Attenuation of endotoxin-induced acute lung injury by the Rho associated kinase inhibitor, Y-27632

Sadatomo Tasaka, Hidefumi Koh, Wakako Yamada, Mie Shimizu, Yuko Ogawa, Naoki Hasegawa, Kazuhiro Yamaguchi, Yoshiki Ishii, Sarah E. Richer, Claire M. Doerschuk, Akitoshi Ishizaka

Research output: Contribution to journalArticle

97 Citations (Scopus)

Abstract

A small GTPase, Rho, plays key roles in cell adhesion, motility, and contraction after stimulation. Among Rho effectors isolated, the family of Rho-associated coiled-coil-forming protein kinases (ROCK) is implicated in Rho-mediated cell adhesion and smooth muscle contraction. The effect of a specific inhibitor of ROCK, Y-27632, was evaluated in a murine model of acute lung injury induced by intravenous injection of Escherichia coli endotoxin (lipopolysaccharide [LPS]). Lung edema was evaluated by measuring extravascular leakage of radio-labeled serum albumin, and neutrophil emigration into the lung parenchyma by morphometric observation and measuring myeloperoxidase activity. Pretreatment with Y-27632 attenuated both lung edema and neutrophil emigration after LPS. We also measured albumin transfer through cultured endothelial cell monolayers on a porous filter. Tumor necrosis factor-α significantly increased albumin transfer, which was attenuated by pretreatment with Y-27632. Fluorescence microscopy revealed that morphologic changes in endothelial cells induced by tumor necrosis factor-α were inhibited by Y-27632. In contrast, the increased fraction of neutrophils with polymerized actin after formyl-methionyl-leucyl-phenylalanine was not altered by Y-27632. These data suggest that ROCK may play an important role in the pathogenesis of LPS-induced lung injury and that ROCK inhibition could attenuate cytoskeletal rearrangement of endothelial cells, leading to decreased neutrophil emigration into the lung parenchyma.

Original languageEnglish
Pages (from-to)504-510
Number of pages7
JournalAmerican journal of respiratory cell and molecular biology
Volume32
Issue number6
DOIs
Publication statusPublished - 2005 Jun 1

Keywords

  • Lipopolysaccharide
  • Lung
  • Neutrophils
  • Rodent

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

Fingerprint Dive into the research topics of 'Attenuation of endotoxin-induced acute lung injury by the Rho associated kinase inhibitor, Y-27632'. Together they form a unique fingerprint.

  • Cite this