Brealey, D.A.; (2004) Mitochondrial dysfunction in critical illness. Doctoral thesis , University of London.

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Abstract

The mortality from septic shock is approximately 50%. Most patients die from the ensuing multi-organ dysfunction syndrome rather than the acute septic inflammatory process per se. The aetiology of the organ dysfunction is unknown. A characteristic phenomenon of an increasing severity of sepsis is a decrease in tissue oxygen extraction with a decrease (relative and/or absolute) in tissue oxygen consumption. Two theories have been advanced to explain this observed decrease in oxygen extraction. Traditionally, this has been ascribed to micro vascular shunting of blood away from nutrient capillaries. However, findings in both patients and animal models have demonstrated a raised tissue PO2, suggesting that the oxygen is available to cells but cannot be metabolised, i.e. a state of dysoxia. As mitochondria account for over 90% of total oxygen consumption, in the process of oxidative phosphorylation, it has been hypothesised that sepsis results in an inhibition of the mitochondrial enzymes involved in this process. If severe, this would be expected to lead to energy failure in the organs and, possibly, to initiation of apoptotic or necrotic cell death. Marked over-production of the intercellular messenger nitric oxide is a characteristic feature of sepsis; the mitochondrial damage theory has been given additional credence by the discovery that nitric oxide and its derivative, peroxynitrite, can inhibit or permanently damage mitochondrial enzymes involved in the oxidative phosphorylation pathway. The work leading to this thesis has demonstrated that sepsis is associated with an increase in nitric oxide production, a reduction in antioxidant protection, respiratory chain enzyme inhibition, and a depletion in tissue ATP levels. These changes were shown in both skeletal muscle biopsies obtained from critically ill patients in septic shock, and in skeletal muscle and liver biopsies obtained from a long-term septic rat model. These changes correlated with the severity of disease and eventual outcome. These findings thus demonstrate a mechanism that is present in both 'non-vital' and 'vital' organs, and across species. These findings may be epiphenomenal and causation needs to be definitively demonstrated. However, this work does suggest that mitochondrial dysfunction could be an important pathophysiological mechanism underlying sepsis-induced organ failure.

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