Mitochondrial dysfunction in septic shock and multiple organ dysfunction syndrome
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.
Section snippets
The case for ‘cytopathic hypoxia’: a historical perspective
The causal link between inadequate tissue oxygen delivery and mortality of critically ill patients was proposed 40 years ago in a frequently cited publication (Broder and Weil, 1964). The study group consisted of 56 patients with ‘clinical signs of circulatory failure’, including patients with heart failure, sepsis, and hypovolemia, wherein blood lactate levels were monitored over time. Based on the assumption that excess blood lactate levels equate with accelerated anaerobic metabolism or
In vitro mitochondrial analyses
The functional status of mitochondria in vital organs during sepsis has been a topic of controversy for over 3 decades. In an elegant study published in 1971, Mela and colleagues assessed the respiratory capacity of rat liver mitochondria in the context of shock induced by either Escherichia coli endotoxin or hemorrhage (Mela et al., 1971). A lethal dose of endotoxin was shown to induce ultrastructural mitochondrial damage within 2–3 h, at which time ADP-linked mitochondrial respiration was
If not ischemia, what are the mechanisms of mitochondrial damage during sepsis?
Acute infectious insults, particularly circulating factors such as live bacteria or components of bacteria (e.g. LPS), are rapidly detected by the immune system through various receptors found on macrophages and monocytes, including CD 14 and toll-like receptors, resulting in a vigorous inflammatory response (reviewed in Oberholzer et al., 2001) and, in many cases, refractory systemic hypotension (shock). Although tissue ischemia attendant to shock undoubtedly contributes to mitochondrial
Depletion of mitochondrial DNA during sepsis
The mitochondrial genome is particularly prone to oxidative stress. Mitochondrial DNA (mtDNA) is directly susceptible to attack by ROS produced during oxidative phosphorylation, and mitochondrial DNA lack histones and requisite repair enzymes that are protective of nuclear DNA. Moreover, expression of the entire mitochondrial genome is required to maintain the functional integrity of mitochondria; whereas, only about 7% of the nuclear genome is ever expressed at any given stage of cellular
Summary
Given that mitochondria are the primary source of cellular ATP, key regulators of cell death and the major producers of ROS, there is a strong likelihood that mitochondrial pathology, such as documented in cases of severe sepsis in humans and in relevant models of sepsis, contributes significantly to morbidity and mortality in the clinical setting. In particular, mitochondrial death pathways appear to participate in the depletion of lymphocytes and intestinal epithelial cells (Coopersmith et
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