Effect of nafamostat mesilate on pulmonary vascular injury induced by lipopolysaccharide in rats.
Nafamostat mesilate (NM) is a synthetic protease inhibitor that is capable of inhibiting the various coagulation factors such as factor VIIa and thrombin. To determine whether NM may also be useful in treating adult respiratory distress syndrome (ARDS) related in sepsis, we investigated the effect of NM on lipopolysaccharide (LPS)-induced pulmonary vascular injury in rats. The intraperitoneal administration of NM prevented the pulmonary vascular injury and coagulation abnormalities induced by LPS. DEGR-factor VIIa, a selective inhibitor of factor VIIa, prevented the coagulation abnormalities, but not the pulmonary vascular injury, induced by LPS. NM did not reduce LPS-induced increase in pulmonary accumulation of leukocytes. NM did not inhibit the increase in the plasma concentration of tumor necrosis factor-alpha (TNF-alpha) observed after administration of LPS. NM did not inhibit the function of activated neutrophils in vitro. Plasma values of total serum hemolytic complement (CH50) were markedly decreased after the administration of LPS. NM inhibited the LPS-induced decrease in plasma CH50 values. Findings suggest that NM may reduce the pulmonary vascular injury as well as the coagulation abnormalities induced by LPS. The former effect may be independent of the anticoagulant effect but dependent on the inhibitory effect of the activation of the complement system in rats administered LPS.
Uchiba
M
M
Department of Medicine, Kumamoto University Medical School, Japan.
Okajima
K
K
Murakami
K
K
Okabe
H
H
Takatsuki
K
K
D000818:Animals; D001550:Benzamidines; D001808:Blood Vessels / Q000187:drug effects / Q000378:metabolism; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D006146:Guanidines / Q000494:pharmacology*; D006801:Humans; D007958:Leukocyte Count; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000633:toxicity*; D008168:Lung / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D008297:Male; D009504:Neutrophils / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D001550:Benzamidines; D006146:Guanidines; D008070:Lipopolysaccharides; D015842:Serine Proteinase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D009195:Peroxidase; C032855:nafamostat