Potential for Gene Therapy in the Treatment of Sepsis

Abstract

It now appears that much of the tissue injury which occurs in sepsis is a consequence of the inflammatory response run amok. This conclusion seemed first apparent when it became clear that the accumulation of neutrophils and their activation was intimately related to the pathogenesis of sepsis induced injury. The simple pathogenetic scheme initially cast neutrophils in the central role and implicated toxic products of neutrophils as the proximate mediators of cell injury. This concept provided several rationales for designing therapeutic interventions. These included interventions which might alter responses of neutrophils to activating stimuli and interventions which might inactivate either aggressive oxygen species or proteolytic enzymes released by activated neutrophils. As our understanding of the inflammatory process has progressed, the complexity of that process has become more clear. It is now obvious that a host of factors including cytokines, cell adhesion molecules, lipid mediators, and biologically active factors derived from endothelial cells, epithelial cells, and other cells all play important roles in inflammation and that all of these factors network their effects to result in the inflammatory response. While greatly complicating perception of the pathogenetic process in sepsis, this complexity offers a large number of new possibilities for therapeutic intervention. Several such interventions are currently under intensive investigation in the laboratory and some have reached the level of clinical investigation. Both increased understanding of the pathogenesis of sepsis induced injury and the emergence of many new pharmacologic agents with specific effects on the inflammatory response hold promise that effective pharmacologic intervention will be identified.