title: Effect of human urinary thrombomodulin on endotoxin-induced intravascular coagulation and pulmonary vascular injury in rats.
abstract: 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.
authors.affiliation: Department of Medicine, Kumamoto University Medical School, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Uchiba
authors.forename: K
authors.initials: K
authors.lastname: Okajima
authors.forename: K
authors.initials: K
authors.lastname: Murakami
authors.forename: M
authors.initials: M
authors.lastname: Johno
authors.forename: H
authors.initials: H
authors.lastname: Okabe
authors.forename: K
authors.initials: K
authors.lastname: Takatsuki
mesh_terms: 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
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D000991:Antithrombins; D004731:Endotoxins; D018180:Thrombomodulin; C097736:dansyl-glutamyl-glycyl-arginyl chloromethyl ketone-treated factor Xa; D015951:Factor Xa