title: Calpastatin controls polymicrobial sepsis by limiting procoagulant microparticle release.
abstract: BACKGROUND
  Sepsis, 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.
  
  
  OBJECTIVE
  We investigated the contribution of calpain in eliciting tissue damage during sepsis.
  
  
  METHODS
  To 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.
  
  
  RESULTS
  In 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.
  
  
  CONCLUSIONS
  These 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.
authors.affiliation: Université Pierre et Marie Curie, Paris VI, UMR S 702, Paris, France. larazafrani@hotmail.com
authors.forename: Lara
authors.initials: L
authors.lastname: Zafrani
authors.forename: Grigoris
authors.initials: G
authors.lastname: Gerotziafas
authors.forename: Colleen
authors.initials: C
authors.lastname: Byrnes
authors.forename: Xuzhen
authors.initials: X
authors.lastname: Hu
authors.forename: Joelle
authors.initials: J
authors.lastname: Perez
authors.forename: Charlène
authors.initials: C
authors.lastname: Lévi
authors.forename: Sandrine
authors.initials: S
authors.lastname: Placier
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Letavernier
authors.forename: Asada
authors.initials: A
authors.lastname: Leelahavanichkul
authors.forename: Jean-philippe
authors.initials: JP
authors.lastname: Haymann
authors.forename: Ismail
authors.initials: I
authors.lastname: Elalamy
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Miller
authors.forename: Robert A
authors.initials: RA
authors.lastname: Star
authors.forename: Peter S T
authors.initials: PS
authors.lastname: Yuen
authors.forename: Laurent
authors.initials: L
authors.lastname: Baud
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002135:Calcium-Binding Proteins / Q000502:physiology*; D002154:Calpain / Q000502:physiology; D055252:Cell-Derived Microparticles / Q000502:physiology; D016207:Cytokines / Q000502:physiology; D004195:Disease Models, Animal; D004211:Disseminated Intravascular Coagulation / Q000503:physiopathology; D008214:Lymphocytes / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009102:Multiple Organ Failure / Q000503:physiopathology; D016328:NF-kappa B / Q000502:physiology; D018805:Sepsis / Q000401:mortality / Q000503:physiopathology*; D013925:Thromboplastin / Q000502:physiology
chemical_list: D002135:Calcium-Binding Proteins; D016207:Cytokines; D016328:NF-kappa B; C033668:calpastatin; D013925:Thromboplastin; D002154:Calpain