Mitochondrially Targeted Therapies for Sepsis Induced Diaphragm Dysfunction

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Severe ICU acquired diaphragm dysfunction is present in the majority of mechanically ventilated MICU patients. Importantly, recent work indicates that patients with weak diaphragms have a much longer requirement for mechanical ventilation and a markedly higher mortality. As a result, therapies that increase diaphragm function have the potential to improve MICU patient outcomes. These recent studies also suggest that a major risk factor for ICU acquired diaphragm weakness is infection. Infections elicit a marked increase in diaphragm mitochondrial free radical production, and these free radicals contribute to weakness and fatigue. The present proposal, therefore, will test the hypothesis that pharmacological therapies designed to either inhibit mitochondrial free radical generation or induce mitochondrial repair will prevent and/or reverse sepsis mediated diaphragm dysfunction. This theory will be tested in four groups of studies: Aim 1 studies will test the hypothesis that sepsis induced diaphragm dysfunction can be reduced by using agents which inhibit mitochondrial free radicals. Experiments will utilize the cecal ligation puncture sepsis model (CLP) and compare diaphragm function in sham operated, CLP, CLP plus drug, and sham plus drug groups. Drugs to be tested include mitoTEMPOL, SKQ1, and necrostatin. Aim 2 studies will test the hypothesis that administration of activators of mitochondrial biogenesis can improve infection induced diaphragm dysfunction. Sepsis will again be produced with CLP and we will examine the ability of three treatments (i.e. AICAR+PQQ, PQQ, and AICAR+GW1506) to prevent CLP induced diaphragm dysfunction. Aim 3 studies will evaluate the mechanisms by which Aim 1 and Aim 2 drugs produce their effects on muscle cells. These experiments will also test the hypothesis that these agents induce release of myokines which have autocrine effects to attenuate cytokine induced muscle cell damage. Aim 4 studies will test the hypothesis that myokine administration can be used as a pharmacological treatment to attenuate sepsis induced diaphragm dysfunction in animals. Myokines to be tested include irisin and other proteins found in Aim 3 studies to block cytokine induced muscle cell damage in vitro.