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01 April 2010

Fasudil attenuates lipopolysaccharide-induced acute lung injury in mice through the Rho/Rho kinase pathway

Yan LiABCDEF, Yiling WuADG, Zhi WangAEF, Xuan-hong ZhangAEF, Wei-kang WuABCDEFG

Med Sci Monit 2010; 16(4): BR112-118 :: ID: 878494

Abstract

Background
The transendothelial migration of polymorphonuclear leukocytes (PMNs, neutrophils) may be a hallmark of acute lung injury (ALI). The breakdown of the vascular endothelial barrier has likewise been considered to have etiologic linkage in the pathogenesis of ALI. Rho-associated coiled-coil-forming protein kinase (ROCK), a downstream target effector of the small GTP-binding protein Rho, plays a key role in cell adhesion, motility, and contraction mediated by reorganization of the actin cytoskeleton. The aims were to investigate protection by fasudil in lipopolysaccharide (LPS)-induced ALI and the role of ROCK2 in neutrophil transendothelial migration in a murine model.
Material and Method
Mice were assigned to three groups: sham-treated controls (Sham group), LPS instillation (LPS group), and 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
Permeability pulmonary edema (histopathological examination, lung injury score, and lung wet-to-dry weight ratio) was ameliorated and neutrophil infiltration in the 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 fourfold; however, fasudil did not affect the increase.
Conclusions
The 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 by attenuating cytoskeletal rearrangement of endothelial cells, leading to the inhibition of ALI development.

Keywords: Protein Kinase Inhibitors - pharmacology, Organ Size, Neutrophils - metabolism, Mice, Inbred C57BL, Lung - enzymology, Lipopolysaccharides - toxicity, Gene Expression Regulation, Enzymologic, Endothelium, Vascular - pathology, RNA, Messenger - metabolism, Bronchoalveolar Lavage, 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine - pharmacology, rho GTP-Binding Proteins - metabolism, rho-Associated Kinases - metabolism

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