Low-Molecular-Weight Heparin Reduces Ventilation-Induced Lung Injury through Hypoxia Inducible Factor-1α in a Murine Endotoxemia Model

• Published in: International journal of molecular sciences Vol. 21; no. 9; p. 3097
• Main Authors: Li, Li-Fu, Liu, Yung-Yang, Lin, Shih-Wei, Chang, Chih-Hao, Chen, Ning-Hung, Hung, Chen-Yiu, Lee, Chung-Shu
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 28-04-2020; MDPI
• Subjects: Animals; Anti-Inflammatory Agents - administration & dosage; Anti-Inflammatory Agents - pharmacology; Anticoagulants; Apoptosis; Chemokine CXCL2 - metabolism; Cytokines; Disease Models, Animal; Edema; Endotoxemia; Endotoxemia - chemically induced; Endotoxemia - genetics; Endotoxemia - metabolism; Endotoxemia - rehabilitation; Endotoxins; Enoxaparin - administration & dosage; Enoxaparin - pharmacology; Free radicals; Gene expression; Gene Expression Regulation - drug effects; Growth factors; Heparin; Hypoxia; hypoxia-inducible factor; Hypoxia-Inducible Factor 1, alpha Subunit - genetics; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Hypoxia-inducible factors; Inflammation; Injections, Subcutaneous; Injuries; Injury prevention; Interleukin 6; Interleukin-6 - metabolism; Lipopolysaccharides - adverse effects; low-molecular-weight heparin; Lungs; Macrophage inflammatory protein; Male; Metastases; Mice; Microvasculature; mRNA; Multiple organ dysfunction syndrome; Neutrophils; Oxidative stress; Oxidative Stress - drug effects; Permeability; Proteins; Respiration, Artificial - adverse effects; Respiratory function; Salmonella typhi - metabolism; Salmonella typhi - pathogenicity; Sepsis; Transcription factors; Tumor Necrosis Factor-alpha - metabolism; Tumor necrosis factor-TNF; Tumor necrosis factor-α; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - metabolism; ventilator-induced lung injury; Ventilator-Induced Lung Injury - drug therapy; Ventilator-Induced Lung Injury - etiology; Ventilator-Induced Lung Injury - genetics; Ventilator-Induced Lung Injury - metabolism; Ventilators; Weight reduction; hypoxia-inducible factor; low-molecular-weight heparin; ventilator-induced lung injury; endotoxemia
• DOI: 10.3390/ijms21093097
• EISSN: 1422-0067
• ISSN: 1422-0067; 1661-6596

Patients with sepsis frequently require mechanical ventilation (MV) to survive. However, MV has been shown to induce the production of proinflammatory cytokines, causing ventilator-induced lung injury (VILI). It has been demonstrated that hypoxia-inducible factor (HIF)-1α plays a crucial role in inducing both apoptotic and inflammatory processes. Low-molecular-weight heparin (LMWH) has been shown to have anti-inflammatory activities. However, the effects of HIF-1α and LMWH on sepsis-related acute lung injury (ALI) have not been fully delineated. We hypothesized that LMWH would reduce lung injury, production of free radicals and epithelial apoptosis through the HIF-1α pathway. Male C57BL/6 mice were exposed to 6-mL/kg or 30-mL/kg MV for 5 h. Enoxaparin, 4 mg/kg, was administered subcutaneously 30 min before MV. We observed that MV with endotoxemia induced microvascular permeability; interleukin-6, tumor necrosis factor-α, macrophage inflammatory protein-2 and vascular endothelial growth factor protein production; neutrophil infiltration; oxidative loads; HIF-1α mRNA activation; HIF-1α expression; bronchial epithelial apoptosis; and decreased respiratory function in mice (
< 0.05). Endotoxin-induced augmentation of VILI and epithelial apoptosis were reduced in the HIF-1α-deficient mice and in the wild-type mice following enoxaparin administration (
< 0.05). Our data suggest that enoxaparin reduces endotoxin-augmented MV-induced ALI, partially by inhibiting the HIF-1α pathway.