Reduction in Ventilation-Induced Diaphragmatic Mitochondrial Injury through Hypoxia-Inducible Factor 1α in a Murine Endotoxemia Model

• Published in: International journal of molecular sciences 2022-01, Vol.23 (3), p.1083
• Main Authors: Li, Li-Fu, Yu, Chung-Chieh, Wu, Huang-Pin, Chu, Chien-Ming, Huang, Chih-Yu, Liu, Ping-Chi, Liu, Yung-Yang
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Atrophy; Autophagy; biogenesis; Biosynthesis; Contractility; Cytochrome; Diaphragm; Diaphragm (Anatomy); Diaphragm - injuries; Diaphragm - metabolism; Diaphragm - physiopathology; Disease Models, Animal; dynamics; Dynamin; Electron transport; Electron transport chain; Endotoxemia; Endotoxemia - etiology; Endotoxemia - metabolism; Endotoxemia - therapy; Endotoxins; Endotoxins - adverse effects; Free radicals; Gene Knockout Techniques; Hydroxylase; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit - genetics; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Hypoxia-inducible factor 1a; hypoxia-inducible factor-1α; Immune response; Immunomodulation; Injuries; Injury prevention; Kinases; Mice; Mice, Inbred C57BL; Mitochondria; Mitochondria - metabolism; Mitochondrial DNA; Muscle Contraction; Myofibrils; Oxidation; Oxidative Stress; Prolyl hydroxylase; Proteins; Respiration, Artificial - adverse effects; Respiratory failure; Rodents; Sepsis; Signal Transduction; Ventilation; ventilator-induced diaphragm dysfunction; Ventilators; Weaning
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms23031083

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 1α (HIF-1α) is crucial in the modulation of diaphragm immune responses. The mechanism through which HIF-1α 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-1α. C57BL/6 mice, either wild-type or HIF-1α-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-1α 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-γ coactivator-1α, and prolyl hydroxylase domain 2 were observed ( < 0.05). Endotoxin-stimulated VIDD and mitochondrial injuries were alleviated in HIF-1α-deficient mice ( < 0.05). Our data revealed that endotoxin aggravated MV-induced diaphragmatic dysfunction and mitochondrial damages, partially through the HIF-1α signaling pathway.