A matrix metalloprotease-PAR1 system regulates vascular integrity, systemic inflammation and death in sepsis

Area of Science:

• Sepsis pathophysiology
• Endothelial cell biology
• Coagulation and inflammation

Background:

• Sepsis involves dysregulated inflammatory and coagulation responses, with the endothelium playing a critical role.
• The precise mechanisms driving sepsis-induced endothelial dysfunction remain poorly understood, hindering therapeutic development.
• Matrix metalloproteinases (MMPs) are implicated in host defense but can also mediate tissue damage and mortality in sepsis.

Purpose of the Study:

• To investigate the role of MMP-1 in sepsis pathogenesis.
• To identify the specific endothelial receptor targeted by MMP-1 during sepsis.
• To evaluate the therapeutic potential of targeting the MMP-1/PAR1 axis in sepsis.

Main Methods:

• Measured plasma levels of proMMP-1 and active MMP-1 in human sepsis patients and MMP-1a in septic mice.
• Identified MMP-1a as a protease-activated receptor-1 (PAR1) agonist on endothelial cells.
• Utilized genetic deficiency (PAR1-deficient mice) and pharmacological blockade to assess the impact of MMP-1/PAR1 signaling on sepsis outcomes.

Main Results:

• Elevated plasma MMP-1 levels in human sepsis patients correlated with mortality.
• Mice with sepsis exhibited increased MMP-1a levels, acting as a PAR1 agonist on endothelial cells.
• Blocking MMP-1 activity or PAR1 signaling ameliorated endothelial barrier disruption, disseminated intravascular coagulation (DIC), lung vascular permeability, and cytokine storm, improving survival.

Conclusions:

• MMP-1 is a key activator of PAR1 on endothelial cells in sepsis.
• The MMP-1/PAR1 signaling pathway contributes significantly to sepsis-induced organ damage and mortality.
• Targeting the MMP-1/PAR1 interaction represents a potential therapeutic strategy for sepsis treatment.