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Zhang N, Zhang Q, Zhang Z, Yu J, Fu Y, Gao J, Jiang X, Jiang P, Wen Z. IRF1 and IL1A associated with PANoptosis serve as potential immune signatures for lung ischemia reperfusion injury following lung transplantation. Int Immunopharmacol 2024; 139:112739. [PMID: 39074415 DOI: 10.1016/j.intimp.2024.112739] [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: 05/13/2024] [Revised: 07/17/2024] [Accepted: 07/18/2024] [Indexed: 07/31/2024]
Abstract
BACKGROUND Lung ischemia reperfusion injury (IRI) is the principal cause of primary graft dysfunction (PGD) after lung transplantation, affecting short-term and long-term mortality post-transplantation. PANoptosis, a newly identified form of regulated cell death involving apoptosis, necroptosis, and pyroptosis, is now considered a possible cause of organ damage and IRI. However, the specific role of PANoptosis to the development of lung IRI following lung transplantation is still not fully understood. METHODS In this study, we identified differentially expressed genes (DEGs) by analyzing the gene expression data from the GEO database related to lung IRI following lung transplantation. PANoptosis-IRI DEGs were determined based on the intersection of PANoptosis-related genes and screened DEGs. Hub genes associated with lung IRI were further screened using Lasso regression and the SVM-RFE algorithm. Additionally, the Cibersort algorithm was employed to assess immune cell infiltration and investigate the interaction between immune cells and hub genes. The upstream miRNAs that may regulate hub genes and compounds that may interact with hub genes were also analyzed. Moreover, an external dataset was utilized to validate the differential expression analysis of hub genes. Finally, the expressions of hub genes were ultimately confirmed using quantitative real-time PCR, western blotting, and immunohistochemistry in both animal models of lung IRI and lung transplant patients. RESULTS PANoptosis-related genes, specifically interferon regulatory factor 1 (IRF1) and interleukin 1 alpha (IL1A), have been identified as potential biomarkers for lung IRI following lung transplantation. In mouse models of lung IRI, both the mRNA and protein expression levels of IRF1 and IL1A were significantly elevated in lung tissues of the IRI group compared to the control group. Moreover, lung transplant recipients exhibited significantly higher protein levels of IRF1 and IL1A in PBMCs when compared to healthy controls. Patients who experienced PGD showed elevated levels of IRF1 and IL1A proteins in their blood samples. Furthermore, in patients undergoing lung transplantation, the protein levels of IRF1 and IL1A were notably increased in peripheral blood mononuclear cells (PBMCs) compared to healthy controls. In addition, patients who developed primary graft dysfunction (PGD) exhibited even higher protein levels of IRF1 and IL1A than those without PGD. Furthermore, PANoptosis was observed in the lung tissues of mouse models of lung IRI and in the PBMCs of patients who underwent lung transplantation. CONCLUSIONS Our research identified IRF1 and IL1A as biomarkers associated with PANoptosis in lung IRI, suggesting their potential utility as targets for diagnosing and therapeutically intervening in lung IRI and PGD following lung transplantation.
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Affiliation(s)
- Nan Zhang
- Department of Anesthesiology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Qingqing Zhang
- Department of Anesthesiology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Zhiyuan Zhang
- Department of Anesthesiology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Jing Yu
- Department of Anesthesiology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Yu Fu
- Department of Anesthesiology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Jiameng Gao
- Department of Anesthesiology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Xuemei Jiang
- Department of Anesthesiology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Ping Jiang
- Department of Respiratory and Critical Care Medicine, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China.
| | - Zongmei Wen
- Department of Anesthesiology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China.
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Li Q, Nie H. Advances in lung ischemia/reperfusion injury: unraveling the role of innate immunity. Inflamm Res 2024; 73:393-405. [PMID: 38265687 DOI: 10.1007/s00011-023-01844-7] [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: 10/18/2023] [Revised: 12/03/2023] [Accepted: 12/18/2023] [Indexed: 01/25/2024] Open
Abstract
BACKGROUND Lung ischemia/reperfusion injury (LIRI) is a common occurrence in clinical practice and represents a significant complication following pulmonary transplantation and various diseases. At the core of pulmonary ischemia/reperfusion injury lies sterile inflammation, where the innate immune response plays a pivotal role. This review aims to investigate recent advancements in comprehending the role of innate immunity in LIRI. METHODS A computer-based online search was performed using the PubMed database and Web of Science database for published articles concerning lung ischemia/reperfusion injury, cell death, damage-associated molecular pattern molecules (DAMPs), innate immune cells, innate immunity, inflammation. RESULTS During the process of lung ischemia/reperfusion, cellular injury even death can occur. When cells are injured or undergo cell death, endogenous ligands known as DAMPs are released. These molecules can be recognized and bound by pattern recognition receptors (PRRs), leading to the recruitment and activation of innate immune cells. Subsequently, a cascade of inflammatory responses is triggered, ultimately exacerbating pulmonary injury. These steps are complex and interrelated rather than being in a linear relationship. In recent years, significant progress has been made in understanding the immunological mechanisms of LIRI, involving novel types of cell death, the ability of receptors other than PRRs to recognize DAMPs, and a more detailed mechanism of action of innate immune cells in ischemia/reperfusion injury (IRI), laying the groundwork for the development of novel diagnostic and therapeutic approaches. CONCLUSIONS Various immune components of the innate immune system play critical roles in lung injury after ischemia/reperfusion. Preventing cell death and the release of DAMPs, interrupting DAMPs receptor interactions, disrupting intracellular inflammatory signaling pathways, and minimizing immune cell recruitment are essential for lung protection in LIRI.
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Affiliation(s)
- Qingqing Li
- Department of Respiratory and Critical Care Medicine, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuchang District, Wuhan, 430060, China
| | - Hanxiang Nie
- Department of Respiratory and Critical Care Medicine, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuchang District, Wuhan, 430060, China.
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Bejeshk MA, Najafipour H, Khaksari M, Nematollahi MH, Rajizadeh MA, Dabiri S, Beik A, Samareh-Fekri M, Sepehri G. Preparation and Evaluation of Preventive Effects of Inhalational and Intraperitoneal Injection of Myrtenol Loaded Nano-Niosomes on Lung Ischemia-Reperfusion Injury in Rats. J Pharm Sci 2024; 113:85-94. [PMID: 37931787 DOI: 10.1016/j.xphs.2023.11.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Revised: 11/01/2023] [Accepted: 11/01/2023] [Indexed: 11/08/2023]
Abstract
INTRODUCTION Ischemia-reperfusion injury (IRI) is directly related to forming reactive oxygen species, endothelial cell injury, increased vascular permeability, and the activation of neutrophils and cytokines. Niosomes are nanocarriers and an essential part of drug delivery systems. We aimed to investigate the effects of myrtenol's inhaled and intraperitoneal niosomal form, compared to its simple form, on lung ischemia reperfusion injury (LIRI). MATERIAL AND METHOD Wistar rats were divided into ten groups. Simple and niosomal forms of myrtenol were inhaled or intraperitoneally injected daily for one week prior to LIRI. We evaluated oxidative stress, apoptotic, and inflammatory indices, nitric oxide, inducible nitric oxide synthase (iNOS), endothelial nitric oxide synthase (eNOS) and histopathological indices. RESULTS Pretreatment with simple and niosomal forms of myrtenol significantly inhibited the indices of pulmonary edema, pro-inflammatory cytokines and proteins, oxidant agents, nitric oxide, iNOS, apoptotic proteins, congestion of capillaries, neutrophil infiltration, and bleeding in the alveoli. Furthermore, myrtenol increased anti-inflammatory cytokines, anti-oxidants agents, eNOS, anti-apoptotic proteins and the survival time of animals. The niosomal form of myrtenol showed a more ameliorative effect than its simple form. CONCLUSION The results showed the superior protective effect of the inhalation of myrtenol niosomal form against LIRI compared to its simple form and systemic use.
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Affiliation(s)
- Mohammad Abbas Bejeshk
- Department of Physiology and Pharmacology, Afzalipour Medical Faculty, Kerman university of Medical Sciences, Kerman, Iran; Physiology Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
| | - Hamid Najafipour
- Department of Physiology and Pharmacology, Afzalipour Medical Faculty, Kerman university of Medical Sciences, Kerman, Iran; Cardiovascular Research Center, Institute of Basic and Clinical Physiology Sciences, Kerman University of Medical Sciences, Kerman, Iran
| | - Mohammad Khaksari
- Department of Physiology and Pharmacology, Afzalipour Medical Faculty, Kerman university of Medical Sciences, Kerman, Iran; Endocrinology and Metabolism Research Center, Institute of Basic and Clinical Physiology Sciences, Kerman University of Medical Sciences, Kerman, Iran
| | | | - Mohammad Amin Rajizadeh
- Department of Physiology and Pharmacology, Afzalipour Medical Faculty, Kerman university of Medical Sciences, Kerman, Iran; Physiology Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
| | - Shahriar Dabiri
- Pathology and Stem Cells Research Center, Department of Pathology, School of Medicine, Kerman University of Medical Science, Kerman, Iran
| | - Ahmad Beik
- Department of Physiology and Pharmacology, Afzalipour Medical Faculty, Kerman university of Medical Sciences, Kerman, Iran; Cardiovascular Research Center, Institute of Basic and Clinical Physiology Sciences, Kerman University of Medical Sciences, Kerman, Iran
| | - Mitra Samareh-Fekri
- Physiology Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
| | - Gholamreza Sepehri
- Department of Physiology and Pharmacology, Afzalipour Medical Faculty, Kerman university of Medical Sciences, Kerman, Iran; Neuroscience Research Center, Kerman University of Medical Sciences, Kerman, Iran.
