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.