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

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-alpha 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-alpha 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.
AuthorsSadatomo Tasaka, Hidefumi Koh, Wakako Yamada, Mie Shimizu, Yuko Ogawa, Naoki Hasegawa, Kazuhiro Yamaguchi, Yoshiki Ishii, Sarah E Richer, Claire M Doerschuk, Akitoshi Ishizaka
JournalAmerican journal of respiratory cell and molecular biology (Am J Respir Cell Mol Biol) Vol. 32 Issue 6 Pg. 504-10 (Jun 2005) ISSN: 1044-1549 [Print] United States
PMID15778497 (Publication Type: Journal Article)
Chemical References
  • Amides
  • Enzyme Inhibitors
  • Intracellular Signaling Peptides and Proteins
  • Lipopolysaccharides
  • Pyridines
  • Serum Albumin
  • Y 27632
  • Protein-Serine-Threonine Kinases
  • rho-Associated Kinases
Topics
  • Amides (pharmacology)
  • Animals
  • Cell Movement (immunology)
  • Endothelium (metabolism, pathology)
  • Enzyme Inhibitors (pharmacology)
  • Intracellular Signaling Peptides and Proteins
  • Leukocyte Count
  • Lipopolysaccharides
  • Mice
  • Mice, Inbred C57BL
  • Neutrophils (cytology)
  • Protein-Serine-Threonine Kinases (antagonists & inhibitors)
  • Pulmonary Alveoli (enzymology, immunology, pathology)
  • Pulmonary Edema (chemically induced, drug therapy, immunology)
  • Pyridines (pharmacology)
  • Respiratory Distress Syndrome, Adult (chemically induced, drug therapy, immunology)
  • Serum Albumin (metabolism)
  • rho-Associated Kinases

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