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Rajizadeh M, Hosseini MH, Bahrami M, Hosseini NS, Rostamabadi F, Bagheri F, Khoramipour K, Najafipour H, Bejeshk M. Comparison of preventive and therapeutic effects of continuous exercise on acute lung injury induced with methotrexate. Exp Physiol 2023; 108:1215-1227. [PMID: 37497815 PMCID: PMC10988479 DOI: 10.1113/ep091162] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Accepted: 07/10/2023] [Indexed: 07/28/2023]
Abstract
Methotrexate (Mtx) is used to treat various diseases, including cancer, arthritis and other rheumatic diseases. However, it induces oxidative stress and pulmonary inflammation by stimulating production of reactive oxygen species and cytokines. Considering the positive effects of physical activity, our goal was to investigate the preventive and therapeutic role of continuous training (CT) on Mtx-induced lung injury in rats. The rats were divided into five groups of 14 animals: a control group (C); a continuous exercise training group (CT; healthy rats that experienced CT); an acute lung injury with Mtx group (ALI); a pretreatment group with CT (the rats experienced CT before ALI induction), and a post-treatment group with CT (the rats experienced CT after ALI induction). One dose of 20 mg/kg Mtx intraperitoneal was administered in the Mtx and training groups. Forty-eight hours after the last exercise session all rats were sacrificed. According to our results, the levels of tumour necrosis factor-α (TNF-α), malondialdehyde (MDA), myeloperoxidase (MPO), GATA binding protein 3 (GATA3) and caspase-3 in the ALI group significantly increased compared to the control group, and the levels of superoxide dismutase (SOD), glutathione peroxidase (GPX), total antioxidant capacity (TAC), interleukin-10 (IL-10), forkhead box protein 3 (FOXP3), and T-bet decreased. In contrast, compared to the acute lung injury group, pretreatment and treatment with CT reduced TNF-α, MDA, MPO, GATA3 and caspase-3 and increased SOD, GPX, TAC, IL-10, FOXP3 and T-bet levels. The effects of CT pretreatment were more significant than the effects of CT post-treatment. Continuous exercise training effectively reduced oxidative stress and inflammatory cytokines and ameliorated Mtx-induced injury, and the effects of CT pretreatment were more significant than the effects of CT post-treatment. NEW FINDINGS: What is the central question of this study? Considering the high prevalence of lung injury in society, does exercise as a non-pharmacological intervention have ameliorating effects on lung injury? What is the main finding and its importance? Exercise can have healing effects on the lung after pulmonary injury through reducing inflammation, oxidative stress and apoptosis. Considering the lower side effects of exercise compared to drug treatments, the results of this study may be useful in the future.
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Affiliation(s)
- Mohammad‐Amin Rajizadeh
- Department of Physiology and PharmacologyKerman University of Medical SciencesKermanIran
- Physiology Research Center, Institute of Pulmonary PhysiologyKerman University of Medical SciencesKermanIran
| | - Mahdiyeh Haj Hosseini
- Physiology Research Center, Institute of Pulmonary PhysiologyKerman University of Medical SciencesKermanIran
- Faculty of Physical Education and Sports Sciences, Department of Exercise Physiology, Shahid Bahonar University of KermanKermanIran
| | - Mina Bahrami
- Physiology Research Center, Institute of Pulmonary PhysiologyKerman University of Medical SciencesKermanIran
- Faculty of Physical Education and Sports Sciences, Department of Exercise Physiology, Shahid Bahonar University of KermanKermanIran
| | - Najmeh Sadat Hosseini
- Physiology Research Center, Institute of Pulmonary PhysiologyKerman University of Medical SciencesKermanIran
- Faculty of Physical Education and Sports Sciences, Department of Exercise Physiology, Shahid Bahonar University of KermanKermanIran
| | - Fahimeh Rostamabadi
- Noncommunicable Diseases Research CenterBam University of Medical Sciences, BamKermanIran
- Faculty of MedicineDepartment of Medical ImmunologyRafsanjan University of Medical SciencesRafsanjanIran
| | - Fatemeh Bagheri
- Pathology and Stem Cell Research Center, Department of PathologyAfzalipour School of MedicineKermanIran
- Legal Medicine Research CenterLegal Medicine OrganizationKermanIran
| | - Kayvan Khoramipour
- Department of Physiology and PharmacologyKerman University of Medical SciencesKermanIran
| | - Hamid Najafipour
- Department of Physiology and PharmacologyKerman University of Medical SciencesKermanIran
- Physiology Research Center, Institute of Pulmonary PhysiologyKerman University of Medical SciencesKermanIran
| | - Mohammad‐Abbas Bejeshk
- Department of Physiology and PharmacologyKerman University of Medical SciencesKermanIran
- Physiology Research Center, Institute of Pulmonary PhysiologyKerman University of Medical SciencesKermanIran
- Student Research CommitteeKerman University of Medical SciencesKermanIran
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Kostyo J, Lallande AT, Sells CA, Shuda MR, Kane RR. Sulfonamide Prodrugs with a Two-Stage Release Mechanism for the Efficient Delivery of the TLR4 Antagonist TAK-242. ACS Med Chem Lett 2023; 14:110-115. [PMID: 36660224 PMCID: PMC9841982 DOI: 10.1021/acsmedchemlett.2c00492] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Accepted: 12/05/2022] [Indexed: 12/14/2022] Open
Abstract
We previously demonstrated that the potent TLR4 inhibitor TAK-242 could be covalently conjugated to pancreatic islets using a linker that afforded an effective sustained delivery of the active drug after transplant. This drug-eluting tissue achieved local inhibition of TLR4-linked inflammation and proved beneficial to the islet graft survival. Here, we describe a new family of prodrugs with a modular design featuring a self-immolative para-aminobenzyl spacer bonded directly to the TAK-242 sulfonamide nitrogen, a tether for bioconjugation, and a β-eliminative arylsulfone "trigger". The inclusion of the para-aminobenzyl spacer affords a more stable prodrug which exhibits complex drug-release kinetics due to a two-stage release mechanism. This manuscript reports the preparation and characterization of several TAK-242 prodrugs fitted with different triggers and linkers and demonstrates that these second-generation prodrugs effectively release TAK-242 while avoiding nonproductive sulfonamide hydrolysis.
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Affiliation(s)
- Jessica
H. Kostyo
- Department
of Chemistry and Biochemistry, Baylor University, Waco, Texas76798, United States
| | - Avery T. Lallande
- Department
of Chemistry and Biochemistry, Baylor University, Waco, Texas76798, United States
| | - Chloë A. Sells
- Department
of Chemistry and Biochemistry, Baylor University, Waco, Texas76798, United States
| | - Mina R. Shuda
- Department
of Chemistry and Biochemistry, Baylor University, Waco, Texas76798, United States
| | - Robert R. Kane
- Department
of Chemistry and Biochemistry, Baylor University, Waco, Texas76798, United States
- Institute
of Biomedical Studies, Baylor University, Waco, Texas76798, United States
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Lung injury induced by different negative suction pressure in patients with pneumoconiosis undergoing whole lung lavage. BMC Pulm Med 2022; 22:152. [PMID: 35459122 PMCID: PMC9034602 DOI: 10.1186/s12890-022-01952-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Accepted: 04/15/2022] [Indexed: 11/10/2022] Open
Abstract
Background Pneumoconiosis is a diffuse interstitial fibronodular lung disease, which is caused by the inhalation of crystalline silica. Whole lung lavage (WLL) is a therapeutic procedure used to treat pneumoconiosis. This study is to compare the effects of different negative pressure suction on lung injury in patients with pneumoconiosis undergoing WLL. Materials and methods A prospective study was conducted with 24 consecutively pneumoconiosis patients who underwent WLL from March 2020 to July 2020 at Emergency General Hospital, China. The patients were divided into two groups: high negative suction pressure group (group H, n = 13, negative suction pressure of 300–400 mmHg) and low negative suction pressure group (group L, n = 11, negative suction pressure of 40–50 mmHg). The arterial blood gas, lung function, lavage data, oxidative stress, and inflammatory responses to access lung injury were monitored. Results Compared with those of group H, the right and left lung residual were significantly increased in the group L (P = 0.04, P = 0.01). Potential of hydrogen (pH), arterial partial pressure of oxygen (PaO2), arterial partial pressure of carbon dioxide (PaCO2), lactic acid (LAC) and glucose (GLU) varied from point to point in time (P < 0.01, respectively). There was statistical difference in the trend of superoxide dismutase (SOD) and interleukin-10 (IL-10) over time between the two groups (P < 0.01, P = 0.02). In comparison with the group H, the levels of IL-10 (P = 0.01) and SOD (P < 0.01) in WLL fluid were significantly increased in the group L. There was no statistical difference in the trend of maximal volumtary ventilation (MVV), forced vital capacity (FVC), forced expiratory volume in one second (FEV1%), residual volume (RV), residual volume/total lung capacity (RV/TLC), carbon monoxide dispersion factor (DLCO%), forced expiratory volume in one second/ forced vital capacity (FEV1/FVC%) over time between the two groups (P > 0.05, respectively). Conclusion Low negative suction pressure has the potential benefit to reduce lung injury in patients with pneumoconiosis undergoing WLL, although it can lead to increased residual lavage fluid. Despite differing suction strategies, pulmonary function parameters including FEV1%, RV and DLCO% became worse than before WLL. Trial Registration Chinese Clinical Trial registration number ChiCTR2000031024, 21/03/2020.
