Suppression of hypoxia‐inducible factor 1α by low‐molecular‐ weight heparin mitigates ventilation‐induced diaphragm dysfunction in a murine endotoxemia model

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 micro-tubule‐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.