Publications (2)2.12 Total impact
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ABSTRACT: Rho-associated coiled coil-forming protein kinase (Rho-kinase), a downstream target effector of the small GTP-binding protein Rho, plays a key role in cell adhesion, motility, and contraction. The goal of the present study was to determine the role of the Rho/Rho-kinase signal pathway in the pathogenesis of lipopolysaccharide (LPS)-induced vascular hyperpermeability using the Rho-kinase inhibitor fasudil. To evaluate plasma leakage, fasudil (3 or 10 mg/kg) or saline was intravenously administered 30 min before LPS injection. LPS (100, 300, and 1,000 μg/0.1 mL/site) and saline (0.1 mL/site) were administered intracutaneously in the dorsum of guinea pigs. Vascular permeability was measured on the dorsal skin by the local accumulation of Evans Blue dye after intracutaneous injection of LPS (100-1000 μg/site) from Escherichia coli. For the measurement of colonic muscle tension, fasudil (3 mg/kg) or saline was intravenously administered 30 min before LPS injection. LPS (1 mg/kg) was administered intravenously. Dye leakage in the skin increased significantly 2 h after the injection of LPS. This LPS-induced dye leakage was significantly suppressed by fasudil (3 and 10 mg/kg). LPS caused a transient decrease in colonic muscle tension, which peaked 2.5 h after the injection. This decrease in muscle tension was significantly suppressed by pretreatment with fasudil (3 mg/kg). The Rho/Rho-kinase pathway might play an important role in the pathogenesis of LPS-induced endotoxemia, and fasudil could attenuate LPS-induced microvascular permeability, leading to inhibition of endotoxemia.Journal of Surgical Research 04/2012; 178(1):352-7. · 2.12 Impact Factor
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ABSTRACT: Using an endotoxaemia model in conscious guinea pigs, we previously reported that polymyxin B immobilized fiber-direct hemoperfusion (PMX-DHP) or administration of sivelestat are effective treatments for sepsis. In the present study, we investigated whether simultaneous treatment with PMX-DHP and sivelestat sodium was more effective than either treatment alone for sepsis. Measurements examined included intestinal paralysis, blood pressure, serum HMGB1 level and survival rate. Colonic motion was monitored continuously by telemetry using a transducer attached to the taenia caecum, while blood pressure was monitored with a carotid artery catheter. The guinea pigs were divided into 4 groups and lipopolysaccharide (LPS) was administered to all animals. The control group received only LPS. The remaining three groups received PMX treatment for 2 hours, sivelestat sodium administration for 2 hours or simultaneous PMX and sivelestat treatment for 2 hours. In the control group, decreased colonic muscle tension and arterial pressure, and increased serum HMGB1 levels were observed and all animals died within 30 hours. In the PMX-DHP treated group, the decreases in colonic tension and arterial pressure were less severe than for the control group and the survival rate was higher than the control group, but serum HMGB1 levels were not significantly different. In the sivelestat group, decreases in colonic tension and arterial pressure were not significantly different with the control group, but serum HMGB1 levels were lower than in the control group. Simultaneous treatment with both PMX-DHP and sivelestat sodium did not exhibit synergistic effects for the treatment of LPS- induced endotoxaemia and mortality. PMX-DHP was effective at treating sepsis induced by administration of a high dose of LPS in guinea pigs, but simultaneous administration of sivelestat sodium did not augment the efficacy of PMX-DHP treatment.Nihon Kyukyu Igakukai Zasshi 01/2012; 23(1):12-20.
Nippon Medical School
Edo, Tōkyō, Japan
- Department of Emergency and Critical Care Medicine