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7
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Clausen E, Cantu E. Primary graft dysfunction: what we know. J Thorac Dis 2021; 13:6618-6627. [PMID: 34992840 PMCID: PMC8662499 DOI: 10.21037/jtd-2021-18] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Accepted: 05/21/2021] [Indexed: 12/19/2022]
Abstract
Many advances in lung transplant have occurred over the last few decades in the understanding of primary graft dysfunction (PGD) though effective prevention and treatment remain elusive. This review will cover prior understanding of PGD, recent findings, and directions for future research. A consensus statement updating the definition of PGD in 2016 highlights the growing complexity of lung transplant perioperative care taking into account the increasing use of high flow oxygen delivery and pulmonary vasodilators in the current era. PGD, particularly more severe grades, is associated with worse short- and long-term outcomes after transplant such as chronic lung allograft dysfunction. Growing experience have helped identify recipient, donor, and intraoperative risk factors for PGD. Understanding the pathophysiology of PGD has advanced with increasing knowledge of the role of innate immune response, humoral cell immunity, and epithelial cell injury. Supportive care post-transplant with technological advances in extracorporeal membranous oxygenation (ECMO) remain the mainstay of treatment for severe PGD. Future directions include the evolving utility of ex vivo lung perfusion (EVLP) both in PGD research and potential pre-transplant treatment applications. PGD remains an important outcome in lung transplant and the future holds a lot of potential for improvement in understanding its pathophysiology as well as development of preventative therapies and treatment.
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Affiliation(s)
- Emily Clausen
- Pulmonary, Allergy, and Critical Care Division, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Edward Cantu
- Division of Cardiovascular Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
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8
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Shepherd HM, Gauthier JM, Li W, Krupnick AS, Gelman AE, Kreisel D. Innate immunity in lung transplantation. J Heart Lung Transplant 2021; 40:562-568. [PMID: 34020867 PMCID: PMC10977655 DOI: 10.1016/j.healun.2021.03.017] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 03/12/2021] [Accepted: 03/17/2021] [Indexed: 01/11/2023] Open
Abstract
Innate immune pathways early after pulmonary transplantation have been shown to cause primary graft dysfunction (PGD) and also predispose to late graft failure. Recent studies in animal models have elucidated critical mechanisms governing such innate immune responses. Here, we discuss pathways of inflammatory cell death, triggers for sterile and infectious inflammation, and signaling cascades that mediate lung injury early after transplantation. These studies highlight potential avenues for lung-specific therapies early following lung transplantation to dampen innate immune responses and improve outcomes.
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Affiliation(s)
- Hailey M Shepherd
- Department of Surgery, Washington University School of Medicine, Saint Louis, Missouri
| | - Jason M Gauthier
- Department of Surgery, Washington University School of Medicine, Saint Louis, Missouri
| | - Wenjun Li
- Department of Surgery, Washington University School of Medicine, Saint Louis, Missouri
| | | | - Andrew E Gelman
- Department of Surgery, Washington University School of Medicine, Saint Louis, Missouri; Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, Missouri
| | - Daniel Kreisel
- Department of Surgery, Washington University School of Medicine, Saint Louis, Missouri; Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, Missouri.
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9
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Abstract
Primary graft dysfunction (PGD) is a form of acute lung injury after transplantation characterized by hypoxemia and the development of alveolar infiltrates on chest radiograph that occurs within 72 hours of reperfusion. PGD is among the most common early complications following lung transplantation and significantly contributes to increased short-term morbidity and mortality. In addition, severe PGD has been associated with higher 90-day and 1-year mortality rates compared with absent or less severe PGD and is a significant risk factor for the subsequent development of chronic lung allograft dysfunction. The International Society for Heart and Lung Transplantation released updated consensus guidelines in 2017, defining grade 3 PGD, the most severe form, by the presence of alveolar infiltrates and a ratio of PaO2:FiO2 less than 200. Multiple donor-related, recipient-related, and perioperative risk factors for PGD have been identified, many of which are potentially modifiable. Consistently identified risk factors include donor tobacco and alcohol use; increased recipient body mass index; recipient history of pulmonary hypertension, sarcoidosis, or pulmonary fibrosis; single lung transplantation; and use of cardiopulmonary bypass, among others. Several cellular pathways have been implicated in the pathogenesis of PGD, thus presenting several possible therapeutic targets for preventing and treating PGD. Notably, use of ex vivo lung perfusion (EVLP) has become more widespread and offers a potential platform to safely investigate novel PGD treatments while expanding the lung donor pool. Even in the presence of significantly prolonged ischemic times, EVLP has not been associated with an increased risk for PGD.
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Affiliation(s)
- Jake G Natalini
- Division of Pulmonary, Allergy, and Critical Care, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.,Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Joshua M Diamond
- Division of Pulmonary, Allergy, and Critical Care, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
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Wang M, Liu Y, Liang Y, Naruse K, Takahashi K. Systematic Understanding of Pathophysiological Mechanisms of Oxidative Stress-Related Conditions-Diabetes Mellitus, Cardiovascular Diseases, and Ischemia-Reperfusion Injury. Front Cardiovasc Med 2021; 8:649785. [PMID: 33928135 PMCID: PMC8076504 DOI: 10.3389/fcvm.2021.649785] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Accepted: 03/22/2021] [Indexed: 12/14/2022] Open
Abstract
Reactive oxygen species (ROS) plays a role in intracellular signal transduction under physiological conditions while also playing an essential role in diseases such as hypertension, ischemic heart disease, and diabetes, as well as in the process of aging. The influence of ROS has some influence on the frequent occurrence of cardiovascular diseases (CVD) in diabetic patients. In this review, we considered the pathophysiological relationship between diabetes and CVD from the perspective of ROS. In addition, considering organ damage due to ROS elevation during ischemia-reperfusion, we discussed heart and lung injuries. Furthermore, we have focused on the transient receptor potential (TRP) channels and L-type calcium channels as molecular targets for ROS in ROS-induced tissue damages and have discussed about the pathophysiological mechanism of the injury.
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Affiliation(s)
| | | | | | | | - Ken Takahashi
- Department of Cardiovascular Physiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
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11
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Ischemia-reperfusion Injury in the Transplanted Lung: A Literature Review. Transplant Direct 2021; 7:e652. [PMID: 33437867 PMCID: PMC7793349 DOI: 10.1097/txd.0000000000001104] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Revised: 11/04/2020] [Accepted: 11/06/2020] [Indexed: 02/07/2023] Open
Abstract
Lung ischemia-reperfusion injury (LIRI) and primary graft dysfunction are leading causes of morbidity and mortality among lung transplant recipients. Although extensive research endeavors have been undertaken, few preventative and therapeutic treatments have emerged for clinical use. Novel strategies are still needed to improve outcomes after lung transplantation. In this review, we discuss the underlying mechanisms of transplanted LIRI, potential modifiable targets, current practices, and areas of ongoing investigation to reduce LIRI and primary graft dysfunction in lung transplant recipients.
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12
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Oshima Y, Otsuki A, Endo R, Nakasone M, Harada T, Takahashi S, Inagaki Y. The Effects of Volatile Anesthetics on Lung Ischemia-Reperfusion Injury: Basic to Clinical Studies. J Surg Res 2020; 260:325-344. [PMID: 33373852 DOI: 10.1016/j.jss.2020.11.042] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Accepted: 11/01/2020] [Indexed: 02/08/2023]
Abstract
Case reports from as early as the 1970s have shown that intravenous injection of even a small dose of volatile anesthetics result in fatal lung injury. Direct contact between volatile anesthetics and pulmonary vasculature triggers chemical damage in the vessel walls. A wide variety of factors are involved in lung ischemia-reperfusion injury (LIRI), such as pulmonary endothelial cells, alveolar epithelial cells, alveolar macrophages, neutrophils, mast cells, platelets, proinflammatory cytokines, and surfactant. With a constellation of factors involved, the assessment of the protective effect of volatile anesthetics in LIRI is difficult. Multiple animal studies have reported that with regards to LIRI, sevoflurane demonstrates an anti-inflammatory effect in immunocompetent cells and an anti-apoptotic effect on lung tissue. Scattered studies have dismissed a protective effect of desflurane against LIRI. While a single-center randomized controlled trial (RCT) found that volatile anesthetics including desflurane demonstrated a lung-protective effect in thoracic surgery, a multicenter RCT did not demonstrate a lung-protective effect of desflurane. LIRI is common in lung transplantation. One study, although limited due to its small sample size, found that the use of volatile anesthetics in organ procurement surgery involving "death by neurologic criteria" donors did not improve lung graft survival. Future studies on the protective effect of volatile anesthetics against LIRI must examine not only the mechanism of the protective effect but also differences in the effects of different types of volatile anesthetics, their optimal dosage, and the appropriateness of their use in the event of marked alveolar capillary barrier damage.
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Affiliation(s)
- Yoshiaki Oshima
- Department of Anesthesiology, Yonago Medical Center, Yonago, Tottori, Japan.
