Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250014, P.R. China
| | - Zhen Fu
- Department of General Surgery, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong 250014, P.R. China
| | - Feng Liu
- Department of General Surgery, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong 250014, P.R. China
| | - Jing Cui
- Department of Pathology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong 250014, P.R. China
| | - Ju Liu
- Laboratory of Microvascular Medicine, Medical Research Center, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong 250014, P.R. China
| | - Hu Tian
- Department of General Surgery, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong 250014, P.R. China
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Accelerated inflammation and oxidative stress induced by LPS in acute lung injury: Ιnhibition by ST1926. Int J Mol Med 2018; 41:3405-3421. [PMID: 29568857 PMCID: PMC5881729 DOI: 10.3892/ijmm.2018.3574] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2017] [Accepted: 02/20/2018] [Indexed: 01/01/2023] Open
Abstract
Bioavailable and less toxic synthetic retinoids, such as the atypical adamantyl retinoid ST1926, have been well developed and investigated in clinical trials for many diseases. The aim of our study was to explore the role of ST1926 in lipopolysaccharide (LPS)-induced acute lung injury (ALI) and to reveal the possible molecular mechanism. Mice were treated with LPS to induce acute lung injury followed by ST1926 administration. After LPS induction, mice administered with ST1926 showed lower inflammation infiltration in bronchoalveolar lavage (BAL) fluid, and pro-inflammatory cytokines, including interleukin-1β (IL-1β), IL-18, IL-6 and tumor necrosis factor-α (TNF-α) in serum and lung tissue samples obtained from mice. In addition, western blot assays suggested that ST1926 suppressed nuclear factor-κB (NF-κB), inhibitor-κB kinase-α (IκBα) and IκB kinase (IKKα), as well as Toll-like receptor 4 (TLR4) induced by LPS. In addition, reactive oxygen species (ROS) stimulated by LPS was also suppressed for ST1926 through inhibiting p38 and extracellular receptor kinase (ERK) signaling pathway. Taken together, the data here indicated that ST1926 may be of potential value in treating acute lung injury through inflammation and ROS suppression via inactivating TLR4/NF-κB and p38/ERK1/2 signaling pathways.
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10
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Li Y, Shi X, Yang L, Mou Y, Li Y, Dang R, Li C. Hypoxia promotes the skewed differentiation of umbilical cord mesenchymal stem cells toward type II alveolar epithelial cells by regulating microRNA-145. Gene 2017; 630:68-75. [PMID: 28789953 DOI: 10.1016/j.gene.2017.08.006] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2016] [Revised: 07/19/2017] [Accepted: 08/04/2017] [Indexed: 01/26/2023]
Abstract
Mesenchymal stem cells (MSCs) are well recognized for their ability to differentiate into type II alveolar epithelial (ATII) cells in damaged lungs, which is critical for reepithelization and recovery in acute lung injury (ALI). However, the high level of transforming growth factor-β (TGF-β) commonly seen in injured lung tissues is also able to induce MSCs to differentiate into fibroblast-like cells. In this study, we found that hypoxia could promote umbilical cord mesenchymal stem cells (UCMSCs) differentiation into ATII cells rather than into fibroblast-like cells, and this effect was mainly mediated by microRNA-145 (miR-145), which could induce the inhibition of TGF-β signaling by targeting TGF-β receptor II (TGFβRII). Clarifying the function of hypoxia in the fate determination of MSCs is important for improving stem cell-based therapies for ALI.
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Affiliation(s)
- Yang Li
- Department of Thoracic Surgery, The First Hospital of Jilin University, Changchun 130000, Jilin Province, China
| | - Xu Shi
- Central Laboratory, The First Hospital of Jilin University, Changchun 130000, Jilin Province, China
| | - Liming Yang
- Department of Nephropathy, The First Hospital of Jilin University, Changchun 130000, Jilin Province, China
| | - Yan Mou
- Department of Dermatology, The Second Hospital of Jilin University, Changchun 130000, Jilin Province, China
| | - Yingbo Li
- Central Laboratory, The First Hospital of Jilin University, Changchun 130000, Jilin Province, China
| | - Rongjing Dang
- Central Laboratory, The First Hospital of Jilin University, Changchun 130000, Jilin Province, China
| | - Changyuan Li
- Department of Thoracic Surgery, The First Hospital of Jilin University, Changchun 130000, Jilin Province, China.
