Uchiba M, Okajima K, Murakami K, Johno M, Okabe H, Takatsuki K
Department of Medicine, Kumamoto University Medical School, Japan.
Am J Hematol. 1997 Feb;54(2):118-23. doi: 10.1002/(sici)1096-8652(199702)54:2<118::aid-ajh4>3.0.co;2-#.
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.
成人呼吸窘迫综合征（ARDS）和弥散性血管内凝血（DIC）是脓毒症的严重并发症。血栓调节蛋白是一种重要的内皮抗凝剂，它与凝血酶结合生成活化蛋白C（APC）。为了确定从人尿中纯化的血栓调节蛋白（尿血栓调节蛋白，UTM）是否可用于治疗脓毒症中的DIC和ARDS，我们研究了UTM对大鼠内毒素（ET）诱导的凝血异常和肺血管损伤的影响。静脉注射UTM可预防ET诱导的白细胞在肺内积聚、肺血管通透性增加，以及ET诱导的组织学变化，如白细胞浸润和肺间质水肿。另一方面，丹磺酰 - 谷氨酸 - 甘氨酸 - 精氨酸 - 氯甲基酮处理的因子Xa（DEGR-Xa），一种凝血酶生成的选择性抑制剂，不能预防ET的这些作用。UTM不能预防用DEGR-Xa预处理的大鼠中ET诱导的白细胞在肺内积聚和肺血管损伤。我们的研究结果表明，UTM可减轻ET诱导的凝血异常和肺血管损伤。此外，后一种作用可能取决于UTM激活蛋白C的能力。
