Unraveling the Role of The Fibrinolytic-Inflammatory Axis in Severe Trauma Adverse Outcomes: From Acute Organ Dysfunction to Chronic Disability

Severe trauma remains a leading cause of mortality and long-term disability worldwide. Patients who survive the initial injury face a continuum of complications, from early-phase multi-organ dysfunction syndrome (MODS) to late-phase post-injury syndrome (PIS). Despite extensive research, a critical knowledge gap remains in understanding how specific innate immune cells drive these adverse outcomes. This proposal aims to elucidate the dynamic interplay between the fibrinolytic system and inflammatory response, specifically neutrophil activation in early injury response, followed by sustained macrophage-driven inflammation in late-phase complications. Our central hypothesis posits that the spectrum of adverse outcomes stems from sequential immune cell responses to fibrinolytic dysfunction, centered on the management of the 'damage matrisome.' We propose a three-phase progression: 1) initial hyperfibrinolysis triggers neutrophil activation and DNAnet formation, 2) neutrophil-mediated fortification of the damage matrisome creates a fibrinolysis-resistant matrix that while initially protective, leads to organ inflammation and a hypofibrinolytic state within tissues, and 3) persistent hypofibrinolysis combined with chronic macrophage activation drives failure of tissue repair, degeneration and pain (PIS). To test this hypothesis, we will employ a clinically relevant murine model of severe trauma complemented by comprehensive flow cytometry-based immune cell phenotyping and tissue-specific transcriptomic analysis. Aim 1 will determine if early hyperfibrinolysis drives neutrophil activation and MODS by modulating fibrinolysis and assessing its impact on neutrophil phenotype and organ inflammation. Aim 2 will investigate whether activated neutrophils drive hypofibrinolysis both systemically and within tissues by manipulating neutrophil responses in both severe and non-severe injury models. Aim 3 will evaluate if modulating either fibrinolysis, chronic inflammation, or both can mitigate PIS. Important to the clinical relevance of this work, measures of PIS will include tissue fibrosis/calcification, musculoskeletal inflammation and degeneration, pain, and musculoskeletal function- all changes observed in severely injured patients. This research has the potential to revolutionize our understanding of trauma pathophysiology by defining how specific immune cell populations drive adverse outcomes. By elucidating these mechanisms, we aim to develop targeted, phase-specific interventions that address both immediate life-threatening complications and prevent long-term disabilities, ultimately improving outcomes for millions of trauma survivors worldwide.