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11
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Singla S, Chen J, Sethuraman S, Sysol JR, Gampa A, Zhao S, Machado RF. Loss of lung WWOX expression causes neutrophilic inflammation. Am J Physiol Lung Cell Mol Physiol 2017; 312:L903-L911. [PMID: 28283473 DOI: 10.1152/ajplung.00034.2017] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2017] [Revised: 03/01/2017] [Accepted: 03/02/2017] [Indexed: 12/18/2022] Open
Abstract
The tumor suppressor WW domain-containing oxidoreductase (WWOX) exhibits regulatory interactions with an array of transcription factors and signaling molecules that are positioned at the well-known crossroads between inflammation and cancer. WWOX is also subject to downregulation by genotoxic environmental exposures, making it of potential interest to the study of lung pathobiology. Knockdown of lung WWOX expression in mice was observed to cause neutrophil influx and was accompanied by a corresponding vascular leak and inflammatory cytokine production. In cultured human alveolar epithelial cells, loss of WWOX expression resulted in increased c-Jun- and IL-8-dependent neutrophil chemotaxis toward cell monolayers. WWOX was observed to directly interact with c-Jun in these cells, and its absence resulted in increased nuclear translocation of c-Jun. Finally, inhibition of the c-Jun-activating kinase JNK abrogated the lung neutrophil influx observed during WWOX knockdown in mice. Altogether, these observations represent a novel mechanism of pulmonary neutrophil influx that is highly relevant to the pathobiology and potential treatment of a number of different lung inflammatory conditions.
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Affiliation(s)
- Sunit Singla
- Division of Pulmonary, Critical Care, Sleep, and Allergy Medicine, Department of Medicine, University of Illinois, Chicago, Illinois
| | - Jiwang Chen
- Division of Pulmonary, Critical Care, Sleep, and Allergy Medicine, Department of Medicine, University of Illinois, Chicago, Illinois
| | - Shruthi Sethuraman
- Division of Pulmonary, Critical Care, Sleep, and Allergy Medicine, Department of Medicine, University of Illinois, Chicago, Illinois
| | - Justin R Sysol
- Division of Pulmonary, Critical Care, Sleep, and Allergy Medicine, Department of Medicine, University of Illinois, Chicago, Illinois
| | - Amulya Gampa
- Division of Pulmonary, Critical Care, Sleep, and Allergy Medicine, Department of Medicine, University of Illinois, Chicago, Illinois
| | - Shuangping Zhao
- Division of Pulmonary, Critical Care, Sleep, and Allergy Medicine, Department of Medicine, University of Illinois, Chicago, Illinois
| | - Roberto F Machado
- Division of Pulmonary, Critical Care, Sleep, and Allergy Medicine, Department of Medicine, University of Illinois, Chicago, Illinois
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12
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Aziz NM, Kamel MY, Rifaai RA. Eff ects of hemin, a heme oxygenase-1 inducer in L-arginine-induced acute pancreatitis and associated lung injury in adult male albino rats. Endocr Regul 2017; 51:20-30. [DOI: 10.1515/enr-2017-0003] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Abstract
Objective. The aim of the current study was to assess the protective outcome of hemin, a heme oxygenase-1 (HO-1) inducer on L-arginine-induced acute pancreatitis in rats. Acute pancreatitis (AP) is considered to be a critical inflammatory disorder with a major impact on the patient health. Various theories have been recommended regarding the pathophysiology of AP and associated pulmonary complications.
Methods. Twenty-four adult male albino rats were randomly divided into four groups: control group, acute pancreatitis (AP), hemin pre-treated AP group, and hemin post-treated AP group.
