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 h 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 proinflammatory 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.

Sepsis Disrupts Mitochondrial Function and Diaphragm Morphology

“…The Extensor digitorum longus (EDL), fast-twitch muscle, ex vivo -specific force decreases 1 week and 1 month in septic induced by cecal slurry compared with control mice ( Owen et al, 2019 ). Moreover, the ex vivo diaphragm function was reduced 6 and 24 h after sepsis induction ( Zolfaghari et al, 2015 ; Eyenga et al, 2021 ). This model resamples severe acute sepsis.…”

“…However, it did not present a significant change in the SOD protein level ( Talarmin et al, 2017 ). Another group demonstrated that acute sepsis increased H 2 O 2 production in the diaphragm ( Eyenga et al, 2021 ). Reduction in Sod expression observed herein can be a consequence of the decrease in Pgc1 α observed ( Figures 5 , 6 ).…”

Regulation of Oxidative Phosphorylation of Liver Mitochondria in Sepsis

“…Recently, we have shown, in an experimental model of sepsis, that early initiation of mechanical ventilation restores mitochondrial function in the diaphragm. In this study, not only did mechanical ventilation preserve the cytochrome c oxidase content and activity in the diaphragms of septic rats, but it also maintained the efficiency of oxidative phosphorylation (ATP:O) and lowered mitochondrial ROS production by Complex III [79]. In addition to these simple resuscitation measures, interfering with the inflammatory system [80] or cell signaling pathways [56] could improve the function of cytochrome c oxidase.…”

“…Moreover, the authors did not quantify the content of the cytochrome c oxidase subunit, so it cannot be excluded that the increase in oxygen consumption reflected increased oxygen reduction, but without efficient proton pumping [52]. Two recent studies have examined the effect of common symptomatic treatments for sepsis on the function of cytochrome c oxidase in the liver [78] and diaphragm in a rodent model of sepsis [79]. Yang et al [78] have shown that fluid resuscitation improves the function of cytochrome c oxidase; however, the mechanism remains unclear.…”

Aminophylline Improves Ventilator-Induced Diaphragmatic Dysfunction by Targeting IGF-1-FOXO1-MURF1 Pathway

“…Given the dense packing of mitochondria in skeletal muscles due to their high metabolic demand, a significant amount of reactive oxygen species (ROS) is produced in muscles after damage, a factor considered crucial for muscle functions. It has been established that ROS, primarily originating from mitochondria in the diaphragm, contributes to mitochondrial oxidative stress (MOS), playing a key role in promoting protein degradation and exacerbating VIDD [25,26]. Additionally, oxidative stress is known to activate a feedback loop with ROS, promoting autophagy, thereby creating a cycle of increased ROS generation and elevated autophagy levels [27].…”