Plasmin drives burn-induced systemic inflammatory response syndrome

Breanne H Y Gibson,Matthew J Flick,Alexey R Revenko,Jonathan G Schoenecker,Stephanie N Moore-Lotridge,Timothy S Blackwell,Colby C Wollenman,J Blair Summitt,Patrick R Keller

doi:10.1172/jci.insight.154439

Abstract

Severe injuries, such as burns, provoke a systemic inflammatory response syndrome (SIRS) that imposes pathology on all organs. Simultaneously, severe injury also elicits activation of the fibrinolytic protease plasmin. While the principal adverse outcome of plasmin activation in severe injury is compromised hemostasis, plasmin also possesses proinflammatory properties. We hypothesized that, following a severe injury, early activation of plasmin drives SIRS. Plasmin activation was measured and related to injury severity, SIRS, coagulopathy, and outcomes prospectively in burn patients who are not at risk of hemorrhage. Patients exhibited early, significant activation of plasmin that correlated with burn severity, cytokines, coagulopathy, and death. Burn with a concomitant, remote muscle injury was employed in mice to determine the role of plasmin in the cytokine storm and inflammatory cascades in injured tissue distant from the burn injury. Genetic and pharmacologic inhibition of plasmin reduced the burn-induced cytokine storm and inflammatory signaling in injured tissue. These findings demonstrate (a) that severe injury–induced plasmin activation is a key pathologic component of the SIRS-driven cytokine storm and SIRS-activated inflammatory cascades in tissues distant from the inciting injury and (b) that targeted inhibition of plasmin activation may be effective for limiting both hemorrhage and tissue-damaging inflammation following injury.

Highlights

The acute phase response (APR) is the physiologic process by which the body survives and resolves tissue injury
To circumvent bleeding as both a confounding variable and a significant cause of early death after severe injury, we investigated plasmin activation in both clinical and preclinical models of severe burn in which systemic inflammatory response syndrome (SIRS) occurs without the risk of lethal blood loss
Within the first week of hospitalization, 87% (27 of 31) of burn patients developed markers of organ dysfunction based on the Sequential Organ Failure Assessment (SOFA) scoring system [27], and 42% (13 of 31) developed multiple organ dysfunction defined as a SOFA score ≥ 6 (Table 2)

Summary

Introduction

The acute phase response (APR) is the physiologic process by which the body survives and resolves tissue injury. The APR is comprised of initial, synergistic activation of coagulation and inflammation to contain the damage and prevent infection at the site of injury. A severe injury provokes a deranged APR that imposes global, pathologic effects on distant organ systems. The hallmark of a pathologic, severe injury–induced APR is dysregulated inflammation and coagulation [3, 4]. The inflammatory pathology is referred to as systemic inflammatory response syndrome (SIRS) highlighted by a “cytokine storm” [5]. SIRS and TIC result in an “immunocoagulopathic” condition that affects the vasculature and peripheral tissues, increasing the risk of multiple-organ dysfunction syndrome A critical knowledge gap is apparent regarding molecular mechanisms that initiate this detrimental immunocoagulopathy in a severe injury–induced APR

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