Results. Administration of hemin before induction of AP significantly attenuated the L-arginine- induced pancreatitis and associated pulmonary complications characterized by the increasing serum levels of amylase, lipase, tumor necrosis factor-α, nitric oxide, and histo-architectural changes in pancreas and lungs as compared to control group. Additionally, pre-treatment with hemin significantly compensated the deficits in total antioxidant capacities and lowered the elevated malondialdehyde levels observed with AP. On the other hand, post-hemin administration did not show any protection against L-arginine-induced AP.
Conclusions. The current study indicates that the induction of HO-1 by hemin pre-treatment significantly ameliorated the L-arginine-induced pancreatitis and associated pulmonary complications may be due to its anti-inflammatory and antioxidant properties.
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Affiliation(s)
- N. M. Aziz
- Assistant Professor, Department of Physiology, Faculty of Medicine, Minia University, 61111, Minia, Egypt
| | - M. Y. Kamel
- Departments of Physiology, Pharmacology and Histology, Faculty of Medicine, Minia University, Minia, Egypt
| | - R. A. Rifaai
- Departments of Physiology, Pharmacology and Histology, Faculty of Medicine, Minia University, Minia, Egypt
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13
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Nilotinib, a tyrosine kinase inhibitor exhibits protection against acute pancreatitis-induced lung and liver damage in rats. Naunyn Schmiedebergs Arch Pharmacol 2016; 390:291-300. [PMID: 27975299 DOI: 10.1007/s00210-016-1327-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2016] [Accepted: 11/29/2016] [Indexed: 12/20/2022]
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14
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Zhou J, Huang Z, Lin N, Liu W, Yang G, Wu D, Xiao H, Sun H, Tang L. Abdominal paracentesis drainage protects rats against severe acute pancreatitis-associated lung injury by reducing the mobilization of intestinal XDH/XOD. Free Radic Biol Med 2016; 99:374-384. [PMID: 27585949 DOI: 10.1016/j.freeradbiomed.2016.08.029] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2016] [Revised: 08/12/2016] [Accepted: 08/27/2016] [Indexed: 12/20/2022]
Abstract
Our previous study showed that abdominal paracentesis drainage (APD) benefits patients with severe acute pancreatitis (SAP) by delaying or avoiding multiple organ failure. However, the role of APD treatment in SAP-associated lung injury (PALI) remains unclear. Therefore, we investigated the impact of APD on PALI in rats to explore the mechanisms underlying its potential treatment benefits. A drainage tube was inserted into the right lower quadrant of rats immediately after SAP induction via the retrograde infusion of 5% sodium taurocholate into the biliopancreatic duct. Mortality rates, histological scores, wet-to-dry weight (W/D) ratios, inflammatory infiltration and oxidative stress in lung tissues were then examined. Xanthine dehydrogenase (XDH) and xanthine oxidase (XOD) activities in the sera, intestines and lungs were assessed, as was P-selectin expression. APD treatment significantly decreased pathological damage scores, oxidative stress and neutrophil infiltration in lung tissues, indicating that APD has protective effects against PALI in rats. Moreover, APD decreased the levels of serum α-amylase and trypsin and resulted in a significant decrease in XDH mobilization from the intestines, which suppressed P-selectin expression in lung tissues following SAP induction. APD treatment exerts a significant protective effect against lung injury secondary to SAP by reducing the mobilization of intestinal XDH or XOD (XDH/XOD) and the expression of P-selectin in the lungs. These findings provide novel insights into the mechanisms underlying the effectiveness of APD in patients with SAP.
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Affiliation(s)
- Jing Zhou
- The Third Military Medical University, Chongqing 400038, China; General Surgery Center of PLA, Chengdu Military General Hospital, Chengdu, Sichuan 610083, China
| | - Zhu Huang
- The Third Military Medical University, Chongqing 400038, China; General Surgery Center of PLA, Chengdu Military General Hospital, Chengdu, Sichuan 610083, China
| | - Ning Lin
- General Surgery Center of PLA, Chengdu Military General Hospital, Chengdu, Sichuan 610083, China
| | - Weihui Liu
- General Surgery Center of PLA, Chengdu Military General Hospital, Chengdu, Sichuan 610083, China
| | - Guan Yang
- General Surgery Center of PLA, Chengdu Military General Hospital, Chengdu, Sichuan 610083, China
| | - Dongye Wu
- General Surgery Center of PLA, Chengdu Military General Hospital, Chengdu, Sichuan 610083, China
| | - Heda Xiao
- General Surgery Center of PLA, Chengdu Military General Hospital, Chengdu, Sichuan 610083, China
| | - Hongyu Sun
- General Surgery Center of PLA, Chengdu Military General Hospital, Chengdu, Sichuan 610083, China.
