The Role of the Endothelium in Systemic Inflammatory Response Syndrome and Sepsis

The terms systemic inflammatory response syndrome ( SIRS ), sepsis, severe sepsis, septic shock and multiorgan failure ( MOF ) are currently used to characterize the progressive stages of a very complex and therapeutically challenging disorder of the immune and inflammatory systems. Although SIRS is a result of a systemic activation of the innate immune system regardless of cause, sepsis, severe sepsis, and septic shock are accompanied by proven or suspected infection with or without impaired organ function. Despite tremendous research efforts for over 20 years, sepsis remains the leading cause of death in intensive care units (ICUs). SIRS and sepsis occur in approximately 750,000 patients per year in the United States, with a rising incidence of approximately 1.5% per year (1). With a mortality rate of currently 30% to 70%, sepsis and related disorders represent a major burden to the U.S. health care system, with costs estimated to be approximately $16.7 billion per year (2). The endothelium represents the natural barrier between the intravascular and extravascular spaces. However, endothelial cells (ECs) are not inactive “border controls”; in fact, among other functions, they are involved in maintaining vasomotor tone, blood flow, local balance of various mediators, programmed cell death (apoptosis), and hemostatic balance. During infectious conditions, activated leukocytes must transmigrate to infectious sites to engulf, phagocytose, and destroy invading microbes. This is an active process not only for the migrating leukocytes but also for the ECs. During this process, numerous pro- and anti-inflammatory mediators lead to activation of the endothelium and result in the expression of various adhesion molecules, which in turn facilitate or inhibit the transmigration of activated leukocytes into tissues. In addition, ECs can generate their own inflammatory mediators and express adhesion molecules.