Abstract
IntroductionSuccessful treatment of severe sepsis and septic shock remains a major challenge in critical care medicine. The recently introduced recombinant human activated protein C (APC) remarkably improved the outcome of septic patients. The influence of APC on intestinal circulation is still poorly understood. Therefore, the present study aimed to investigate the effects of APC on intestinal microcirculation during experimental endotoxaemia in rats by using intravital microscopy.MethodsA total of 44 male Lewis rats were randomly assigned to receive intravenous injections of 15 mg/kg lipopolysaccharide alone (LPS) (n = 11) or LPS followed by subsequent injection of 2 mg/kg recombinant human APC (LPS + APC) (n = 11), whereas control animals received either APC (n = 11) or saline (n = 11). Animals underwent observations of functional capillary density and leucocyte adherence on venular endothelium in the microcirculation of the intestinal wall by means of intravital fluorescence microscopy. Indicators of macrocirculation as well as plasma levels of tumour necrosis factor-α, interleukin (IL)-1β, IL-6, and IL-10 were measured.ResultsAlthough APC administration of both LPS-treated and control rats did not change macrocirculation or release of inflammatory cytokines, it increased mucosal and muscular functional capillary density (p < 0.001 and p < 0.05, respectively) and reduced the number of firmly adhering leucocytes in intestinal submucosal V1 and V3 venules (p < 0.01) in LPS + APC-treated compared with LPS-treated animals, which did not receive APC. No remarkable differences that could be attributed to APC treatment were observed between the two control groups.ConclusionAPC administration during experimental endotoxaemia improved intestinal microcirculation by protecting functional capillary density as a measure of microvascular perfusion and exerted anti-inflammatory effects by reducing leucocyte adherence to the endothelium in submucosal venules. Therefore, beneficial effects of APC in septic patients might be due, in part, to improved intestinal microcirculation.
Highlights
Successful treatment of severe sepsis and septic shock remains a major challenge in critical care medicine
lipopolysaccharide alone (LPS) groups with and without activated protein C (APC) treatment did not differ in Mean arterial pressure (MAP) or heart rate (HR) two hours after endotoxin challenge
We showed that APC administration improved functional capillary density (FCD) as a measure of microvascular perfusion in the intestinal wall during experimental endotoxaemia
Summary
Successful treatment of severe sepsis and septic shock remains a major challenge in critical care medicine. The present study aimed to investigate the effects of APC on intestinal microcirculation during experimental endotoxaemia in rats by using intravital microscopy. Published studies investigated the effects of APC on microcirculation during experimental endotoxaemia by intravital fluorescence microscopy (IVM) [12,13]. They were able to show that APC diminishes endotoxin-derived reduction of functional capillary density (FCD) as well as leucocyte adherence to the endothelium in dorsal skinfold chamber preparations and in the mesentery, but they did not investigate the intestinal wall. With respect to the role of the intestinal microcirculation in sepsis [14], the aim of our study was to evaluate the effects of APC administration during experimental endotoxaemia in the terminal ileum wall of the rat by using IVM
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