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

Abstract

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 leukocyteendothelial 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-1ß 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-1ß 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.

A novel fibrinogenase fromAgkistrodon acutusvenom protects against LPS-induced endotoxemiaviaregulating NF-κB pathway

“…As the accumulation of pro-inflammatory cytokines could lead to inflammatory cascades and results in organ failure and mortality, many of them have been chosen as therapeutic targets for endotoxemia. It was reported that activated protein C decreased the deterioration of the mesenteric microcirculation and endotoxin-induced TNF-a production 8 . Since TNF-a is thought to be one early released inflammatory cytokines, which would reach to peak within 1.5-2 h after the administration of LPS 2 , and thus suppressing the level of TNF-a could attenuate the overwhelming inflammation responses in endotoxemia.…”

“…TNF-a is one of the most important early releasing cytokines in endotoxemia, and it was reported that the accumulation of TNF-a would lead to the secondary inflammatory cascades, such as up-regulation of cell adhesion molecule and reactive oxygen species 7,8 . Numbers of treatments of endotoxemia studies showed protective effect by suppressing TNF-a level [9][10][11] .…”

“…Wang et alImmunopharmacol Immunotoxicol, Early Online:[1][2][3][4][5][6][7][8] Immunopharmacology and Immunotoxicology…”

The endocannabinoid system in sepsis – a potential target to improve microcirculation?

“…aminosteroids), anti-inflammatory drugs and anticoagulants. (20,(24)(25)(26) Also, several antibiotics which possess vasoactive and anti-inflammatory properties may ameliorate decrements in microcirculation function. (27) Another approach is the use of different crystalloid and/ or colloid fluids.…”

Activated Protein C Restores Hepatic Microcirculation During Sepsis by Modulating Vasoregulator Expression

“…We have previously reported that aPC modulates the hepatic inflammatory response, at least in part, via a leukocyte-dependent mechanism (14). Furthermore, treatment with aPC attenuates mesenteric microcirculatory failure induced by endotoxin challenge (15). Despite these findings, the precise mechanism(s) by which aPC modulates hepatic endothelial dysfunction remain to be fully elucidated.…”