Uchiba M, Okajima K, Murakami K, Johno M, Okabe H, Takatsuki K
Department of Medicine, Kumamoto University Medical School, Japan.
Am J Physiol. 1996 Sep;271(3 Pt 1):L470-5. doi: 10.1152/ajplung.1996.271.3.L470.
Acute respiratory distress syndrome (ARDS) is a serious complication of sepsis. Thrombomodulin, an important endothelial anticoagulant, binds thrombin to generate activated protein C (APC). We have previously demonstrated that APC prevents endotoxin (ET)-induced pulmonary vascular injury by inhibiting activated leukocytes. We therefore examined whether recombinant human soluble thrombomodulin (rhs-TM) prevents activated leukocyte-induced pulmonary vascular injury in rats receiving ET. Intravenous administration of rhs-TM prevented ET-induced pulmonary accumulation of leukocytes and increase in pulmonary vascular permeability, as well as ET-induced histological changes, such as leukocyte infiltration and pulmonary interstitial edema. Dansyl-Glu-Gly-Arg-chloromethyl ketone-treated factor Xa (DEGR-Xa), a selective inhibitor of thrombin generation, did not prevent these effects of ET. rhs-TM did not prevent ET-induced pulmonary accumulation of leukocytes and pulmonary vascular injury in rats pretreated with DEGR-Xa. These results suggest that rhs-TM prevents ET-induced pulmonary vascular injury by inhibiting pulmonary accumulation of leukocytes and that this effect may be mediated primarily by APC generation.
急性呼吸窘迫综合征（ARDS）是脓毒症的一种严重并发症。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）。我们之前已经证明，APC通过抑制活化的白细胞来预防内毒素（ET）诱导的肺血管损伤。因此，我们研究了重组人可溶性血栓调节蛋白（rhs-TM）是否能预防接受ET的大鼠中活化白细胞诱导的肺血管损伤。静脉注射rhs-TM可预防ET诱导的白细胞在肺内的积聚以及肺血管通透性增加，以及ET诱导的组织学变化，如白细胞浸润和肺间质水肿。丹磺酰 - 谷氨酸 - 甘氨酸 - 精氨酸 - 氯甲基酮处理的因子Xa（DEGR-Xa）是一种凝血酶生成的选择性抑制剂，它不能预防ET的这些作用。在预先用DEGR-Xa处理的大鼠中，rhs-TM不能预防ET诱导的白细胞在肺内的积聚和肺血管损伤。这些结果表明，rhs-TM通过抑制白细胞在肺内的积聚来预防ET诱导的肺血管损伤，并且这种作用可能主要由APC的生成介导。