| | - Akihiro Otsuki
- Division of Anesthesiology and Critical Care Medicine, Department of Surgery, Tottori University Faculty of Medicine, Yonago, Tottori, Japan
| | - Ryo Endo
- Division of Anesthesiology and Critical Care Medicine, Department of Surgery, Tottori University Faculty of Medicine, Yonago, Tottori, Japan
| | - Masato Nakasone
- Division of Anesthesiology and Critical Care Medicine, Department of Surgery, Tottori University Faculty of Medicine, Yonago, Tottori, Japan
| | - Tomomi Harada
- Division of Anesthesiology and Critical Care Medicine, Department of Surgery, Tottori University Faculty of Medicine, Yonago, Tottori, Japan
| | - Shunsaku Takahashi
- Division of Anesthesiology and Critical Care Medicine, Department of Surgery, Tottori University Faculty of Medicine, Yonago, Tottori, Japan
| | - Yoshimi Inagaki
- Division of Anesthesiology and Critical Care Medicine, Department of Surgery, Tottori University Faculty of Medicine, Yonago, Tottori, Japan
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13
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Chen JK, Guo MK, Bai XH, Chen LQ, Su SM, Li L, Li JQ. Astragaloside IV ameliorates intermittent hypoxia-induced inflammatory dysfunction by suppressing MAPK/NF-κB signalling pathways in Beas-2B cells. Sleep Breath 2020; 24:1237-1245. [PMID: 31907823 DOI: 10.1007/s11325-019-01947-8] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2019] [Revised: 09/12/2019] [Accepted: 09/18/2019] [Indexed: 11/28/2022]
Abstract
PURPOSE Intermittent hypoxia is a characteristic pathological change in obstructive sleep apnoea (OSA) that can initiate oxidative stress reaction and pro-inflammatory cytokine release. The purpose of this study was to assess the effect and protective mechanism of Astragaloside IV (AS-IV) in intermittent hypoxia-induced human lung epithelial Beas-2B cells. METHODS Human lung epithelial Beas-2B cells were exposed to intermittent hypoxia or normoxia in the absence or presence of AS-IV. MTT assay was performed to determine the cell viability. The levels of reactive oxygen species (ROS), lactate dehydrogenase (LDH), malonaldehyde (MDA), and superoxide dismutase (SOD) were measured to evaluate oxidative stress. The levels of cytokines interleukin (IL)-8, IL-1β, and IL-6 were evaluated by enzyme-linked immunosorbent assay and real-time PCR. The expression of Toll-like receptor 4 (TLR4), mitogen-activated protein kinase (MAPK), and nuclear transcription factor-kappa B (NF-κB) signalling pathways was analysed by western blot. RESULTS The results showed that AS-IV significantly reduced the levels of ROS, LDH, MDA, IL-8, IL-1β, and IL-6, and increased the level of SOD in intermittent hypoxia-induced Beas-2B cells. It also suppressed the phosphorylation of MAPKs, including P38, c-Jun N-terminal kinase and extracellular signal-regulated kinase, and inhibited the activation of the NF-κB signalling pathway by reducing the phosphorylation of IκBα and p65. CONCLUSIONS AS-IV attenuates inflammation and oxidative stress by inhibiting TLR4-mediated MAPK/NF-κB signalling pathways in intermittent hypoxia-induced Beas-2B cells.
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Affiliation(s)
- Jian-Kun Chen
- The Second Clinical College, Guangzhou University of Chinese Medicine, Guangzhou, 510120, China
- The Third Comprehensive Department, The Second Affiliated Hospital, Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou, 510120, China
| | - Ming-Kai Guo
- The Second Clinical College, Guangzhou University of Chinese Medicine, Guangzhou, 510120, China
- The Third Comprehensive Department, The Second Affiliated Hospital, Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou, 510120, China
| | - Xiao-Hui Bai
- The Second Clinical College, Guangzhou University of Chinese Medicine, Guangzhou, 510120, China
- The Third Comprehensive Department, The Second Affiliated Hospital, Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou, 510120, China
| | - Li-Qin Chen
- The Second Clinical College, Guangzhou University of Chinese Medicine, Guangzhou, 510120, China
- The Third Comprehensive Department, The Second Affiliated Hospital, Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou, 510120, China
| | - Shun-Mei Su
- The Second Clinical College, Guangzhou University of Chinese Medicine, Guangzhou, 510120, China
- The Third Comprehensive Department, The Second Affiliated Hospital, Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou, 510120, China
| | - Li Li
- The First Respiratory Department, The First People's Hospital of Kashi, Xinjiang, 844000, China.
| | - Ji-Qiang Li
- The Second Clinical College, Guangzhou University of Chinese Medicine, Guangzhou, 510120, China.
- The Third Comprehensive Department, The Second Affiliated Hospital, Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou, 510120, China.
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Dorrello NV, Vunjak-Novakovic G. Bioengineering of Pulmonary Epithelium With Preservation of the Vascular Niche. Front Bioeng Biotechnol 2020; 8:269. [PMID: 32351946 PMCID: PMC7174601 DOI: 10.3389/fbioe.2020.00269] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2019] [Accepted: 03/16/2020] [Indexed: 12/20/2022] Open
Abstract
The shortage of transplantable donor organs directly affects patients with end-stage lung disease, for which transplantation remains the only definitive treatment. With the current acceptance rate of donor lungs of only 20%, rescuing even one half of the rejected donor lungs would increase the number of transplantable lungs threefold, to 60%. We review recent advances in lung bioengineering that have potential to repair the epithelial and vascular compartments of the lung. Our focus is on the long-term support and recovery of the lung ex vivo, and the replacement of defective epithelium with healthy therapeutic cells. To this end, we first review the roles of the lung epithelium and vasculature, with focus on the alveolar-capillary membrane, and then discuss the available and emerging technologies for ex vivo bioengineering of the lung by decellularization and recellularization. While there have been many meritorious advances in these technologies for recovering marginal quality lungs to the levels needed to meet the standards for transplantation – many challenges remain, motivating further studies of the extended ex vivo support and interventions in the lung. We propose that the repair of injured epithelium with preservation of quiescent vasculature will be critical for the immediate blood supply to the lung and the lung survival and function following transplantation.
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Affiliation(s)
- N Valerio Dorrello
- Department of Pediatrics, Columbia University, New York, NY, United States
| | - Gordana Vunjak-Novakovic
- Department of Biomedical Engineering, Columbia University, New York, NY, United States.,Department of Medicine, Columbia University, New York, NY, United States
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15
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Kawashima M, Juvet SC. The role of innate immunity in the long-term outcome of lung transplantation. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:412. [PMID: 32355856 PMCID: PMC7186608 DOI: 10.21037/atm.2020.03.20] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Long-term survival after lung transplantation remains suboptimal due to chronic lung allograft dysfunction (CLAD), a progressive scarring process affecting the graft. Although anti-donor alloimmunity is central to the pathogenesis of CLAD, its underlying mechanisms are not fully elucidated and it is neither preventable nor treatable using currently available immunosuppression. Recent evidence has shown that innate immune stimuli are fundamental to the development of CLAD. Here, we examine long-standing assumptions and new concepts linking innate immune activation to late lung allograft fibrosis.
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Affiliation(s)
- Mitsuaki Kawashima
- Latner Thoracic Research Laboratories, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Stephen C Juvet
- Latner Thoracic Research Laboratories, University Health Network, University of Toronto, Toronto, Ontario, Canada
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16
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Yang JJ, Wang SJ, Gao X, Wang B, Dong YT, Bai Y, Chen Y, Gong JN, Huang YQ, An DD. Toll-Like Receptor 4 (TLR-4) Pathway Promotes Pulmonary Inflammation in Chronic Intermittent Hypoxia-Induced Obstructive Sleep Apnea. Med Sci Monit 2018; 24:7152-7161. [PMID: 30293084 PMCID: PMC6190728 DOI: 10.12659/msm.910632] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Background Studies have shown that intermittent hypoxia mimics obstructive sleep apnea in causing pulmonary inflammation, but the mechanism is not yet clear.TLR-4 is a recognized proinflammatory factor, so the purpose of this study was to assess the function of TLR-4 in pulmonary inflammation induced by chronic intermittent hypoxia simulating obstructive sleep apnea. Material/Methods Healthy male Wistar rats were divided into 3 groups (8 in each group): the normoxia control group (CG), the intermittent hypoxia group (IH), and the TLR4 antagonist TAK242 treatment group (3 mg/kg, daily), with exposure durations of 12 weeks and 16 weeks (HI). The morphological changes of lung tissue were determined with hematoxylin-eosin (HE) staining. The expressions of the TLR-4 pathway in lung tissue were tested by Western blotting and RT-PCR. The levels of IL-6 and TNF-α in serum and lung tissue were detected by enzyme-linked immunosorbent assay (ELISA). The levels of SOD and MDA in lung tissue were detected by use of SOD and MDA kits, respectively. Results After TAK242 treatment, damage to lung tissue was increased, and the expressions of TLR-4, MYD88, P65, IL-6, TNF-α, MDA, and SOD were decreased. Intermittent hypoxic exposure caused alveolar expansion, thickening of alveolar septum, and fusion of adjacent alveoli into larger cysts under intermittent hypoxia in a time-dependent manner. Compared with the CG and HI groups, the mean lining interval (MLI) become more thickened and the alveolar destruction index (DI) increased significantly in the IH group. Conclusions Chronic intermittent hypoxia causes pulmonary inflammatory response and the inflammatory pathway involved in TLR4 receptor may be one of the mechanisms that trigger lung inflammation.