| | - Lijun Tang
- The Third Military Medical University, Chongqing 400038, China; General Surgery Center of PLA, Chengdu Military General Hospital, Chengdu, Sichuan 610083, China.
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15
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Ateyya H, Wagih HM, El-Sherbeeny NA. Effect of tiron on remote organ injury in rats with severe acute pancreatitis induced by L-arginine. Naunyn Schmiedebergs Arch Pharmacol 2016; 389:873-85. [PMID: 27118662 DOI: 10.1007/s00210-016-1250-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2016] [Accepted: 04/19/2016] [Indexed: 12/11/2022]
Abstract
Acute pancreatitis (AP) is an acute inflammatory disorder of the pancreas that can be complicated by involvement of other remote organs. Oxidative stress is known to have a crucial role in the development of pancreatic acinar damage and one of the main causes in multisystem organ failure in experimental AP. The aim of the study was to determine the effect of tiron on pancreas and remote organ damage in L-arginine (L-Arg) induced AP rat model. Thirty-two male rats were divided in random into four groups: control, tiron, L-Arg, and tiron with L-Arg. At the end of the experiment, blood samples were withdrawn for biochemical analysis. The pancreas, lung, kidney, and liver were collected for histopathological examination. Estimation of pancreatic water content was done. Analysis of pulmonary, hepatic, renal, and pancreatic lipid peroxide levels (MDA), superoxide dismutase (SOD), and reduced glutathione (GSH) were carried out. Finally, nuclear factor kappa B (NF-κB) and transforming growth factor β1 (TGF-β1) expression in pancreatic tissue was determined. Results indicated that treatment with tiron significantly decreased lipid peroxide levels and markedly increased both SOD activity and GSH level. Moreover, histopathological analysis further confirmed that administration of tiron relatively ameliorates pancreatic acinar cells and remote organ damage. Increased immunoreactivity of NF-κB and TGF-β1 were reduced also by tiron treatment. These findings pointed out the protective role of the mitochondrial antioxidant, tiron against AP induced by L-Arg.
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Affiliation(s)
- Hayam Ateyya
- College of Pharmacy, Taibah University, El-Madinah, El-Munawarah, Saudi Arabia. .,Department of Clinical Pharmacology, Faculty of Medicine, Cairo University, Giza, Egypt.
| | - Heba M Wagih
- Medical Laboratories Technology Department, Faculty of Applied Medical Sciences, Taibah University, El-Madinah El-Munawarah, Saudi Arabia.,Pathology Department, Faculty of Medicine, Suez Canal University, Ismailia, Egypt
| | - Nagla A El-Sherbeeny
- College of Pharmacy, Taibah University, El-Madinah, El-Munawarah, Saudi Arabia.,Department of Clinical Pharmacology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt
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16
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Wujak ŁA, Blume A, Baloğlu E, Wygrecka M, Wygowski J, Herold S, Mayer K, Vadász I, Besuch P, Mairbäurl H, Seeger W, Morty RE. FXYD1 negatively regulates Na(+)/K(+)-ATPase activity in lung alveolar epithelial cells. Respir Physiol Neurobiol 2015; 220:54-61. [PMID: 26410457 DOI: 10.1016/j.resp.2015.09.008] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2015] [Revised: 09/17/2015] [Accepted: 09/20/2015] [Indexed: 01/10/2023]
Abstract
Acute respiratory distress syndrome (ARDS) is clinical syndrome characterized by decreased lung fluid reabsorption, causing alveolar edema. Defective alveolar ion transport undertaken in part by the Na(+)/K(+)-ATPase underlies this compromised fluid balance, although the molecular mechanisms at play are not understood. We describe here increased expression of FXYD1, FXYD3 and FXYD5, three regulatory subunits of the Na(+)/K(+)-ATPase, in the lungs of ARDS patients. Transforming growth factor (TGF)-β, a pathogenic mediator of ARDS, drove increased FXYD1 expression in A549 human lung alveolar epithelial cells, suggesting that pathogenic TGF-β signaling altered Na(+)/K(+)-ATPase activity in affected lungs. Lentivirus-mediated delivery of FXYD1 and FXYD3 allowed for overexpression of both regulatory subunits in polarized H441 cell monolayers on an air/liquid interface. FXYD1 but not FXYD3 overexpression inhibited amphotericin B-sensitive equivalent short-circuit current in Ussing chamber studies. Thus, we speculate that FXYD1 overexpression in ARDS patient lungs may limit Na(+)/K(+)-ATPase activity, and contribute to edema persistence.
