Mitochondrial dysfunction in septic shock and multiple organ dysfunction syndrome

Abstract

Sepsis is the leading cause of death in medical intensive care units. In most fatal cases of sepsis the patient experiences an insidious, progressive decline in vital organ function, i.e. multiple organ dysfunction syndrome (MODS), which is commonly associated with signs of accelerated anaerobic metabolism despite supernormal systemic oxygen delivery. Based on this clinical scenario, tissue hypoxia has long been considered the putative mechanism of MODS. However, efforts to enhance tissue oxygenation during severe sepsis have proved ineffective, and a growing body of evidence indicates that mitochondria contribute significantly to the pathogenesis of sepsis-induced MODS. In addition to dysregulation of oxygen metabolism (‘cytopathic hypoxia’), sepsis-induced mitochondrial dysfunction contributes to organ injury through accelerated oxidant production and by promoting cell death. Advances in our understanding of the mechanisms of mitochondrial damage and in its detection could revolutionize the management of this devastating disease.

Introduction

Sepsis is the leading cause of death in medical intensive care units, accounting for an estimated 215,000 deaths per year in the USA alone (Angus et al., 2001). Despite the gravity of the problem, the ultimate cause of death in septic patients remains obscure. In most cases, infections are successfully eradicated from the host by way of an intense, localized inflammatory response. By contrast, fatal infections are characterized by an inability to contain the inflammatory response such that potent cytokines are released into the systemic circulation, thereby activating inflammatory cells in remote locations, a condition referred to as ‘the systemic inflammatory response syndrome’ (SIRS). As illustrated schematically in Fig. 1, it is theorized that SIRS promotes systemic organ injury and dysfunction, but the exact mechanism is unclear. Possibilities include inadequate tissue oxygenation related to maldistribution of blood flow (DeBacker et al., 2002), ‘collateral tissue damage’ caused by activated immune cells (Abraham, 2003), and cytopathic changes consequent to cytokine-cell receptor interactions. Whatever the cause, organ (cell) damage perpetuates SIRS by further activating macrophages (Scaffidi et al., 2002). This feed-forward mechanism explains why patients typically die of ‘multiple organ dysfunction syndrome’ (MODS) days to weeks after the onset of the initial infection, and in many cases, after the original infection had been eradicated (Czura and Tracey, 2003).

To date, most of the intellectual energy of the critical care community has focused on optimization of tissue oxygenation to avoid ischemic cell damage and modulation of the immune system to protect against the ravaging effects of SIRS, but the results of each line of investigation have been equally disappointing. Despite billions of dollars invested, no specific drug or therapy has been developed to effectively prevent the onset of SIRS or MODS. For instance, immunomodulation strategies, such as anti-TNFα or anti-endotoxin antibodies, appear to be of little or no benefit in humans (Freedman and Natanson, 2000), and efforts to enhance tissue oxygen delivery are at least of no benefit and may ultimately be harmful to patients with established sepsis (Hayes et al., 1994, Gattinoni et al., 1995). Based on the disappointing results of previous studies, and in view of the fact that mortality due to sepsis is on the rise (Angus et al., 2001), an objective reappraisal of the relationship between sepsis and MODS is indicated.

Recent investigations indicate that mitochondria are primary targets of injury in systemic organs during the acute phase of sepsis. As will be apparent from the following discussion, debate surrounding the role played by mitochondria in the failure of vital organs during severe sepsis has come full circle over 30 years, and the controversy continues. In the final analysis, advances in our understanding of mitochondria, coupled with new clinical and experimental evidence, strongly support a contributory role of mitochondria to the pathogenesis of sepsis-induced MODS.