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Affiliation(s)
- Jiao-Jiao Yang
- 2nd Department of Clinical Medicine, Shanxi Medical University, Taiyuan, Shanxi, China (mainland)
| | - Shu-Juan Wang
- 2nd Department of Clinical Medicine, Shanxi Medical University, Taiyuan, Shanxi, China (mainland)
| | - Xiaoling Gao
- Department of Respiratory and Critical Care Medicine, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, China (mainland)
| | - Bei Wang
- Department of Respiratory and Critical Care Medicine, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, China (mainland)
| | - Yan-Ting Dong
- Department of Respiratory and Critical Care Medicine, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, China (mainland)
| | - Yang Bai
- Jiaozuo People's Hospital, Jiaozuo, Henan, China (mainland)
| | - Yan Chen
- Department of Respiratory and Critical Care Medicine, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, China (mainland)
| | - Jian-Nan Gong
- Department of Respiratory and Critical Care Medicine, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, China (mainland)
| | - Ya-Qiong Huang
- 2nd Department of Clinical Medicine, Shanxi Medical University, Taiyuan, Shanxi, China (mainland)
| | - Dong-Dong An
- 2nd Department of Clinical Medicine, Shanxi Medical University, Taiyuan, Shanxi, China (mainland)
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17
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Shen CH, Lin JY, Chang YL, Wu SY, Peng CK, Wu CP, Huang KL. Inhibition of NKCC1 Modulates Alveolar Fluid Clearance and Inflammation in Ischemia-Reperfusion Lung Injury via TRAF6-Mediated Pathways. Front Immunol 2018; 9:2049. [PMID: 30271405 PMCID: PMC6146090 DOI: 10.3389/fimmu.2018.02049] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2018] [Accepted: 08/20/2018] [Indexed: 12/15/2022] Open
Abstract
Background: The expression of Na-K-2Cl cotransporter 1 (NKCC1) in the alveolar epithelium is responsible for fluid homeostasis in acute lung injury (ALI). Increasing evidence suggests that NKCC1 is associated with inflammation in ALI. We hypothesized that inhibiting NKCC1 would attenuate ALI after ischemia-reperfusion (IR) by modulating pathways that are mediated by tumor necrosis-associated factor 6 (TRAF6). Methods: IR-ALI was induced by producing 30 min of ischemia followed by 90 min of reperfusion in situ in an isolated and perfused rat lung model. The rats were randomly allotted into four groups comprising two control groups and two IR groups with and without bumetanide. Alveolar fluid clearance (AFC) was measured for each group. Mouse alveolar MLE-12 cells were cultured in control and hypoxia-reoxygenation (HR) conditions with or without bumetanide. Flow cytometry and transwell monolayer permeability assay were carried out for each group. Results: Bumetanide attenuated the activation of p-NKCC1 and lung edema after IR. In the HR model, bumetanide decreased the cellular volume and increased the transwell permeability. In contrast, bumetanide increased the expression of epithelial sodium channel (ENaC) via p38 mitogen-activated protein kinase (p38 MAPK), which attenuated the reduction of AFC after IR. Bumetanide also modulated lung inflammation via nuclear factor-κB (NF-κB). TRAF6, which is upstream of p38 MAPK and NF-κB, was attenuated by bumetanide after IR and HR. Conclusions: Inhibition of NKCC1 by bumetanide reciprocally modulated epithelial p38 MAPK and NF-κB via TRAF6 in IR-ALI. This interaction attenuated the reduction of AFC via upregulating ENaC expression and reduced lung inflammation.
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Affiliation(s)
- Chih-Hao Shen
- Division of Pulmonary and Critical Care, Department of Internal Medicine, Tri-Service General Hospital, Taipei, Taiwan.,Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan.,Institute of Aerospace and Undersea Medicine, National Defense Medical Center, Taipei, Taiwan
| | - Jr-Yu Lin
- Institute of Aerospace and Undersea Medicine, National Defense Medical Center, Taipei, Taiwan
| | - Yung-Lung Chang
- Department of Biochemistry, National Defense Medical Center, Taipei, Taiwan
| | - Shu-Yu Wu
- Institute of Aerospace and Undersea Medicine, National Defense Medical Center, Taipei, Taiwan
| | - Chung-Kan Peng
- Division of Pulmonary and Critical Care, Department of Internal Medicine, Tri-Service General Hospital, Taipei, Taiwan
| | - Chin-Pyng Wu
- Department of Critical Care Medicine, Landseed Hospital, Taoyuan, Taiwan
| | - Kun-Lun Huang
- Division of Pulmonary and Critical Care, Department of Internal Medicine, Tri-Service General Hospital, Taipei, Taiwan.,Institute of Aerospace and Undersea Medicine, National Defense Medical Center, Taipei, Taiwan
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18
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Penehyclidine hydrochloride preconditioning provides pulmonary and systemic protection in a rat model of lung ischaemia reperfusion injury. Eur J Pharmacol 2018; 839:1-11. [PMID: 30201378 DOI: 10.1016/j.ejphar.2018.09.012] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2018] [Revised: 09/04/2018] [Accepted: 09/05/2018] [Indexed: 11/23/2022]
Abstract
Penehyclidine hydrochloride (PHC) is a new anticholinergic agent that provides protective effects in experimental models of heart and brain ischaemia as well as reperfusion (I/R) injury. In this study, we tested the hypothesis that PHC can alleviate lung ischaemia-reperfusion injury and improve pulmonary and systemic function in rats. PHC was administered intravenously at various doses (d= 0.1, 0.3, 1, 3 mg/kg) to I/R rats. We used six indicators, including lung function, histologic examination, pulmonary oedema, oxidative stress, inflammatory responses, and apoptosis staining to quantify the pulmonary and systemic protective effects of PHC. Haematoxylin and eosin staining was used for pulmonary histologic examination. The expression of Toll-like receptor (TLR) 4, phospho-inhibitor of NF-κB (p-IκB) and nuclear factor-kappa B (NF-κB) was analysed using western blotting. ELISA was conducted to detect inflammatory mediators. Oxidative stress markers as well as myeloperoxidase (MPO) were determined using an assay kit. PHC preconditioning (with concentrations ranging from 0.3 mg/kg to 3 mg/kg 30 min before the onset of I/R) significantly reduced lung histopathological changes, down regulated TLR4, p-IκB and NF-κB expression, and decreased inflammatory mediators as well as the total number of leukocytes and neutrophils in bronchoalveolar lavage (BAL) fluid and plasma. The lung tissue contents of reactive oxygen species (ROS), malondialdehyde (MDA), and MPO as well as pulmonary oedema formation decreased, while SOD (superoxide dismutase) activity was significantly upregulated. PHC preconditioning (with concentrations ranging from 1 mg/kg to 3 mg/kg) significantly improved the lung function and attenuated the apoptotic rate. The probable mechanism for this finding is the inhibition of proinflammatory mediators via the suppression of reactive oxygen species production and the TLR4/NF-κB signalling pathway.
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19
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Yan J, Li J, Zhang L, Sun Y, Jiang J, Huang Y, Xu H, Jiang H, Hu R. Nrf2 protects against acute lung injury and inflammation by modulating TLR4 and Akt signaling. Free Radic Biol Med 2018; 121:78-85. [PMID: 29678610 DOI: 10.1016/j.freeradbiomed.2018.04.557] [Citation(s) in RCA: 108] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2017] [Revised: 04/13/2018] [Accepted: 04/16/2018] [Indexed: 12/19/2022]
Abstract
Lung injury, which is associated with systemic inflammatory responses, is a common problem with significant morbidity and mortality. Here, we examined the involvement of toll-like receptor 4 (TLR4) and nuclear factor erythroid 2-related factor 2 (Nrf2) on intestinal ischemia-reperfusion (I/R)-induced lung injury in vivo and in vitro. Analysis of lung tissues in Nrf2-knockout mice by western blotting, immunohistochemistry, and TUNEL assay, and analysis of bronchoalveolar lavage fluid showed that Nrf2 deficiency upregulated TLR4, enhanced I/R-induced lung injury, apoptosis, inflammation, and autophagy, and increased the I/R-induced inactivation of Akt. In mouse lung epithelial cells subjected to oxygen and glucose deprivation/reperfusion (OGD/Rep), Nrf2 silencing increased the OGD/Rep-induced upregulation of TLR4 and MyD88 and downregulation of HO-1, and exacerbated OGD/Rep-induced apoptosis, autophagy, and the downregulation of phospho-Akt. TLR4 silencing and Akt inhibition experiments indicated that OGD/Rep-induced cell death by suppressing Akt signaling, and Nrf2 protected lung cells by modulating TLR4 and Akt signaling. These results indicated that the Nrf2/TLR4/Akt axis plays a role in inflammation-associated lung damage, suggesting potential therapeutic targets for the treatment of lung injury.
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Affiliation(s)
- Jia Yan
- Department of Anesthesiology, Shanghai JiaoTong University School of Medicine, Center for Specialty Strategy Research of Shanghai Jiao Tong University China Hospital Development Institute, Shanghai Ninth People's Hospital, No. 639 Zhizaoju Road, Shanghai 200011, China
| | - Jingjie Li
- Department of Anesthesiology, Shanghai JiaoTong University School of Medicine, Center for Specialty Strategy Research of Shanghai Jiao Tong University China Hospital Development Institute, Shanghai Ninth People's Hospital, No. 639 Zhizaoju Road, Shanghai 200011, China
| | - Lei Zhang
- Department of Anesthesiology, Shanghai JiaoTong University School of Medicine, Center for Specialty Strategy Research of Shanghai Jiao Tong University China Hospital Development Institute, Shanghai Ninth People's Hospital, No. 639 Zhizaoju Road, Shanghai 200011, China
| | - Yu Sun
- Department of Anesthesiology, Shanghai JiaoTong University School of Medicine, Center for Specialty Strategy Research of Shanghai Jiao Tong University China Hospital Development Institute, Shanghai Ninth People's Hospital, No. 639 Zhizaoju Road, Shanghai 200011, China
| | - Jue Jiang
- Department of Anesthesiology, Shanghai JiaoTong University School of Medicine, Center for Specialty Strategy Research of Shanghai Jiao Tong University China Hospital Development Institute, Shanghai Ninth People's Hospital, No. 639 Zhizaoju Road, Shanghai 200011, China
| | - Yan Huang
- Department of Anesthesiology, Shanghai JiaoTong University School of Medicine, Center for Specialty Strategy Research of Shanghai Jiao Tong University China Hospital Development Institute, Shanghai Ninth People's Hospital, No. 639 Zhizaoju Road, Shanghai 200011, China
| | - Hui Xu
- Department of Anesthesiology, Shanghai JiaoTong University School of Medicine, Center for Specialty Strategy Research of Shanghai Jiao Tong University China Hospital Development Institute, Shanghai Ninth People's Hospital, No. 639 Zhizaoju Road, Shanghai 200011, China
| | - Hong Jiang
- Department of Anesthesiology, Shanghai JiaoTong University School of Medicine, Center for Specialty Strategy Research of Shanghai Jiao Tong University China Hospital Development Institute, Shanghai Ninth People's Hospital, No. 639 Zhizaoju Road, Shanghai 200011, China.
| | - Rong Hu
- Department of Anesthesiology, Shanghai JiaoTong University School of Medicine, Center for Specialty Strategy Research of Shanghai Jiao Tong University China Hospital Development Institute, Shanghai Ninth People's Hospital, No. 639 Zhizaoju Road, Shanghai 200011, China.
