Abstract
Mechanical ventilation (MV) is required to maintain life for patients with sepsis-related acute lung injury but can cause diaphragmatic myotrauma with muscle damage and weakness, known as ventilator-induced diaphragm dysfunction (VIDD). Hypoxia-inducible factor 1α (HIF-1α) plays a crucial role in inducing inflammation and apoptosis. Low-molecular-weight heparin (LMWH) was proven to have anti-inflammatory properties. However, HIF-1α and LMWH affect sepsis-related diaphragm injury has not been investigated. We hypothesized that LMWH would reduce endotoxin-augmented VIDD through HIF-1α. C57BL/6 mice, either wild-type or HIF-1α–deficient, were exposed to MV with or without endotoxemia for 8 h. Enoxaparin (4 mg/kg) was administered subcutaneously 30 min before MV. MV with endotoxemia aggravated VIDD, as demonstrated by increased interleukin-6 and macrophage inflammatory protein-2 levels, oxidative loads, and the expression of HIF-1α, calpain, caspase-3, atrogin-1, muscle ring finger-1, and microtubule-associated protein light chain 3-II. Disorganized myofibrils, disrupted mitochondria, increased numbers of autophagic and apoptotic mediators, substantial apoptosis of diaphragm muscle fibers, and decreased diaphragm function were also observed (p < 0.05). Endotoxin-exacerbated VIDD and myonuclear apoptosis were attenuated by pharmacologic inhibition by LMWH and in HIF-1α–deficient mice (p < 0.05). Our data indicate that enoxaparin reduces endotoxin-augmented MV-induced diaphragmatic injury, partially through HIF-1α pathway inhibition.
Highlights
Decreased diaphragm excursion and thickening fraction were observed in mice with endotoxemia subjected to VT = 10 mL/kg compared with the other Mechanical ventilation (MV) treatment groups and the non-ventilated control mice (Figure 1H,I)
Increased levels of malondialdehyde (MDA), macrophage inflammatory protein-2 (MIP-2), and IL-6 but decreased production of total antioxidant capacity was observed in mice with endotoxemia subjected to VT = 10 mL/kg compared with the other MV treatment groups and the non-ventilated control mice (Figure 2A–D)
MV has been proven to evoke the production of proinflammatory cytokines and contribute to ventilator-induced diaphragmatic dysfunction (VIDD), and infection is a primary risk factor for the development of severe diaphragm weakness in critically ill patients receiving MV [29]
Summary
Mechanical ventilation (MV) is indispensable for patients with acute respiratory failure, but it may entail patient dependence on ventilators due to rapid deterioration of diaphragm muscle endurance and strength, known as ventilator-induced diaphragmatic dysfunction (VIDD) [7,8,9]. Endotoxin is known to stimulate calpain activation influenced by the increased levels of oxidative stress in the diaphragm [12]. Sepsis-exacerbated diaphragm damage and VIDD are considered to share common molecular mechanisms, including increased oxidative stress, muscle proteolysis (emerging from calpain, caspase-3, autophagy–lysosomal pathway, and ubiquitin–proteasome system activation), and mitochondrial abnormalities within the diaphragm myofibrils, implying that sepsis may be a synergistic contributor to VIDD [12,13]. The mechanisms orchestrating the interactions among sepsis, MV, and these inflammatory cascades remain unclear
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