Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 23, Issue 3, Pages -Publisher
MDPI
DOI: 10.3390/ijms23031083
Keywords
autophagy; biogenesis; dynamics; hypoxia-inducible factor-1 alpha; mitochondria; ventilator-induced diaphragm dysfunction
Funding
- Ministry of Science and Technology [107-2314-B-182A-143-MY3]
- Chang Gung Medical Research Project [CMRPG2L0301]
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Mechanical ventilation combined with endotoxin administration exacerbates diaphragmatic dysfunction and mitochondrial damage through the HIF-1 alpha signaling pathway.
Mechanical ventilation (MV) is essential for patients with sepsis-related respiratory failure but can cause ventilator-induced diaphragm dysfunction (VIDD), which involves diaphragmatic myofiber atrophy and contractile inactivity. Mitochondrial DNA, oxidative stress, mitochondrial dynamics, and biogenesis are associated with VIDD. Hypoxia-inducible factor 1 alpha (HIF-1 alpha) is crucial in the modulation of diaphragm immune responses. The mechanism through which HIF-1 alpha and mitochondria affect sepsis-related diaphragm injury is unknown. We hypothesized that MV with or without endotoxin administration would aggravate diaphragmatic and mitochondrial injuries through HIF-1 alpha. C57BL/6 mice, either wild-type or HIF-1 alpha-deficient, were exposed to MV with or without endotoxemia for 8 h. MV with endotoxemia augmented VIDD and mitochondrial damage, which presented as increased oxidative loads, dynamin-related protein 1 level, mitochondrial DNA level, and the expressions of HIF-1 alpha and light chain 3-II. Furthermore, disarrayed myofibrils; disorganized mitochondria; increased autophagosome numbers; and substantially decreased diaphragm contractility, electron transport chain activities, mitofusin 2, mitochondrial transcription factor A, peroxisome proliferator activated receptor-gamma coactivator-1 alpha, and prolyl hydroxylase domain 2 were observed (p < 0.05). Endotoxin-stimulated VIDD and mitochondrial injuries were alleviated in HIF-1 alpha-deficient mice (p < 0.05). Our data revealed that endotoxin aggravated MV-induced diaphragmatic dysfunction and mitochondrial damages, partially through the HIF-1 alpha signaling pathway.
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