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20
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He Q, Zhao X, Bi S, Cao Y. Pretreatment with Erythropoietin Attenuates Lung Ischemia/Reperfusion Injury via Toll-Like Receptor-4/Nuclear Factor-κB (TLR4/NF-κB) Pathway. Med Sci Monit 2018; 24:1251-1257. [PMID: 29493564 PMCID: PMC5842661 DOI: 10.12659/msm.905690] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Background Lung ischemia/reperfusion injury (LIRI) is a medical problem featuring pulmonary dysfunction and damage. The present study aimed to investigate the protective effects of erythropoietin (EPO), which has been reported to be an anti-inflammatory agent, on LIRI through inhibiting the TLR-4/NF-κB signaling pathway. Material/Methods All rats were randomly divided into 3 groups (n=8): a control group, a vehicle+LIRI group, and an EPO+LIRI group. LIRI included 90-min ischemia and 120-min reperfusion, while RhEpo was administered (3 kU/kg) intraperitoneally 2 h before the operation. Levels of pulmonary inflammatory responses were examined by analyzing pulmonary permeability index (PPI), oxygenation index, histology, and expressions of inflammatory cytokines. Results Pretreatment with EPO significantly decreased lung W/D ratio, BALF leukocytes count and percentage, and PPI but increased oxygenation index compared with the LIRI group (P<0.05). More importantly, with EPO pretreatment there was less pathological damage compared with the vehicle group. Expressions of inflammatory cytokines (TNF-α, IL-6, and IL-1β) in the serum were significantly lower in the EPO group than in the LIRI group (P<0.05). In addition, gene expression and protein expression of TLR-4 and NF-κB were significantly inhibited with EPO pretreatment compared with the LIRI group (P<0.05). Conclusions Our study id the first to report that EPO protects lung injuries after LIRI through inhibiting the TLR4-NF-κB signaling pathway, which provides solid evidence for the use of EPO as a therapeutic agent for treating LIRI in the future.
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Affiliation(s)
- Qian He
- Department of Emergency Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, China (mainland)
| | - Xueshan Zhao
- West China School of Medicine, Sichuan University, Chengdu, Sichuan, China (mainland)
| | - Siwei Bi
- West China School of Medicine, Sichuan University, Chengdu, Sichuan, China (mainland)
| | - Yu Cao
- Department of Emergency Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, China (mainland)
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21
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Effects of Hypercapnia on Acute Cellular Rejection after Lung Transplantation in Rats. Anesthesiology 2017; 128:130-139. [PMID: 29023354 DOI: 10.1097/aln.0000000000001908] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
BACKGROUND Hypercapnia alleviates pulmonary ischemia-reperfusion injury, regulates T lymphocytes, and inhibits immune reaction. This study aimed to evaluate the effect of hypercapnia on acute cellular rejection in a rat lung transplantation model. METHODS Recipient rats in sham-operated (Wistar), isograft (Wistar to Wistar), and allograft (Sprague-Dawley to Wistar) groups were ventilated with 50% oxygen, whereas rats in the hypercapnia (Sprague-Dawley to Wistar) group were administered 50% oxygen and 8% carbon dioxide for 90 min during reperfusion (n = 8). Recipients were euthanized 7 days after transplantation. RESULTS The hypercapnia group showed a higher oxygenation index (413 ± 78 vs. 223 ± 24), lower wet weight-to-dry weight ratio (4.23 ± 0.54 vs. 7.04 ± 0.80), lower rejection scores (2 ± 1 vs. 4 ± 1), and lower apoptosis index (31 ± 6 vs. 57 ± 4) as compared with the allograft group. The hypercapnia group showed lower CD8 (17 ± 4 vs. 31 ± 3) and CD68 (24 ± 3 vs. 43 ± 2), lower CD8 T cells (12 ± 2 vs. 35 ± 6), and higher CD4/CD8 ratio (2.2 ± 0.6 vs. 1.1 ± 0.4) compared to the allograft group. Tumor necrosis factor-α (208 ± 40 vs. 292 ± 49), interleukin-2 (30.6 ± 6.7 vs. 52.7 ± 8.3), and interferon-γ (28.1 ± 4.9 vs. 62.7 ± 10.1) levels in the hypercapnia group were lower than those in allograft group. CD4, CD4 T cells, and interleukin-10 levels were similar between groups. CONCLUSIONS Hypercapnia ameliorated acute cellular rejection in a rat lung transplantation model.
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Abstract
Primary graft dysfunction is a form of acute injury after lung transplantation that is associated with significant short- and long-term morbidity and mortality. Multiple mechanisms contribute to the pathogenesis of primary graft dysfunction, including ischemia reperfusion injury, epithelial cell death, endothelial cell dysfunction, innate immune activation, oxidative stress, and release of inflammatory cytokines and chemokines. This article reviews the epidemiology, pathogenesis, risk factors, prevention, and treatment of primary graft dysfunction.
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Affiliation(s)
- Mary K Porteous
- Department of Medicine, Perelman School of Medicine, University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104, USA; Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine, University of Pennsylvania, 423 Guardian Drive, Philadelphia, PA 19104, USA.
| | - James C Lee
- Department of Medicine, Perelman School of Medicine, University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104, USA
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Abstract
PURPOSE OF REVIEW Lungs are extremely susceptible to injury, and despite advances in surgical management and immunosuppression, outcomes for lung transplantation are the worst of any solid organ transplant. The success of lung transplantation is limited by high rates of primary graft dysfunction because of ischemia-reperfusion injury characterized by robust inflammation, alveolar damage, and vascular permeability. This review will summarize major mechanisms of lung ischemia-reperfusion injury with a focus on the most recent findings in this area. RECENT FINDINGS Over the past 18 months, numerous studies have described strategies to limit lung ischemia-reperfusion injury in experimental settings, which often reveal mechanistic insight. Many of these strategies involved the use of various antioxidants, anti-inflammatory agents, mesenchymal stem cells, and ventilation with gaseous molecules. Further advancements have been achieved in understanding mechanisms of innate immune cell activation, neutrophil infiltration, endothelial barrier dysfunction, and oxidative stress responses. SUMMARY Methods for prevention of primary graft dysfunction after lung transplant are urgently needed, and understanding mechanisms of ischemia-reperfusion injury is critical for the development of novel and effective therapeutic approaches. In doing so, both acute and chronic outcomes of lung transplant recipients will be significantly improved.
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Tian X, Sun H, Casbon AJ, Lim E, Francis KP, Hellman J, Prakash A. NLRP3 Inflammasome Mediates Dormant Neutrophil Recruitment following Sterile Lung Injury and Protects against Subsequent Bacterial Pneumonia in Mice. Front Immunol 2017; 8:1337. [PMID: 29163464 PMCID: PMC5671513 DOI: 10.3389/fimmu.2017.01337] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2017] [Accepted: 10/03/2017] [Indexed: 02/06/2023] Open
Abstract
Sterile lung injury is an important clinical problem that complicates the course of severely ill patients. Interruption of blood flow, namely ischemia-reperfusion (IR), initiates a sterile inflammatory response in the lung that is believed to be maladaptive. The rationale for this study was to elucidate the molecular basis for lung IR inflammation and whether it is maladaptive or beneficial. Using a mouse model of lung IR, we demonstrate that sequential blocking of inflammasomes [specifically, NOD-, LRR-, and pyrin domain-containing 3 (NLRP3)], inflammatory caspases, and interleukin (IL)-1β, all resulted in an attenuated inflammatory response. IL-1β production appeared to predominantly originate in conjunction with alveolar type 2 epithelial cells. Lung IR injury recruited unactivated or dormant neutrophils producing less reactive oxygen species thereby challenging the notion that recruited neutrophils are terminally activated. However, lung IR inflammation was able to limit or reduce the bacterial burden from subsequent experimentally induced pneumonia. Notably, inflammasome-deficient mice were unable to alter this bacterial burden following IR. Thus, we conclude that the NLRP3 inflammasome, through IL-1β production, regulates lung IR inflammation, which includes recruitment of dormant neutrophils. The sterile IR inflammatory response appears to serve an important function in inducing resistance to subsequent bacterial pneumonia and may constitute a critical part of early host responses to infection in trauma.
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Affiliation(s)
- Xiaoli Tian
- Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, CA, United States
| | - He Sun
- Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, CA, United States
| | - Amy-Jo Casbon
- Department of Anatomy, University of California, San Francisco, San Francisco, CA, United States
| | - Edward Lim
- Preclinical Imaging, PerkinElmer, Hopkinton, MA, United States
| | - Kevin P Francis
- Preclinical Imaging, PerkinElmer, Hopkinton, MA, United States
| | - Judith Hellman
- Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, CA, United States.,Division of Critical Care Medicine, Department of Anthesia and Perioperative Care, University of California, San Francisco, San Francisco, CA, United States
| | - Arun Prakash
- Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, CA, United States
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Gelman AE, Fisher AJ, Huang HJ, Baz MA, Shaver CM, Egan TM, Mulligan MS. Report of the ISHLT Working Group on Primary Lung Graft Dysfunction Part III: Mechanisms: A 2016 Consensus Group Statement of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant 2017; 36:1114-1120. [PMID: 28818404 DOI: 10.1016/j.healun.2017.07.014] [Citation(s) in RCA: 68] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2017] [Accepted: 07/16/2017] [Indexed: 01/17/2023] Open
Affiliation(s)
- Andrew E Gelman
- Department of Surgery, Washington University School of Medicine, St. Louis, Missouri, USA.
