Abstract
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 (p < 0.05). Endotoxin-stimulated VIDD and mitochondrial injuries were alleviated in HIF-1α-deficient mice (p < 0.05). Our data revealed that endotoxin aggravated MV-induced diaphragmatic dysfunction and mitochondrial damages, partially through the HIF-1α signaling pathway.
Highlights
Hypoxia-inducible factor 1α (HIF-1α)-deficient mice were employed to identify the role of HIF-1α in the modulation of stretch-mediated diaphragm and mitochondrial injuries following endotoxin administration
Decreased diaphragm contractility was observed in mice with endotoxemia subjected to Mechanical ventilation (MV) compared with those without endotoxemia subjected to MV and compared with nonventilated control mice (Figure 1F)
We observed substantial reduction in muscle fiber diameter in mice with endotoxemia subjected to MV compared with those without endotoxemia subjected to MV and compared with nonventilated control mice (Figure 1G)
Summary
Mechanical ventilation (MV) is often lifesaving for patients with sepsis-related multiple organ failure. Prolonged MV can contribute to ventilator-induced diaphragm dysfunction (VIDD), which is characterized by diaphragmatic inactivity and the rapid decline of diaphragm muscle endurance and contractility [1,2,3,4,5,6,7,8]. Sepsis-mediated profound inflammation may provoke diaphragm stretch-related injuries through the enhancement of sarcolemma membrane fragility and aggravate defects in the essential steps of the muscular respiration energy supply chain [9,10]. Sepsis is associated with increased oxidative load, lung tissue hypoxia, and reduction in mitochondrial biogenesis of skeletal muscle [11]. Identifying the effect of the interaction between sepsis and MV on diaphragm dysfunction is clinically crucial
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