Impact of a Novel PI3-KINASE Inhibitor in Preventing Mitochondrial DNA Damage and Damage Associated Molecular Pattern Accumulation: Results from the Biochronicity Project.

BACKGROUND: Despite improvements in the management of severely injured patients, development of multiple organ dysfunction syndrome (MODS) remains a morbid complication of traumatic shock. One of the key attributes of MODS is a profound bioenergetics crisis, for which the mediators and mechanisms are poorly understood. We hypothesized that metabolic uncoupling using an experimental PI3-kinase inhibitor, LY294002 (LY), may prevent mitochondrial abnormalities that lead to the generation of mitochondrial DNA (mtDNA) damage and the release of mtDNA damage associated molecular patterns (DAMPs) METHODS: 16 swine were studied using LY294002 (LY), a non-selective PI3-KI: Animals were assigned to Trauma only (TO, N=3); LY drug only (LYO, N=3); and Experimental (N=10), trauma + drug (LY+T) groups. Both trauma groups underwent laparotomy, 35% hemorrhage, severe ischemia/reperfusion injury, and protocolized resuscitation. A battery of hemodynamic, laboratory, histologic, and bioenergetic parameters were monitored. mtDNA damage was determined in lung, liver, and kidney using Southern blot analyses, while plasma mtDNA DAMP analysis employed PCR amplification of a 200 bp sequence of the mtDNA D-loop region. RESULTS: Relative to control animals, H+I/R produced severe, time dependent decrements in hepatic, renal, cardiovascular, and pulmonary function accompanied by severe acidosis and lactate accumulation indicative of bioenergetics insufficiency. The H-I/R-animals displayed prominent oxidative mtDNA damage in all organs studied, with the most prominent damage in the liver. mtDNA damage was accompanied by accumulation of mtDNA DAMPs in plasma. Pre-treatment of H+I/R animals with LY294002 resulted in profound metabolic suppression, with approximate 50% decreases in O2 consumption and CO2 production. In addition, it prevented organ and bioenergetics dysfunction and was associated with a significant decrease in plasma mtDNA DAMPs to the levels of control animals. CONCLUSIONS: These findings show that H+I/R injury in anesthetized swine is accompanied by MODS and by significant mitochondrial bioenergetic dysfunction, including oxidative mtDNA damage and accumulation in plasma of mtDNA DAMPs. Suppression of these changes with the PI3K inhibitor LY294002 indicates that pharmacologically-induced metabolic uncoupling may comprise a new pharmacologic strategy to prevent mtDNA damage and DAMP release and prevent or treat trauma-related MODS. LEVEL OF EVIDENCE: III STUDY TYPE: Therapeutic Study (C) 2017 Lippincott Williams & Wilkins, Inc.

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