Murakami K, Okajima K, Uchiba M, Johno M, Nakagaki T, Okabe H, Takatsuki K
Department of Medicine, Kumamoto University Medical School, Japan.
Am J Physiol. 1997 Feb;272(2 Pt 1):L197-202. doi: 10.1152/ajplung.1997.272.2.L197.
We investigated the effect of activated protein C (APC) on pulmonary vascular injury and the increase in tumor necrosis factor (TNF) levels in lipopolysaccharide (LPS)-treated rats to determine whether APC reduces LPS-induced endothelial damage by inhibiting cytokine production. Intravenously administered LPS (5 mg/kg) induced pulmonary vascular injury, as indicated by an increase in the lung wet-to-dry weight ratio. LPS-induced pulmonary vascular injury was prevented by APC but not by active site-blocked factor Xa [dansyl glutamyl-glycyl-arginyl chloromethyl detone-treated activated factor X (DEGR-Xa)], a selective inhibitor of thrombin generation, or inactivated APC [diisopropyl fluorophosphate-treated APC (DIP-APC)]. APC, but not DEGR-Xa or DIP-APC, significantly inhibited the LPS-induced increase in the plasma level of TNF. APC significantly inhibited the production of TNF by LPS-stimulated monocytes in a dose-dependent fashion in vitro, but DIP-APC did not. APC did not inhibit the functions of activated neutrophils in vitro. These findings suggest that APC prevented LPS-induced pulmonary vascular injury by inhibiting TNF production by monocytes and not via its anticoagulant activity. The serine protease activity of APC appears to be essential for inhibition of TNF production.
我们研究了活化蛋白C（APC）对脂多糖（LPS）处理的大鼠肺血管损伤及肿瘤坏死因子（TNF）水平升高的影响，以确定APC是否通过抑制细胞因子产生来减轻LPS诱导的内皮损伤。静脉注射LPS（5 mg/kg）可诱导肺血管损伤，表现为肺湿重与干重比值增加。APC可预防LPS诱导的肺血管损伤，但凝血酶生成的选择性抑制剂、活性位点被阻断的因子Xa [丹磺酰谷氨酰-甘氨酰-精氨酰氯甲基酮处理的活化因子X（DEGR-Xa）]或灭活的APC [二异丙基氟磷酸处理的APC（DIP-APC）]则不能。APC可显著抑制LPS诱导的血浆TNF水平升高，但DEGR-Xa或DIP-APC则不能。在体外，APC可剂量依赖性地显著抑制LPS刺激的单核细胞产生TNF，但DIP-APC则不能。APC在体外不抑制活化中性粒细胞的功能。这些发现表明，APC通过抑制单核细胞产生TNF而非通过其抗凝活性来预防LPS诱导的肺血管损伤。APC的丝氨酸蛋白酶活性似乎对抑制TNF产生至关重要。
