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Plasmin drives burn-induced systemic inflammatory response syndrome
Breanne H. Y. Gibson, … , Timothy S. Blackwell, Jonathan G. Schoenecker
Breanne H. Y. Gibson, … , Timothy S. Blackwell, Jonathan G. Schoenecker
Published December 8, 2021
Citation Information: JCI Insight. 2021;6(23):e154439. https://doi.org/10.1172/jci.insight.154439.
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Research Article Inflammation

Plasmin drives burn-induced systemic inflammatory response syndrome

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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.

Authors

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

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Figure 5

A mouse model of burn polytrauma provokes a systemic inflammatory response, affecting circulating and tissue markers of inflammation.

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A mouse model of burn polytrauma provokes a systemic inflammatory respon...
(A) Mouse model of 30% TBSA dorsal burn injury with concomitant, bilateral calf muscle injuries. (B and C) Plasma IL-6 and neutrophil to lymphocyte ratio (NLR) were significantly increased within 6 to 12 hours of the burn injury compared with the muscle injury alone, which does not significantly increase either marker. (D and E) NF-κB signaling in an isolated calf muscle injury is increased 1 to 3 days after injury and is resolved by 7 days. n = 5/group. Boxes represent median, while whiskers represent the 5th–95th percentile; multiple Mann-Whitney U tests at each time point with Holms-Sidak correction for multiple comparisons. *P < 0.05, ***P < 0.001, compared with muscle injury alone. The presence of a dorsal burn distant from the site of muscle injury increases and augments NF-κB signaling in injured muscle. Repeated measures ANOVA, **P < 0.01, ***P < 0.001 compared with muscle injury alone. n = 7 mice/group; points represent mean ± SD with 95% CI.

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