Elsevier

Microvascular Research

Volume 62, Issue 2, September 2001, Pages 164-171
Microvascular Research

Regular Article
Activation of Rho Is Involved in the Mechanism of Hydrogen-Peroxide-Induced Lung Edema in Isolated Perfused Rabbit Lung

https://doi.org/10.1006/mvre.2001.2329Get rights and content

Abstract

Acute lung injury is attributed primarily to increased vascular permeability caused by reactive oxygen species derived from neutrophils, such as hydrogen peroxide (H2O2). Increased permeability is accompanied by the contraction and cytoskeleton reorganization of endothelial cells, resulting in intercellular gap formation. The Rho family of Ras-like GTPases is implicated in the regulation of the cytoskeleton and cell contraction. We examined the role of Rho in H2O2-induced pulmonary edema with the use of isolated perfused rabbit lungs. To our knowledge, this is the first study to examine the role of Rho in increased vascular permeability induced by H2O2 in perfused lungs. Vascular permeability was evaluated on the basis of the capillary filtration coefficient (Kfc, ml/min/cm H2O/100 g). We found that H2O2 (300 μM) increased lung weight, Kfc, and pulmonary capillary pressure. These effects of H2O2 were abolished by treatment with Y-27632 (50 μM), an inhibitor of the Rho effector p160 ROCK. In contrast, the muscular relaxant papaverine inhibited the H2O2-induced rise in pulmonary capillary pressure, but did not suppress the increases in lung weight and Kfc. These findings indicate that H2O2 causes pulmonary edema by elevating hydrostatic pressure and increasing vascular permeability. Y-27632 inhibited the formation of pulmonary edema by blocking both of these H2O2-induced effects. Our results suggest that Rho-related pathways have a part in the mechanism of H2O2-induced pulmonary edema.

References (33)

  • F. Chabot et al.

    Reactive oxygen species in acute lung injury

    Eur. Respir. J.

    (1998)
  • M. Chrzanowska-Wodnicka et al.

    Rho-stimulated contractility drives the formation of stress fibers and focal adhesions

    J. Cell. Biol.

    (1996)
  • J.G. Garcia et al.

    Thrombin-induced increase in albumin permeability across the endothelium

    J. Cell. Physiol.

    (1986)
  • J.G. Garcia et al.

    Regulation of endothelial cell gap formation and barrier dysfunction: Role of myosin light chain phosphorylation

    J. Cell. Physiol.

    (1995)
  • Z.M. Goeckeler et al.

    Myosin light chain kinase-regulated endothelial cell contraction: The relationship between isometric tension, actin polymerization, and myosin phosphorylation

    J. Cell. Biol.

    (1995)
  • A.I. Gottlieb et al.

    Structure and function of the endothelial cytoskeleton

    Lab. Invest.

    (1991)
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    To whom correspondence should be addressed at Department of Pulmonary Medicine and Clinical Immunology, Dokkyo University School of Medicine, 880 Kitakobayashi, Mibu, Tochigi 321-0293, Japan. Fax:+81-282-86-5080. E-mail: [email protected].

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