• Lara Zafrani, Peter S T Yuen, Grigoris Gerotziafas, Colleen Byrnes, Charlène Lévi, Sandrine Placier, Emmanuel Letavernier, Asada Leelahavanichkul, Jean-philippe Haymann, Ismail Elalamy, Jeffrey L Miller, Robert A Star, and Laurent Baud.
• Université Pierre et Marie Curie, Paris VI, UMR S 702, Paris, France. larazafrani@hotmail.com
• Am. J. Respir. Crit. Care Med.. 2012 Apr 1;185(7):744-55.

RationaleSepsis, a leading cause of death worldwide, involves widespread activation of inflammation, massive activation of coagulation, and lymphocyte apoptosis. Calpains, calcium-activated cysteine proteases, have been shown to increase inflammatory reactions and lymphocyte apoptosis. Moreover, calpain plays an essential role in microparticle release.ObjectivesWe investigated the contribution of calpain in eliciting tissue damage during sepsis.MethodsTo test our hypothesis, we induced polymicrobial sepsis by cecal ligation and puncture in wild-type (WT) mice and transgenic mice expressing high levels of calpastatin, a calpain-specific inhibitor.Measurements And Main ResultsIn WT mice, calpain activity increased transiently peaking at 6 hours after cecal ligation and puncture surgery. Calpastatin overexpression improved survival, organ dysfunction (including lung, kidney, and liver damage), and lymphocyte apoptosis. It decreased the sepsis-induced systemic proinflammatory response and disseminated intravascular coagulation, by reducing the number of procoagulant circulating microparticles and therefore delaying thrombin generation. The deleterious effect of microparticles in this model was confirmed by transferring microparticles from septic WT to septic transgenic mice, worsening their survival and coagulopathy.ConclusionsThese results demonstrate an important role of the calpain/calpastatin system in coagulation/inflammation pathways during sepsis, because calpain inhibition is associated with less severe disseminated intravascular coagulation and better overall outcomes in sepsis.

28 keywords...

hide…