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Affiliation(s)
- Łukasz A Wujak
- Department of Internal Medicine (Pulmonology), University of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany; Department of Lung Development and Remodelling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany; Department of Biochemistry, University of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany
| | - Anna Blume
- Department of Internal Medicine (Pulmonology), University of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany
| | - Emel Baloğlu
- Department of Sports Medicine, Medical Clinic VII, University Hospital Heidelberg, University of Heidelberg, Translational Lung Research Center (TLRC), Member of the German Center for Lung Research (DZL), Heidelberg, Germany; Department of Medical Pharmacology, Acibadem University, İstanbul, Turkey
| | - Małgorzata Wygrecka
- Department of Internal Medicine (Pulmonology), University of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany; Department of Biochemistry, University of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany
| | - Jegor Wygowski
- Department of Lung Development and Remodelling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
| | - Susanne Herold
- Department of Internal Medicine (Pulmonology), University of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany
| | - Konstantin Mayer
- Department of Internal Medicine (Pulmonology), University of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany
| | - István Vadász
- Department of Internal Medicine (Pulmonology), University of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany
| | - Petra Besuch
- Department of Pathology, Klinikum Frankfurt (Oder) GmbH, Frankfurt (Oder), Germany
| | - Heimo Mairbäurl
- Department of Biochemistry, University of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany
| | - Werner Seeger
- Department of Internal Medicine (Pulmonology), University of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany; Department of Lung Development and Remodelling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
| | - Rory E Morty
- Department of Internal Medicine (Pulmonology), University of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany; Department of Lung Development and Remodelling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.
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17
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Sharp C, Millar AB, Medford ARL. Advances in understanding of the pathogenesis of acute respiratory distress syndrome. Respiration 2015; 89:420-434. [PMID: 25925331 DOI: 10.1159/000381102] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2014] [Accepted: 02/12/2015] [Indexed: 02/05/2023] Open
Abstract
The clinical syndrome of acute lung injury (ALI) occurs as a result of an initial acute systemic inflammatory response. This can be consequent to a plethora of insults, either direct to the lung or indirect. The insult results in increased epithelial permeability, leading to alveolar flooding with a protein-rich oedema fluid. The resulting loss of gas exchange leads to acute respiratory failure and typically catastrophic illness, termed acute respiratory distress syndrome (ARDS), requiring ventilatory and critical care support. There remains a significant disease burden, with some estimates showing 200,000 cases each year in the USA with a mortality approaching 50%. In addition, there is a significant burden of morbidity in survivors. There are currently no disease-modifying therapies available, and the most effective advances in caring for these patients have been in changes to ventilator strategy as a result of the ARDS network studies nearly 15 years ago. Here, we will give an overview of more recent advances in the understanding of the cellular biology of ALI and highlight areas that may prove fertile for future disease-modifying therapies.
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Affiliation(s)
- Charles Sharp
- Academic Respiratory Unit, University of Bristol, Southmead Hospital, Westbury-on-Trym, UK
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