| | - Andrew J Fisher
- Institute of Transplantation, Freeman Hospital and Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne, UK
| | - Howard J Huang
- Annette C. and Harold C. Simmons Transplant Institute, Baylor University Medical Center, Dallas, Texas, USA
| | - Maher A Baz
- Departments of Medicine and Surgery, University of Kentucky, Lexington, Kentucky, USA
| | - Ciara M Shaver
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - Thomas M Egan
- Department of Surgery, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Micheal S Mulligan
- Department of Surgery, Division of Cardiothoracic Surgery, University of Washington School of Medicine, Seattle, Washington, USA
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Donndorf P, Abubaker S, Vollmar B, Rimmbach C, Steinhoff G, Kaminski A. Therapeutic progenitor cell application for tissue regeneration: Analyzing the impact of toll-like receptor signaling on c-kit + cell migration following ischemia-reperfusion injury in vivo. Microvasc Res 2017; 112:87-92. [DOI: 10.1016/j.mvr.2017.03.011] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2016] [Revised: 02/23/2017] [Accepted: 03/27/2017] [Indexed: 02/08/2023]
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Zhao Q, Wu J, Lin Z, Hua Q, Zhang W, Ye L, Wu G, Du J, Xia J, Chu M, Hu X. Resolvin D1 Alleviates the Lung Ischemia Reperfusion Injury via Complement, Immunoglobulin, TLR4, and Inflammatory Factors in Rats. Inflammation 2017; 39:1319-33. [PMID: 27145782 PMCID: PMC4951504 DOI: 10.1007/s10753-016-0364-9] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Lung ischemia-reperfusion injury (LIRI) is still an unsolved medical issue, which negatively affects the prognosis of many lung diseases. The aim of this study is to determine the effects of RvD1 on LIRI and the potential mechanisms involved. The results revealed that the levels of complement, immunoglobulin, cytokines, sICAM-1, MPO, MDA, CINC-1, MCP-1, ANXA-1, TLR4, NF-κBp65, apoptosis index, and pulmonary permeability index were increased, whereas the levels of SOD, GSH-PX activity, and oxygenation index were decreased in rats with LIRI. Except for ANXA-1, these responses induced by LIRI were significantly inhibited by RvD1 treatment. In addition, LIRI-induced structure damages of lung tissues were also alleviated by RvD1 as shown by H&E staining and transmission electron microscopy. The results suggest that RvD1 may play an important role in protection of LIRI via inhibition of complement, immunoglobulin, and neutrophil activation; down-regulation of TLR4/NF-κB; and the expression of a variety of inflammatory factors.
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Affiliation(s)
- Qifeng Zhao
- The Children's Department of Cardiovascular and Thoracic Surgery, Children's Heart Center, The Second Affiliated Hospital and Yuying Children's Hospital, Institute of Cardiovascular Development and Translational Medicine, Wenzhou Medical University, Wenzhou, 325027, People's Republic of China
| | - Ji Wu
- Wuhan Medical & Healthcare Center for Woman and Children, Wuhan, People's Republic of China
| | - Zhiyong Lin
- The Children's Department of Cardiovascular and Thoracic Surgery, Children's Heart Center, The Second Affiliated Hospital and Yuying Children's Hospital, Institute of Cardiovascular Development and Translational Medicine, Wenzhou Medical University, Wenzhou, 325027, People's Republic of China
| | - Qingwang Hua
- The Children's Department of Cardiovascular and Thoracic Surgery, Children's Heart Center, The Second Affiliated Hospital and Yuying Children's Hospital, Institute of Cardiovascular Development and Translational Medicine, Wenzhou Medical University, Wenzhou, 325027, People's Republic of China
| | - Weixi Zhang
- The Children's Department of Respiration Medicine, The Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, 325027, People's Republic of China
| | - Leping Ye
- The Children's Department of Respiration Medicine, The Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, 325027, People's Republic of China
| | - Guowei Wu
- The Children's Department of Cardiovascular and Thoracic Surgery, Children's Heart Center, The Second Affiliated Hospital and Yuying Children's Hospital, Institute of Cardiovascular Development and Translational Medicine, Wenzhou Medical University, Wenzhou, 325027, People's Republic of China
| | - Jie Du
- The Children's Department of Cardiovascular and Thoracic Surgery, Children's Heart Center, The Second Affiliated Hospital and Yuying Children's Hospital, Institute of Cardiovascular Development and Translational Medicine, Wenzhou Medical University, Wenzhou, 325027, People's Republic of China
| | - Jie Xia
- The Children's Department of Cardiovascular and Thoracic Surgery, Children's Heart Center, The Second Affiliated Hospital and Yuying Children's Hospital, Institute of Cardiovascular Development and Translational Medicine, Wenzhou Medical University, Wenzhou, 325027, People's Republic of China
| | - Maoping Chu
- The Children's Department of Cardiovascular Medicine, Children's Heart Center, the Second Affiliated Hospital and Yuying Children's Hospital, Institute of Cardiovascular Development and Translational Medicine, Wenzhou Medical University, Wenzhou, 325027, People's Republic of China
| | - Xingti Hu
- The Children's Department of Cardiovascular and Thoracic Surgery, Children's Heart Center, The Second Affiliated Hospital and Yuying Children's Hospital, Institute of Cardiovascular Development and Translational Medicine, Wenzhou Medical University, Wenzhou, 325027, People's Republic of China.
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Sheng W, Yang HQ, Chi YF, Niu ZZ, Lin MS, Long S. Independent risk factors for hypoxemia after surgery for acute aortic dissection. Saudi Med J 2016. [PMID: 26219444 PMCID: PMC4549590 DOI: 10.15537/smj.2015.8.11583] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Objectives: To determine risk factors associated with postoperative hypoxemia after surgery for acute type A aortic dissection. Methods: We retrospectively analyzed the clinical data of 192 patients with acute type A aortic dissection who underwent surgery in Qingdao Municipal Hospital, Medical College of Qingdao University, Qingdao, China between January 2007 and December 2013. Patients were divided into hypoxemia group (n=55) [arterial partial pressure of oxygen (PaO2)/fraction of inspired oxygen (FiO2) ≤200 mm Hg] and non-hypoxemia group (n=137) [PaO2/FiO2 >200 mm Hg]. Perioperative clinical data were analyzed and compared between the 2 groups. Results: The incidence of postoperative hypoxemia after surgery for acute aortic dissection was 28.6% (55/192). Perioperative death occurred in 13 patients (6.8%). Multivariate regression identified body mass index (BMI) >25 kg/m2 (OR=21.929, p=0.000), deep hypothermic circulatory arrest (DHCA) (OR=11.551, p=0.000), preoperative PaO2/FiO2 ≤300 mm Hg (OR=7.830, p=0.000) and blood transfusion >6U in 24 hours postoperatively (OR=12.037, p=0.000) as independent predictors of postoperative hypoxemia for patients undergoing Stanford A aortic dissection surgery. Conclusion: Our study demonstrated that BMI >25 kg/m2, DHCA, preoperative PaO2/FiO2 ≤300 mm Hg, and blood transfusion in 24 hours postoperatively >6U were independent risk factors of the hypoxemia after acute type A aortic dissection aneurysm surgery.
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Affiliation(s)
- Wei Sheng
- Department of Cardiovascular Surgery, Qingdao Municipal Hospital, Medical College of Qingdao University, Qingdao, China. E-mail.
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Avlas O, Srara S, Shainberg A, Aravot D, Hochhauser E. Silencing cardiomyocyte TLR4 reduces injury following hypoxia. Exp Cell Res 2016; 348:115-122. [PMID: 27448767 DOI: 10.1016/j.yexcr.2016.07.020] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2016] [Revised: 07/17/2016] [Accepted: 07/18/2016] [Indexed: 01/04/2023]
Abstract
Toll-like receptor 4 (TLR4), the receptor for lipopolysaccharide (LPS) of gram-negative pathogens expressed in the heart, is activated by several endogenous ligands associated with tissue injury in response to myocardial infarction (MI). The aim of this study was to investigate the involvement of TLR4 signaling in cardiomyocytes dysfunction following hypoxia (90min) using multiple methodologies such as knocking down TLR4 and small interfering RNA (siTLR4). Cardiomyocytes of C57Bl/6 mice (WT) subjected to hypoxic stress showed increased cardiac release of LDH, HMGB1, IκB, TNF-α and myocardial apoptotic and necrotic markers (BAX, PI) compared to TLR4 knock out mice (TLR4KO). Treating these cardiomyocytes with siRNA against TLR4 decreased the damage markers (LDH, IκB, TNF-α). TLR4 silencing during hypoxic stress resulted in the activation of the p-AKT and p-GSK3β (by ∼25%). The latter is an indicator that there is a reduction of mitochondrial permeability transition pore (mPTP) opening following hypoxic myocardial induced injury leading to preserved mitochondrial membrane potential. Silencing TLR4 in cardiomyocytes improved cell survival following hypoxic injury through activation of the AKT/GSK3β pathway, reduced inflammatory and apoptotic signals. These findings suggest that TLR4 may serve as a potential target in the treatment of ischemic myocardial injury. Moreover, RNA interfering targeting TLR4 expression represents a therapeutic strategy.
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Affiliation(s)
- Orna Avlas
- The Mina & Everard Goodman Faculty of Life Sciences Bar-Ilan University, Ramat Gan, Israel; The Cardiac Research Laboratory of the Department of Cardiothoracic Surgery, Felsenstein Medical Research Center, Rabin Medical Center, Tel Aviv University, Petah Tikva, Israel
| | - Smadar Srara
- The Mina & Everard Goodman Faculty of Life Sciences Bar-Ilan University, Ramat Gan, Israel
| | - Asher Shainberg
- The Mina & Everard Goodman Faculty of Life Sciences Bar-Ilan University, Ramat Gan, Israel
| | - Dan Aravot
- The Cardiac Research Laboratory of the Department of Cardiothoracic Surgery, Felsenstein Medical Research Center, Rabin Medical Center, Tel Aviv University, Petah Tikva, Israel
| | - Edith Hochhauser
- The Cardiac Research Laboratory of the Department of Cardiothoracic Surgery, Felsenstein Medical Research Center, Rabin Medical Center, Tel Aviv University, Petah Tikva, Israel.
