Mechanical Ventilation Preserves Diaphragm Mitochondrial Function in a Rat Sepsis Model

Abstract

Background: To describe the effect of mechanical ventilation on diaphragm mitochondrial oxygen consumption, ATP production, reactive oxygen species (ROS) generation, and cytochrome-c oxidase activity and content, and their relationship to diaphragm strength in an experimental model of sepsis.Methods: A cecal ligation and puncture (CLP) protocol was performed in 12 rats while 12 controls underwent sham-operation. Half of the rats in each group were paralyzed and mechanically ventilated. We performed blood gas analysis and lactic acid assays 6 hours after surgery. Afterwards, we measured diaphragm strength and mitochondrial oxygen consumption, ATP and ROS generation, and cytochrome-c oxidase activity. We also measured malondialdehyde (MDA) content as an index of lipid peroxidation, and mRNA expression of the pro-inflammatory interleukin-1β (IL-1β) in diaphragms.Results: CLP rats showed severe hypotension, metabolic acidosis, and upregulation of diaphragm IL-1β mRNA expression. Compared to sham controls, spontaneously breathing CLP rats showed lower diaphragm force and increased susceptibility to fatigue, along with depressed mitochondrial oxygen consumption and ATP production and cytochrome-c oxidase activity. These rats also showed increased mitochondrial ROS generation and MDA content. Mechanical ventilation markedly restored mitochondrial oxygen consumption and ATP production in CLP rats; lowered mitochondrial ROS production by the complex 3; and preserved cytochrome-c oxidase activity.Conclusion: In an experimental model of sepsis, early initiation of mechanical ventilation restores diaphragm mitochondrial function.