Activation of rho is involved in the mechanism of hydrogen-peroxide-induced lung edema in isolated perfused rabbit lung.
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 microM) increased lung weight, Kfc, and pulmonary capillary pressure. These effects of H2O2 were abolished by treatment with Y-27632 (50 microM), 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.
Chiba
Y
Y
Department of Pulmonary Medicine, Jichi Medical School, Tochigi, Japan.
Ishii
Y
Y
Kitamura
S
S
Sugiyama
Y
Y
D000577:Amides / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D002196:Capillaries / Q000503:physiopathology; D002199:Capillary Permeability / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D006874:Hydrostatic Pressure; D066298:In Vitro Techniques; D008168:Lung / Q000098:blood supply* / Q000187:drug effects / Q000503:physiopathology; D008297:Male; D009929:Organ Size; D016877:Oxidants / Q000494:pharmacology; D010208:Papaverine / Q000494:pharmacology; D010477:Perfusion; D011654:Pulmonary Edema / Q000139:chemically induced / Q000503:physiopathology*; D011725:Pyridines / Q000494:pharmacology; D011817:Rabbits; D014665:Vasodilator Agents / Q000494:pharmacology; D020741:rho GTP-Binding Proteins / Q000378:metabolism*
D000577:Amides; D004791:Enzyme Inhibitors; D016877:Oxidants; D011725:Pyridines; D014665:Vasodilator Agents; C108830:Y 27632; D006861:Hydrogen Peroxide; D010208:Papaverine; D020741:rho GTP-Binding Proteins