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Protease-Activated Receptor-1 Antagonist Protects Against Lung Ischemia/Reperfusion Injury
Protease-activated receptor (PAR)-1 is a thrombin-activated receptor that plays an essential role in ischemia/reperfusion (IR)-induced acute inflammation. PAR-1 antagonists have been shown to alleviate injuries in various IR models. However, the effect of PAR-1 antagonists on IR-induced acute lung i...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8514687/ https://www.ncbi.nlm.nih.gov/pubmed/34658893 http://dx.doi.org/10.3389/fphar.2021.752507 |
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author | Chu, Shi-Jye Tang, Shih-En Pao, Hsin-Ping Wu, Shu-Yu Liao, Wen-I |
author_facet | Chu, Shi-Jye Tang, Shih-En Pao, Hsin-Ping Wu, Shu-Yu Liao, Wen-I |
author_sort | Chu, Shi-Jye |
collection | PubMed |
description | Protease-activated receptor (PAR)-1 is a thrombin-activated receptor that plays an essential role in ischemia/reperfusion (IR)-induced acute inflammation. PAR-1 antagonists have been shown to alleviate injuries in various IR models. However, the effect of PAR-1 antagonists on IR-induced acute lung injury (ALI) has not yet been elucidated. This study aimed to investigate whether PAR-1 inhibition could attenuate lung IR injury. Lung IR was induced in an isolated perfused rat lung model. Male rats were treated with the specific PAR-1 antagonist SCH530348 (vorapaxar) or vehicle, followed by ischemia for 40 min and reperfusion for 60 min. To examine the role of PAR-1 and the mechanism of SCH530348 in lung IR injury, western blotting and immunohistochemical analysis of lung tissue were performed. In vitro, mouse lung epithelial cells (MLE-12) were treated with SCH530348 or vehicle and subjected to hypoxia-reoxygenation (HR). We found that SCH530348 decreased lung edema and neutrophil infiltration, attenuated thrombin production, reduced inflammatory factors, including cytokine-induced neutrophil chemoattractant-1, interleukin-6 and tumor necrosis factor-α, mitigated lung cell apoptosis, and downregulated the phosphoinositide 3-kinase (PI3K), nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) pathways in IR-injured lungs. In addition, SCH530348 prevented HR-induced NF-κB activation and inflammatory chemokine production in MLE12 cells. Our results demonstrate that SCH530348 exerts protective effects by blocking PAR-1 expression and modulating the downstream PI3K, NF-κB and MAPK pathways. These findings indicate that the PAR-1 antagonist protects against IR-induced ALI and is a potential therapeutic candidate for lung protection following IR injury. |
format | Online Article Text |
id | pubmed-8514687 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-85146872021-10-15 Protease-Activated Receptor-1 Antagonist Protects Against Lung Ischemia/Reperfusion Injury Chu, Shi-Jye Tang, Shih-En Pao, Hsin-Ping Wu, Shu-Yu Liao, Wen-I Front Pharmacol Pharmacology Protease-activated receptor (PAR)-1 is a thrombin-activated receptor that plays an essential role in ischemia/reperfusion (IR)-induced acute inflammation. PAR-1 antagonists have been shown to alleviate injuries in various IR models. However, the effect of PAR-1 antagonists on IR-induced acute lung injury (ALI) has not yet been elucidated. This study aimed to investigate whether PAR-1 inhibition could attenuate lung IR injury. Lung IR was induced in an isolated perfused rat lung model. Male rats were treated with the specific PAR-1 antagonist SCH530348 (vorapaxar) or vehicle, followed by ischemia for 40 min and reperfusion for 60 min. To examine the role of PAR-1 and the mechanism of SCH530348 in lung IR injury, western blotting and immunohistochemical analysis of lung tissue were performed. In vitro, mouse lung epithelial cells (MLE-12) were treated with SCH530348 or vehicle and subjected to hypoxia-reoxygenation (HR). We found that SCH530348 decreased lung edema and neutrophil infiltration, attenuated thrombin production, reduced inflammatory factors, including cytokine-induced neutrophil chemoattractant-1, interleukin-6 and tumor necrosis factor-α, mitigated lung cell apoptosis, and downregulated the phosphoinositide 3-kinase (PI3K), nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) pathways in IR-injured lungs. In addition, SCH530348 prevented HR-induced NF-κB activation and inflammatory chemokine production in MLE12 cells. Our results demonstrate that SCH530348 exerts protective effects by blocking PAR-1 expression and modulating the downstream PI3K, NF-κB and MAPK pathways. These findings indicate that the PAR-1 antagonist protects against IR-induced ALI and is a potential therapeutic candidate for lung protection following IR injury. Frontiers Media S.A. 2021-09-30 /pmc/articles/PMC8514687/ /pubmed/34658893 http://dx.doi.org/10.3389/fphar.2021.752507 Text en Copyright © 2021 Chu, Tang, Pao, Wu and Liao. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Pharmacology Chu, Shi-Jye Tang, Shih-En Pao, Hsin-Ping Wu, Shu-Yu Liao, Wen-I Protease-Activated Receptor-1 Antagonist Protects Against Lung Ischemia/Reperfusion Injury |
title | Protease-Activated Receptor-1 Antagonist Protects Against Lung Ischemia/Reperfusion Injury |
title_full | Protease-Activated Receptor-1 Antagonist Protects Against Lung Ischemia/Reperfusion Injury |
title_fullStr | Protease-Activated Receptor-1 Antagonist Protects Against Lung Ischemia/Reperfusion Injury |
title_full_unstemmed | Protease-Activated Receptor-1 Antagonist Protects Against Lung Ischemia/Reperfusion Injury |
title_short | Protease-Activated Receptor-1 Antagonist Protects Against Lung Ischemia/Reperfusion Injury |
title_sort | protease-activated receptor-1 antagonist protects against lung ischemia/reperfusion injury |
topic | Pharmacology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8514687/ https://www.ncbi.nlm.nih.gov/pubmed/34658893 http://dx.doi.org/10.3389/fphar.2021.752507 |
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