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Hüppe T, Lorenz D, Maurer F, Albrecht FW, Schnauber K, Wolf B, Sessler DI, Volk T, Fink T, Kreuer S. Exhalation of volatile organic compounds during hemorrhagic shock and reperfusion in rats: an exploratory trial. J Breath Res 2016; 10:016016. [DOI: 10.1088/1752-7155/10/1/016016] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
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Abstract
Toll-like receptor 4 (TLR4), one of pattern recognition receptors (PRRs) which can recognize pathogen-associated molecular patterns (PAMPs) and danger associated molecular patterns (DAMPs), regulates the innate immune system at early phase by presenting danger signals to the host. Because of its role in immune response, inflammation regulation and tumorigenesis, a growing number of oncology studies, including those on hepatocellular carcinoma (HCC), have started to focus on TLR4; however, there are very few studies on the specific mechanism of TLR4 in HCC. Pathogenesis of HCC involves cell damage and eventual cell malignant transformation caused by chronic inflammation, and this process involves many molecular pathways. Therefore, clarifying the role of TLR4 in the occurrence, development, metastasis and treatment of HCC has important biological significance and clinical value. This review reviews the role of TLR4 in HCC.
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Takahashi M, Chen-Yoshikawa TF, Menju T, Ohata K, Kondo T, Motoyama H, Hijiya K, Aoyama A, Date H. Inhibition of Toll-like receptor 4 signaling ameliorates lung ischemia-reperfusion injury in acute hyperglycemic conditions. J Heart Lung Transplant 2016; 35:815-22. [PMID: 26922276 DOI: 10.1016/j.healun.2015.12.032] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2015] [Revised: 10/26/2015] [Accepted: 12/15/2015] [Indexed: 11/26/2022] Open
Abstract
BACKGROUND Recent lung transplantation studies have shown that peri-operative hyperglycemia is an important factor affecting recipient survival; however, its underlying mechanisms are not well understood. We hypothesized that acute hyperglycemia exacerbates lung ischemia-reperfusion injury (IRI) through up-regulation of Toll-like receptor 4 (TLR4) signaling pathways. METHODS C57BL/6Ncr mice were divided into 3 treatment groups: sham; IRI; and IRI under acute hyperglycemic conditions (IRI+HG). Mice in the IRI and IRI+HG groups were exposed to IRI via clamping the left hilum for 1 hour, followed by reperfusion for 2 hours. Acute hyperglycemia was established by glucose injection. The severity of lung injury and TLR4 signaling pathway activity were assessed. Further, we performed a pharmacologic blockade of TLR4 signaling to determine the effect of TLR4 signaling inhibition on lung injury. RESULTS Compared with normoglycemic mice, hyperglycemic mice had 2-fold higher blood glucose levels (p < 0.001). Pulmonary compliance was significantly lower, and airway resistance was significantly higher, in the IRI+HG group than in the IRI group (p < 0.05). Levels of inflammatory cytokines in bronchoalveolar lavage fluid were significantly higher in the IRI+HG group than in the IRI group. Correspondingly, TLR4 signaling pathways were up-regulated in the IRI+HG group. Moreover, pharmacologic inhibition of TLR4 signaling significantly decreased lung injury markers under hyperglycemic conditions. CONCLUSIONS Acute hyperglycemia exacerbated lung IRI and was associated with up-regulation of TLR4 signaling pathways. Pharmacologic inhibition of TLR4 signaling ameliorated lung IRI with acute hyperglycemia. Targeting TLR4 appears to be a promising approach to managing coexisting pathologies in lung transplant recipients.
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Affiliation(s)
- Mamoru Takahashi
- Department of Thoracic Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | | | - Toshi Menju
- Department of Thoracic Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Keiji Ohata
- Department of Thoracic Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Takeshi Kondo
- Department of Thoracic Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Hideki Motoyama
- Department of Thoracic Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Kyoko Hijiya
- Department of Thoracic Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Akihiro Aoyama
- Department of Thoracic Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Hiroshi Date
- Department of Thoracic Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.
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Wang J, He GZ, Wang YK, Zhu QK, Chen W, Guo T. TLR4-HMGB1-, MyD88- and TRIF-dependent signaling in mouse intestinal ischemia/reperfusion injury. World J Gastroenterol 2015; 21:8314-8325. [PMID: 26217083 PMCID: PMC4507101 DOI: 10.3748/wjg.v21.i27.8314] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2014] [Accepted: 05/21/2015] [Indexed: 02/06/2023] Open
Abstract
AIM: To characterize high-mobility group protein 1-toll-like receptor 4 (HMGB1-TLR4) and downstream signaling pathways in intestinal ischemia/reperfusion (I/R) injury.
METHODS: Forty specific-pathogen-free male C57BL/6 mice were randomly divided into five groups (n = 8 per group): sham, control, anti-HMGB1, anti-myeloid differentiation gene 88 (MyD88), and anti-translocating-chain-associating membrane protein (TRIF) antibody groups. Vehicle with the control IgG antibody, anti-HMGB1, anti-MyD88, or anti-TRIF antibodies (all 1 mg/kg, 0.025%) were injected via the caudal vein 30 min prior to ischemia. After anesthetization, the abdominal wall was opened and the superior mesenteric artery was exposed, followed by 60 min mesenteric ischemia and then 60 min reperfusion. For the sham group, the abdominal wall was opened for 120 min without I/R. Levels of serum nuclear factor (NF)-κB p65, interleukin (IL)-6, and tumor necrosis factor (TNF)-α were measured, along with myeloperoxidase activity in the lung and liver. In addition,morphologic changes that occurred in the lung and intestinal tissues were evaluated. Levels of mRNA transcripts encoding HMGB1 and NF-κB were measured by real-time quantitative PCR, and levels of HMGB1 and NF-κB protein were measured by Western blot. Results were analyzed using one-way analysis of variance.
RESULTS: Blocking HMGB1, MyD88, and TRIF expression by injecting anti-HMGB1, anti-MyD88, or anti-TRIF antibodies prior to ischemia reduced the levels of inflammatory cytokines in serum; NF-κB p65: 104.64 ± 11.89, 228.53 ± 24.85, 145.00 ± 33.63, 191.12 ± 13.22, and 183.73 ± 10.81 (P < 0.05); IL-6: 50.02 ± 6.33, 104.91 ± 31.18, 62.28 ± 6.73, 85.90 ± 17.37, and 78.14 ± 7.38 (P < 0.05); TNF-α, 43.79 ± 4.18, 70.81 ± 6.97, 52.76 ± 5.71, 63.19 ± 5.47, and 59.70 ± 4.63 (P < 0.05) for the sham, control, anti-HMGB1, anti-MyD88, and anti-TRIF groups, respectively (all in pg/mL).Antibodies also alleviated tissue injury in the lung and small intestine compared with the control group in the mouse intestinal I/R model. The administration of anti-HMGB1, anti-MyD88, and anti-TRIF antibodies markedly reduced damage caused by I/R, for which anti-HMGB1 antibody had the most obvious effect.
CONCLUSION: HMGB1 and its downstream signaling pathway play important roles in the mouse intestinal I/R injury, and the effect of the TRIF-dependent pathway is slightly greater.
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Phelan P, Merry HE, Hwang B, Mulligan MS. Differential toll-like receptor activation in lung ischemia reperfusion injury. J Thorac Cardiovasc Surg 2015; 149:1653-61. [PMID: 25911179 DOI: 10.1016/j.jtcvs.2015.02.045] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2014] [Revised: 02/10/2015] [Accepted: 02/19/2015] [Indexed: 12/20/2022]
Abstract
OBJECTIVE The requirement for toll-like receptors (TLRs) in lung ischemia reperfusion injury (LIRI) has been demonstrated but not fully characterized. Previously, we reported that TLR-4 is required by alveolar macrophages but not pulmonary endothelial or epithelial cells for development of LIRI. Additionally, we demonstrated differential patterns of mitogen-activated protein kinase (MAPK) activation and cytokine release in these cell types during LIRI. Here, we sought to determine whether these differences in activation responses are related to cell-specific TLR activation requirements. METHODS Primary cultures of alveolar macrophages, pulmonary endothelial, and immortalized epithelial cells were pretreated with TLR-2 or TLR-4 short interference RNA (ribonucleic acid) before hypoxia and reoxygenation. Cell lysates and media were analyzed for receptor knockdown, MAPK activation, and cytokine production. Rats were pretreated with TLR-2 or TLR-4 short interference RNA before lung ischemia reperfusion and changes in lung vascular permeability were assessed. RESULTS Knockdown of TLR-2 in alveolar macrophages did not affect MAPK phosphorylation or cytokine secretion. Conversely, TLR-2 knockdown in pulmonary endothelial and epithelial cells demonstrated significant reductions in extracellular signal-regulated kinase 1/2 activation and cytokine secretion. The lung permeability index in LIRI was decreased by TLR-4 but not TLR-2. CONCLUSIONS Differential TLR signaling and MAPK activation in response to LIRI seem to be cell specific. Short interference RNA provides an outstanding tool for examination of the underlying mechanism.
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Affiliation(s)
- Patrick Phelan
- Department of Surgery, University of Washington School of Medicine, Seattle, Wash
| | - Heather E Merry
- Department of Surgery, University of Washington School of Medicine, Seattle, Wash
| | - Billanna Hwang
- Department of Surgery, University of Washington School of Medicine, Seattle, Wash; Center for Lung Biology, University of Washington, Seattle, Wash.
| | - Michael S Mulligan
- Department of Surgery, University of Washington School of Medicine, Seattle, Wash; Center for Lung Biology, University of Washington, Seattle, Wash
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