Effect of human urinary thrombomodulin on endotoxin-induced intravascular coagulation and pulmonary vascular injury in rats.
Adult respiratory distress syndrome (ARDS) and disseminated intravascular coagulation (DIC) are serious complications of sepsis. Thrombomodulin, an important endothelial anticoagulant, binds thrombin to generate activated protein C (APC). To determine whether thrombomodulin purified from human urine (urinary thrombomodulin, UTM) is useful for the treatment of DIC and ARDS in sepsis, we examined the effect of UTM on endotoxin (ET)-induced coagulation abnormalities and pulmonary vascular injury in rats. Intravenous administration of UTM prevented the ET-induced pulmonary accumulation of leukocytes and the increase in pulmonary vascular permeability, as well as ET-induced histological changes such as leukocyte infiltration and pulmonary interstitial edema. On the other hand, dansyl-Glu-Gly-Arg-chloromethyl ketone-treated factor Xa (DEGR-Xa), a selective inhibitor of thrombin generation, did not prevent these effects of ET. UTM did not prevent ET-induced pulmonary accumulation of leukocytes and pulmonary vascular injury in rats pretreated with DEGR-Xa. Our findings suggest that UTM attenuates ET-induced coagulation abnormalities and pulmonary vascular injury. Furthermore, the latter effect may be dependent on the capacity of UTM to activate protein C.
Uchiba
M
M
Department of Medicine, Kumamoto University Medical School, Japan.
Okajima
K
K
Murakami
K
K
Johno
M
M
Okabe
H
H
Takatsuki
K
K
D000590:Amino Acid Chloromethyl Ketones / Q000627:therapeutic use; D000818:Animals; D000991:Antithrombins / Q000627:therapeutic use; D004211:Disseminated Intravascular Coagulation / Q000139:chemically induced / Q000188:drug therapy*; D004731:Endotoxins; D015951:Factor Xa / Q000627:therapeutic use; D006801:Humans; D007962:Leukocytes / Q000473:pathology; D008168:Lung / Q000473:pathology; D008297:Male; D011652:Pulmonary Circulation; D051381:Rats; D017208:Rats, Wistar; D018180:Thrombomodulin / Q000032:analysis / Q000502:physiology*; D014556:Urine / Q000737:chemistry; D014652:Vascular Diseases / Q000139:chemically induced / Q000188:drug therapy
D000590:Amino Acid Chloromethyl Ketones; D000991:Antithrombins; D004731:Endotoxins; D018180:Thrombomodulin; C097736:dansyl-glutamyl-glycyl-arginyl chloromethyl ketone-treated factor Xa; D015951:Factor Xa