Calpastatin controls polymicrobial sepsis by limiting procoagulant microparticle release

Area of Science:

• Biochemistry
• Immunology
• Pathophysiology

Background:

• Sepsis is a major global cause of mortality, characterized by systemic inflammation, coagulation activation, and lymphocyte apoptosis.
• Calpains, calcium-dependent proteases, exacerbate inflammation and lymphocyte death, and are crucial for releasing microparticles.
• Microparticles contribute to tissue damage and coagulopathy during sepsis.

Purpose of the Study:

• To investigate the role of calpain in sepsis-induced tissue damage.
• To determine if inhibiting calpain activity can mitigate sepsis severity.

Main Methods:

• Polymicrobial sepsis was induced in wild-type (WT) mice and transgenic mice overexpressing calpastatin (a calpain inhibitor).
• Calpain activity, survival rates, organ function, lymphocyte apoptosis, inflammatory markers, and coagulation were assessed.
• Microparticles from septic WT mice were transferred to septic transgenic mice to evaluate their direct impact.

Main Results:

• Calpain activity peaked at 6 hours post-sepsis induction in WT mice.
• Calpastatin overexpression improved survival, reduced organ dysfunction (lung, kidney, liver), and decreased lymphocyte apoptosis.
• Inhibition of calpain reduced systemic inflammation, disseminated intravascular coagulation (DIC), and circulating procoagulant microparticles, delaying thrombin generation.
• Transfer of microparticles worsened survival and coagulopathy in septic transgenic mice.

Conclusions:

• The calpain/calpastatin system plays a significant role in sepsis-related coagulation and inflammation.
• Inhibiting calpain activity leads to less severe DIC and improved outcomes in sepsis models.
• Targeting the calpain pathway represents a potential therapeutic strategy for sepsis management.