Protease-Activated Receptor-1 Antagonist Protects Against Lung Ischemia/Reperfusion Injury

Abstract

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.

Therapeutic Effects of a Novel Aptamer on Coronaviral Infection-Induced Lung Injury and Systemic Inflammatory Responses

“…Par -1 gene knock out affords protection to mice from bleomycin-induced lung inflammation and fibrosis [ 34 ]. The PAR-1 antagonist protects against ischemia reperfusion-induced lung injury [ 35 ]. PAR-1 has been proposed as a potential therapeutic target for COVID-19 [ 36 ].…”

Vitamin D3 improved hypoxia-induced lung injury by inhibiting the complement and coagulation cascade and autophagy pathway

“…PAR1-mediated enhancement of alpha (v) beta 6-dependent TGF-β activation could be one mechanism by which activation of the coagulation cascade contributes to the development of acute lung injury [ 72 ]. In an ischemia/reperfusion-induced acute lung injury (ALI) model, the specific PAR-1 antagonist SCH530348 decreased lung edema and neutrophil infiltration, attenuated thrombin production, reduced inflammatory factors, including cytokine-induced neutrophil chemoattractant-1, IL-6, and TNF-α, mitigated lung cell apoptosis, and downregulated phosphoinositide 3-kinase (PI3K), nuclear factor-κB (NF-κB), and mitogen-activated protein kinase (MAPK) pathways [ 73 ]. PAR1, PAR3, and PAR4-induced epithelial-mesenchymal transition (EMT) have been suggested to be a possible mechanism underlying the expanded (myo) fibroblast pool in lung fibrosis [ 74 ].…”

Alda-1 ameliorates air embolism-induced acute lung injury

“…The identification of MPO through immunohistochemical staining was conducted following the previously described methods. 20 In summary, formalin-fixed paraffin lung tissue sections were prepared through the processes of deparaffinization and antigen retrieval pretreatment. We inhibited endogenous peroxidase activity by immersing the sections in a solution of 3% H 2 O 2 and 100% methanol for a duration of 15 min.…”