Molecular Mechanisms Underlying Severe Sepsis: Insights from Epigenetics

Abstract

Recent investigations into the pathogenesis of severe sepsis, septic shock, burn, stroke and ischemia/reperfusion injury have identified common patterns of disease. Despite their disparate etiologies, these syndromes share many similar immunological outcomes. In particular, survivors of life-threatening shock syndromes often exhibit decreased long-term survival rates as compared to the healthy age-matched population [1]. This decrease in survival often correlates with an increased susceptibility to secondary, nosocomial and opportunistic infections [2, 3]. In addition, survivors of severe shock and trauma often exhibit immunosuppressive phenotypes, particularly in regards to cellular immune activation and effector function. These phenotypes can be observed both in human patients and in animal models of severe inflammation and injury, specifically in animal models of severe sepsis [4]. Severe injury and inflammation are often associated with widespread apoptosis; the immunosuppression observed following these events is often ascribed to this loss of immune cells [5]. However, these deficiencies often persist despite the eventual return of immune cells to preinjury levels in peripheral blood and immune organs [6]. The focus of current research into sepsis and shock-induced immunosuppression has been to elucidate the molecular mechanisms underlying the persistent immunosuppressive state in cells that have survived both the acute phase of the disease, and have recovered after the widespread apoptotic event.