Subantimicrobial Doxycycline Targeting Matrix Metalloproteinase Activity to Improve Outcome in Septic Shock

University Of California Los Angeles, Los Angeles CA

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Abstract

Project Summary Septic shock is a severe inflammatory reaction that occurs in response to infection and is a leading cause of death in intensive care. There are at least 750,000 cases of sepsis in the United States per year, with associated mortality estimated between 14.7% and 29.9%. The link between the inciting infection and the resulting organ damage is a severe systemic inflammatory response that is often more harmful than the original infection. Attempts to develop new treatments for septic shock have focused on inhibiting the inflammatory response, which has proven challenging. This may be because different molecular mechanisms can underlie the clinical syndrome recognized as septic shock. At present, shock syndromes are defined by clinical criteria such as the presence of an infection and the end-products of organ damage. Attempting to treat all patients in septic shock by targeting a mechanism that may only be active in a subset of these patients would account for this challenging history. Redefining shock syndromes according to molecular criteria increases precision in diagnosis, and therefore treatment?not only for septic shock, but for related syndromes. Vasoplegic syndrome, a relatively common complication of cardiopulmonary bypass, is a related shock syndrome which also carries a high mortality when severe. Both syndromes result from release of a complex system of inflammatory mediators. However, it is unknown whether there may be subtypes in vasoplegic syndrome that resemble the molecular subtypes seen in septic shock. One promising drug target in septic shock is matrix metalloproteinase 8 (MMP-8), an enzyme involved in tissue breakdown and regulation of other inflammatory proteins. High levels of this enzyme correlate with a poor prognosis in septic shock, and animal models support a causal relationship between high MMP-8 levels and poor outcome. The goal of this study is to define a subset of patients with distributive shock (septic and vasoplegic) and elevated MMP-8 levels. The clinical utility of this molecular categorization will then be tested through a trial of doxycycline, which inhibits MMP-8 activity. The use of an FDA-approved, generic medication minimizes any barrier to widespread access should treatment prove effective. Additionally, the work outlined in this proposal can be translated into an inexpensive PCR-based test to rapidly identify the relevant subgroup in clinical practice.