Aktiviertes Protein C (APC) bei der Sepsis: Zelluläre und mikrohämodynamische Mechanismen der Protektion

Abstract

In a recent prospective randomized trial (PROWESS trial), activated protein C (APC) reduced mortality from severe sepsis. Although there is some in vitro evidence that APC could act anti-inflammatory on a cellular level, the effect of APC on sepsis-associated microcirculatory disorders, including leukocyte-endothelial cell interaction and capillary perfusion failure, has not been analyzed in vivo, yet. We, therefore, studied the action of APC on these parameters in a rodent model of normotensive endotoxemia. In skin fold preparations of Syrian hamsters, endotoxemia was induced by i.v. administration of 2 mg/kg endotoxin (LPS, E. coli, 2 mg/kg). Intravital fluorescence microscopy allowed quantitative analysis of arteriolar and venular leukocyte adhesion and functional capillary density (FCD). These parameters served as measures to detect cellular inflammatory response and microvascular perfusion failure. APC (APC group, n = 8, activated protein C 24 μg/kg i.v.) was substituted continuously during 8h after LPS administration. Buffer-treated animals that also received LPS served as controls. LPS induced a massive increase of venular leukocyte adhesion, which was associated with a progressive decrease of FCD to 50% of baseline values (p < 0.01 vs. baseline). APC treatment effectively (p < 0.05) inhibited LPS-mediated leukocytic response in venules, and significantly (p < 0.05) attenuated endotoxic perfusion failure of the nutritive capillaries. APC-related protection from endotoxin-mediated microcirculatory disorders may represent the in vivo mechanism of the beneficial APC action during human sepsis.