Protection of ripasudil, a Rho kinase inhibitor, in lipopolysaccharides-induced acute pneumonia in mice

摘要

Pneumonia is a major cause of morbidity and mortality of infectious diseases, especially in children. Ripasudil (K-115), a selective ROCK inhibitor, is a promising emerging drug against glaucoma, and reported to have anti-inflammatory activity. However, the anti-inflammatory effect of ripasudil still remains unclear in pneumonia. The goal of this study is to investigate the role and the underlying mechanism of ripasudil in pneumonia. BALB/c mice were used to establish an acute pneumonia model of mice by injection of lipopolysaccharide (LPS) intraperitoneally. Ripasudil (0.5 mg, 1 mg, 2 mg) was administrated 1 h before the induction of LPS. The histoligical change of lung tissue was evaluated by hematoxylin-eosin staining and lung wet/dry ratio. Inflammatory cytokines secretion, oxidant-antioxidant factors levels were measured. Cell apoptosis was examined using TNUEL assay. Western blot and qRT-PCR was used to determine gene expressions. Results showed that ripasudil significantly attenuated LPS-induced histological changes, reduced the production of pro-inflammatory cytokines, and alleviated LPS-induced oxidative stress in mice. LPS-induced cell apoptosis and associated protein expression changes were attenuated by ripasudil. Besides, ripasudil reduced the expression of RhoA, and decreased the activity of RhoA/ROCK signaling. Finally, the level of RhoA and eNOS from pneumonia patients exhibited negatively correlated, whereas the level of RhoA was higher while eNOS level was lower than that in the healthy control. The results of the present study indicate that ripasudil attenuate LPS-induced pneumonia in BALB/c mice by ameliorating inflammation, oxidative stress and apoptosis through inhibiting RhoA/ROCK signaling pathway. Ripasudil might be a novel and effective drug for the treatment of pneumonia.