Dataset Information

Calpastatin controls polymicrobial sepsis by limiting procoagulant microparticle release.

ABSTRACT:

Rationale

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.

Objectives

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.

Measurements and main 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.

SUBMITTER: Zafrani L

PROVIDER: S-EPMC3326423 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature

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Publications

Calpastatin controls polymicrobial sepsis by limiting procoagulant microparticle release.

Zafrani Lara L Gerotziafas Grigoris G Byrnes Colleen C Hu Xuzhen X Perez Joelle J Lévi Charlène C Placier Sandrine S Letavernier Emmanuel E Leelahavanichkul Asada A Haymann Jean-philippe JP Elalamy Ismail I Miller Jeffrey L JL Star Robert A RA Yuen Peter S T PS Baud Laurent L

American journal of respiratory and critical care medicine 20120120 7

<h4>Rationale</h4>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.<h4>Objectives</h4>We investigated the contribution of calpain in eliciting tissue damage during sepsis.<h4>Methods</h4>To test our hypot ...[more]

PMID: 22268136

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Dataset Information

Calpastatin controls polymicrobial sepsis by limiting procoagulant microparticle release.

Rationale

Objectives

Methods

Measurements and main results

Conclusions

Publications

Calpastatin controls polymicrobial sepsis by limiting procoagulant microparticle release.

Similar Datasets

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