High Tidal Volume Induces Mitochondria Damage and Releases Mitochondrial DNA to Aggravate the Ventilator-Induced Lung Injury

Abstract

ObjectiveThis study aimed to determine whether high tidal volume (HTV) induce mitochondria damage and mitophagy, contributing to the release of mitochondrial DNA (mtDNA). Another aim of the present study was to investigate the role and mechanism of mtDNA in ventilator-induced lung injury (VILI) in rats.MethodsRats were tracheotomized and allowed to breathe spontaneously or mechanically ventilated for 4 h. After that, lung injury was assessed. Inhibition of toll-like receptor 9 (TLR9), named ODN2088, was used to determine the involvement of TLR9/myeloid differentiation factor 88 (MyD88)/nuclear factor-κB (NF-κB) signaling pathway in VILI. The mitochondrial damage and release of mtDNA were assessed. Pharmacological inhibition of mtDNA (chloroquine) was used to determine whether mtDNA trigger inflammation via TLR9 in VILI. EDU-labeled mtDNA deriving from mitophagy was assessed by immunofluorescence. The role of mitophagy in VILI was shown by administration of antimycin A and cyclosporine A.Main resultsRats subjected to HTV showed more severe pulmonary edema and inflammation than the other rats. The decreased expression of TLR9, MyD88, and NF-κB were observed following the use of ODN2088. Mechanical ventilation (MV) with HTV damaged mitochondria which resulted in dysfunctional ATP synthesis, accumulation of reactive oxygen species, and loss of mitochondrial membrane potential. Moreover, the results of distribution of fluorescence in rats upon HTV stimulation indicated that mtDNA cleavage was associated with mitophagy. The expression levels of mitophagy related genes (LC3B-II/LC3B-I, PINK1, Parkin, and mitofusin 1) in animals ventilated with HTV were significantly upregulated. Administration of antimycin A aggregated the histological changes and inflammation after MV, but these effects were attenuated when administered in the presence of cyclosporine A.ConclusionMV with HTV induces mitochondrial damage and mitophagy, contributing to the release of mtDNA, which may be induced VILI in rat via TLR9/MyD88/NF-κB signaling pathway.

Mitophagy-Mediated mtDNA Release Aggravates Stretching-Induced Inflammation and Lung Epithelial Cell Injury via the TLR9/MyD88/NF-κB Pathway

“…Previous work in rats suggested that VILI damages mitochondria primarily through mitophagy, such that mitophagy-released mtDNA makes up a significant fraction of total mtDNA (Lin et al, 2018). Consistent with this idea, we found that A549 cells after CS at 20% tension up-regulated the level of mtDNA-79 and mtDNA-230 ( Figures 1G,H).…”

“…It suggested that A549 cells before CS did not activate autophagy; A549 cells immediately after CS induced autophagy with autophagosomes; A549 cells at 4.0 h after the end of CS showed the advanced autophagy with autolysosomes. Our results suggested that our cell culture model of CS recapitulates the mitophagy-induced release of mtDNA that we observed in our rat model of mechanical ventilation (Lin et al, 2018).…”

Mitochondrial Dysfunction, Oxidative Stress, and Neuroinflammation: Intertwined Roads to Neurodegeneration

“…However, mitochondrial ROS also participate in other cellular processes including the activation of mitochondrial permeability transition pore (mPTP), dysregulation of mitophagy, imbalances in mitochondrial dynamics, and programmed cell death [48]. These processes represent potential routes for mtDNA displacement following ROS burst as evidenced by the finding of oxidized mtDNA fragments outside of mitochondria in the setting of several metabolic diseases [43,[49][50][51][52][53] (Figure 1). Under several stressors (e.g., mitochondrial dysfunction and consequent reactive oxygen species (ROS) production, viral and bacterial infections), several types of damage are inflicted to mitochondrial DNA (mtDNA) and a set of signaling pathways are activated to promote mitochondrial recovery or demise depending on the damage severity.…”

Inhibition of calcineurin/NFATc4 signaling attenuates ventilator‑induced lung injury

“…although essential in critically ill patients, mechanical ventilation often induces or aggravates lung injury, which is termed Vili (21). accumulating studies (22,23) have revealed that Vili is mainly characterized by increases in pulmonary vascular permeability, influxes of inflammatory cells and various cytokines. These inflammatory cells could produce inflammatory cytokines.…”