Effects of activated protein C on the mesenteric microcirculation and cytokine release during experimental endotoxemia.
OBJECTIVE
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 x kg(-1) lipopolysaccharide iv), APC (2 mg x 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-alpha, IL-1beta, 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 x mL(-1) in the LPS group vs 1626.1 +/- 427.2 pg x mL(-1) in the LPS+APC group; P = 0.001).


CONCLUSIONS
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.
Lehmann
Christian
C
Department of Anesthesia, Dalhousie University, Halifax, Nova Scotia, Canada. chlehmann@dal.ca
Scheibe
Ricardo
R
Schade
Michael
M
Meissner
Konrad
K
Gründling
Matthias
M
Usichenko
Taras
T
Wendt
Michael
M
Hung
Orlando
O
Whynot
Sara
S
Murphy
Michael
M
Pavlovic
Dragan
D
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects; D016207:Cytokines / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D019446:Endotoxemia / Q000188:drug therapy*; D053583:Interleukin-1beta / Q000187:drug effects / Q000378:metabolism; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism; D008070:Lipopolysaccharides; D008297:Male; D008856:Microscopy, Fluorescence; D011486:Protein C / Q000494:pharmacology*; D051381:Rats; D011917:Rats, Inbred Lew; D013152:Splanchnic Circulation / Q000187:drug effects*; D013997:Time Factors
D000893:Anti-Inflammatory Agents; D016207:Cytokines; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D011486:Protein C