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PROBLEM:
Sepsis and associated systemic inflammatory response syndrome (SIRS) is a common and extremely deadly disease that is rising in incidence in both western and developing countries, with an alarming lack of effective treatment options. A major cause of death in sepsis is due to the inability to properly regulate the inflammatory–coagulation response in which the endothelium plays a key role. The molecular causes of this perturbation remain poorly understood and have hampered the development of effective therapeutic interventions for patients with severe sepsis. Emerging evidence suggests that matrix metalloproteases (MMPs) play pivotal roles in the host response to invading pathogens, but in severe sepsis can also cause uncontrolled tissue damage and contribute to mortality.
RESULTS:
We discovered that MMP‐1 and its mouse homolog, MMP‐1a, activate the G protein‐coupled protease‐activated receptor‐1 (PAR1) in an autocrine manner on the surface of endothelial cells to cause endothelial barrier disruption, vascular leakage, systemic inflammation and death. Inhibition of the mouse MMP‐1 activity significantly improved the survival of wild‐type (WT) and Par2−/− mice but had no effect in Par1−/− mice, thus demonstrating a dependence on PAR1. Sepsis‐ and endotoxin‐induced lung vascular leakage could be attenuated by inhibition of MMP‐1 activity. Pharmacologic inhibition of MMP‐1a also reduced disseminated intravascular coagulation (DIC) and markedly suppressed the pro‐inflammatory cytokine response in WT but not PAR1‐deficient mice with sepsis.
IMPACT:
These data indicate that the MMP1‐PAR1 system plays an important role as an early responder to bacterial infection and systemic inflammation. They may provide the blueprint for a novel prognostic biomarker and completely new treatment modality for high‐risk patients.
INTRODUCTION
Severe sepsis is a leading cause of acute hospital admissions and often complicates the clinical course of medical and surgical patients treated for other diseases (Moore et al, 2010; Remick, 2007). Identification of high‐risk patients with clinically useful prognostic biomarkers remains a substantial challenge (Shapiro et al, 2009). Sepsis is often characterized by marked derangements of the pro‐inflammatory, anti‐inflammatory and coagulation responses, a condition known as systemic inflammatory response syndrome (SIRS; Bone et al, 1992; Hotchkiss & Karl, 2003). SIRS develops when the initial, appropriate innate immune response becomes amplified and then dysregulated. High levels of pathogen‐associated molecular pattern mediators, such as endotoxin...