“Crossroads in Sepsis Research” Review Series Overview of the pathophysiology of sepsis

Abstract

Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation,Oklahoma City, OK, USASepsis is a life-threatening clinical syndrome that arises throughthe innate response to infection [1], and can appear as a compli-cation of trauma, cancer or major elective surgery [2]. Despitegreat strides being made in understanding the pathophysiologyand designing treatment for this disease, mortality rates stillremain unacceptably high. Currently, sepsis rivals myocardialinfarction as a common and potentially reversible cause of mortal-ity in the developed world. At least 8,000,000 people develop thissyndrome in the United States alone, and one-quarter of these diewithin 28 days of its onset. It is, therefore, of great importance toadvance our understanding and hopefully find appropriate therapyfor this major, and increasingly frequent medical problem.The pathogenesis of sepsis and its accompanying systemicinflammatory response syndrome (SIRS) reflect the inability of thebody to regulate the immune response [3] (Fig. 1). Sepsis initiatesas microbial components are recognized by soluble or cell-boundpattern recognition molecules or receptors, such as CD14 andToll-like receptors (TLRs). Activation of these receptors inducesthe transcription of inflammatory and immune response genes,often vianuclear factor-kB (NF-kB), and establishes a hyperactiveinflammatory response. Endothelial and epithelial cells, as well asneutrophils, macrophages and lymphocytes, produce the powerfulpro-inflammatory mediators, such as TNF- , interleukin (IL)-6, IL-1 and IL-8 [4]. Neutrophils and macrophages respond to thesemediators by releasing granular enzymes and producing reactiveoxygen species (ROS) such as H