Plasmin drives burn-induced systemic inflammatory response syndrome

Area of Science:

• Biomedical Science
• Trauma Research
• Inflammation Biology

Background:

• Severe injuries, including burns, trigger a systemic inflammatory response syndrome (SIRS) affecting multiple organs.
• Simultaneously, severe injuries activate the fibrinolytic protease plasmin, which can compromise hemostasis and promote inflammation.

Purpose of the Study:

• To investigate the hypothesis that early plasmin activation following severe injury is a key driver of SIRS.
• To examine the correlation between plasmin activation, injury severity, SIRS, coagulopathy, and patient outcomes.
• To determine the role of plasmin in remote tissue inflammation and cytokine storm after burn injury.

Main Methods:

• Prospective study measuring plasmin activation in burn patients, correlating it with injury severity, SIRS, coagulopathy, and outcomes.
• Utilized a mouse model of burn with concomitant remote muscle injury to assess plasmin's role in distant inflammatory cascades.
• Employed genetic and pharmacologic methods to inhibit plasmin activation in the mouse model.

Main Results:

• Patients showed early and significant plasmin activation, which correlated with burn severity, cytokine levels, coagulopathy, and mortality.
• Inhibition of plasmin in mice significantly reduced the burn-induced cytokine storm and inflammatory signaling in remote injured tissues.
• Findings indicate plasmin activation is a critical factor in SIRS-driven inflammation distant from the initial injury site.

Conclusions:

• Early plasmin activation is a key pathological component of SIRS and associated inflammatory cascades in tissues distant from severe injury.
• Targeted inhibition of plasmin activation presents a potential therapeutic strategy to mitigate both hemorrhage and tissue-damaging inflammation post-injury.