Role of the Rho/ROCK signaling pathway in the protective effects of fasudil against acute lung injury in septic rats

摘要

Fasudil, which is primarily prescribed to treat cerebral vasospasm, may also inhibit systemic inflammation and prevent sepsis-induced acute lung injury (ALI) in rats, although the mechanisms remain elusive. The purpose of the present study was to investigate the role of the rhodopsin (Rho)/Rho-associated protein kinase (ROCK) signaling pathway in the protective effects of fasudil on ALI in septic rats. A total of 60 Wistar rats were pretreated with fasudil (30 mg/kg) through intraperitoneal injections 1 h prior to cecal ligation and puncture. Administration of fasudil led to reductions in polymorphonuclear neutrophil counts, and the protein concentrations of tumor necrosis factor-alpha, interleukin (IL)-1 beta and IL-6 in the bronchoalveolar lavage fluid of rats with sepsis-induced ALI. The results demonstrated that fasudil decreased sepsis-induced bacteremia. In addition, fasudil effectively reduced the Evans blue content, wet/dry lung weight ratio, lung injury score, and expression levels of malondialdehyde and myeloperoxidase. However, the superoxide dismutase activity in the lung tissue of the rats was increased. Activated caspase-3 activity in lung tissue was reduced to 29% by fasudil. Furthermore, the expression of Rho and ROCK1 was significantly downregulated, and the phosphorylation of myosin phosphatase-targeting subunit 1 in lung tissues was markedly decreased, whereas the protein expression levels of zonula occludens 1 were increased in fasudil-treated rats (P0.05). In the in vitro experiments, vascular endothelial growth factor, intracellular adhesion molecule 1 and vascular cell adhesion molecule 1 secreted from human pulmonary microvascular endothelial cells treated with lipopolysaccharide (LPS) were attenuated by fasudil. Fasudil also reduced the fluorescence intensity of filamentous actin induced by LPS. Taken together, the results of the present study demonstrated that fasudil was able to improve endothelial permeability and inhibit inflammation, oxidative stress and cellular apoptosis in order to alleviate ALI in septic rats through inhibition of the Rho/ROCK signaling pathway.