Effects of activated protein C on the mesenteric microcirculation and cytokine release during experimental endotoxemia

Purpose: Activated protein C (APC) is the first anti-inflammatory drug to be approved for the treatment of severe sepsis. However, the underlying mechanisms are not completely elucidated. Therefore, the aim of our study was to evaluate the effects of APC on the microcirculation (mesenteric leukocyte-endothelial interaction, plasma extravasation) using intravital microscopy (IVM) and on cytokine release during experimental endotoxemia in rats. Methods: We divided forty, male, Lewis rats into four groups (n = 10 per group): Controls, LPS (15 mg·kg^-1 lipopolysaccharide iv), APC (2 mg·kg^-1 APC iv), and LPS+APC. We determined mesenteric leukocyte-endothelial interactions and plasma extravasation at zero, one and two hours following administration of LPS and APC by IVM. Plasma levels of tumour necrosis factor-α, IL-1β, interleukin (IL)-6, and IL-10 were measured at zero and at two hours. Results: Leukocyte adherence (-74%) and plasma extravasation (-28%) during endotoxemia were diminished significantly following APC treatment, compared to untreated LPS animals (P = 0.0001 and P = 0.0004, respectively). Interleukin-1β release was also significantly reduced by APC treatment (2567.4 ± 320.9 pg·mL^-1 in the LPS group vs 1626.1 ± 427.2 pg·mL^-1 in the LPS+APC group; P = 0.001). Conclusion: These rodent experiments showed that APC treatment significantly attenuated deterioration of the mesenteric microcirculation and systemic IL-1β release caused by endotoxin challenge. Because of the crucial role of the microcirculation in ongoing sepsis pathogenesis and multiple organ dysfunction syndrome, these effects may be of clinical importance.