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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...

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Detalles Bibliográficos
Autores principales: Chu, Shi-Jye, Tang, Shih-En, Pao, Hsin-Ping, Wu, Shu-Yu, Liao, Wen-I
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
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
Descripción
Sumario: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.