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 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 lipopolysaccharideiv), APC (2 mg·kg−1 APCiv), 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 andP=0.0004, respectively). Interleukin-1β release was also significantly reduced by APC treatment (2567.4 ± 320.9 pg·mL−1 in the LPS groupvs 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.
Résumé
Objectif: La protéine C activée (PCA) est le premier médicament anti-inflammatoire à être approuvé pour le traitement des septicémies sévères. Cependant, les mécanismes sous-jacents de cette protéine ne sont pas encore complètement compris. C’est pourquoi notre étude avait pour but d’évaluer les effets de la PCA sur la microcirculation (interaction mésentérique leucocytaire-endothéliale, extravasation plasmatique) en utilisant la microscopie intravitale (IVM) ainsi que ses effets sur la libération de cytokines pendant une endotoxémie expérimentale chez les rats.
Méthode: Nous avons randomisé quarante rats Lewis mâles en quatre groupes (n=10 par groupe) : témoin, LPS (15 mg·kg−1 lipopolysaccharide iv), PCA (2 mg·kg−1 PCA iv), et LPS+PCA. Nous avons évalué les interactions mésentériques leucocytaires-endothéliales et l’extravasation plasmatique à zéro, une et deux heures après l’administration de LPS et de PCA par MIV. Les niveaux plasmatiques de facteur onconécrosant-α, d’IL-1β, d’interleukine (IL)-6, et d’IL-10 ont été mesurés à zéro et deux heures.
Résultats: L’adhérence leucocytaire (−74 %) et l’extravasation plasmatique (−28 %) pendant l’endotoxémie ont été significativement réduites après un traitement avec PCA, par rapport aux animaux LPS non traités (P=0,0001 et P=0,0004, respectivement). La libération d’interleukine-1β était également réduite de façon significative par le traitement avec PCA (2567,4 ± 320,9 pg·mL−1 dans le groupe LPS vs 1626,1 ± 427,2 pg·mL−1 dans le groupe LPS+PCA ; P=0,001).
Conclusion: Ces expériences sur les rongeurs ont montré que le traitement à base de PCA atténuait de manière significative la détérioration de la microcirculation mésentérique ainsi que la libération systémique d’IL-1β provoquées par le choc endotoxique. En raison du rôle primordial de la microcirculation dans la pathogenèse continue de la septicémie et dans le syndrome de défaillance multisystémique, ces effets pourraient avoir une importance clinique.
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Disclosure: Activated protein C was provided by Lilly Deutschland GmbH.
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Lehmann, C., Scheibe, R., Schade, M. et al. Effects of activated protein C on the mesenteric microcirculation and cytokine release during experimental endotoxemia. Can J Anesth 55, 155–162 (2008). https://doi.org/10.1007/BF03016089
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DOI: https://doi.org/10.1007/BF03016089