Rho kinase inhibition attenuates LPS-induced acute lung injury in mice partly through cytoskeletal signaling mechanism

摘要

Objective: To investigate the protection by Rho kinase inhibitor (fasudil) in lipopolysaccharide (LPS)-induced acute lung injury (ALI) and the role of Rho-associated coiled-coil-forming protein kinase 2 (ROCK2) in neutrophil transendothelial migration in the murine model. Material and Methods: Mice were assigned to three groups: sham-treated control (Sham group); LPS instillation (LPS group); protective application of fasudil and LPS instillation (Fasudil/LPS group) Indexes tested were breathing frequency, histopathological examination, lung injury score, lung wet-to-dry weight ratio, neutrophil percentage in bronchoalveolar lavage fluid (BALF), myeloperoxidase activity and ROCK2 mRNA expression in lung homogenate. Results: The permeability pulmonary edema (histopathohgical examination, lung injury score and lung wet-to-dry weight ratio) was ameliorated and the neutrophil infiltration in lungs (neutrophil percentage in BALF, myeloperoxidase activity) was depressed in response to fasudil administration. Expression of ROCK2 mRNA in the lung homogenates of the LPS-treated mice increased approximately 4-fold, however, fasudil did not affect the increase. Conclusion: Rho/Rho kinase pathway may play an important role in the pathogenesis of LPS-induced ALI, and fasudil as a ROCK inhibitor could decrease neutrophil transendothelial migration via attenuating cytoskeletal rearrangement of endothelial cells, leading to the inhibition of ALI development.