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

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

Research output: Contribution to journalArticle

95 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
Externally publishedYes

Fingerprint

rho-Associated Kinases
Acute Lung Injury
Endotoxins
Endothelial cells
Emigration and Immigration
Neutrophils
Lipopolysaccharides
Lung
Endothelial Cells
Cell adhesion
Cell Adhesion
Albumins
Edema
Tumor Necrosis Factor-alpha
methionyl-leucyl-phenylalanine
Monomeric GTP-Binding Proteins
Fluorescence microscopy
Lung Injury
Muscle Contraction
Radio

Keywords

  • Lipopolysaccharide
  • Lung
  • Neutrophils
  • Rodent

ASJC Scopus subject areas

  • Cell Biology
  • Pulmonary and Respiratory Medicine
  • Molecular Biology

Cite this

Attenuation of endotoxin-induced acute lung injury by the Rho associated kinase inhibitor, Y-27632. / Tasaka, Sadatomo; Koh, Hidefumi; Yamasawa, Wakako; Shimizu, Mie; Ogawa, Yuko; Hasegawa, Naoki; Yamaguchi, Kazuhiro; Ishii, Yoshiki; Richer, Sarah E.; Doerschuk, Claire M.; Ishizaka, Akitoshi.

In: American Journal of Respiratory Cell and Molecular Biology, Vol. 32, No. 6, 06.2005, p. 504-510.

Research output: Contribution to journalArticle

Tasaka, Sadatomo ; Koh, Hidefumi ; Yamasawa, Wakako ; Shimizu, Mie ; Ogawa, Yuko ; Hasegawa, Naoki ; Yamaguchi, Kazuhiro ; Ishii, Yoshiki ; Richer, Sarah E. ; Doerschuk, Claire M. ; Ishizaka, Akitoshi. / Attenuation of endotoxin-induced acute lung injury by the Rho associated kinase inhibitor, Y-27632. In: American Journal of Respiratory Cell and Molecular Biology. 2005 ; Vol. 32, No. 6. pp. 504-510.
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