Yina Liu1, Shengtian Mu2, Xu Li1, Yingjian Liang1, Liang Wang1, Xiaochun Ma3. 1. Department of Critical Care Medicine, The First Affiliated Hospital, China Medical University, Shenyang, People's Republic of China. 2. Department of Critical Care Medicine, Liaoning Cancer Hospital and Institute, Shenyang, People's Republic of China. 3. Department of Critical Care Medicine, The First Affiliated Hospital, China Medical University, Shenyang, People's Republic of China. Electronic address: cmu1hicu2002@sina.com.
Abstract
BACKGROUND: Unfractionated heparin (UFH) has been shown to ameliorate lung edema and lung vascular leakage in lipopolysaccharide-induced lung injury. Impaired tight junction (TJ) function is a sign of sepsis-induced acute respiratory distress syndrome (ARDS) and acute lung injury (ALI), which is closely related to the downregulated expression of TJ-specific proteins or the upregulated expression of inflammatory cytokines. Because UFH has been intensively studied in modulating inflammation, we hypothesize that UFH may play a positive role in treating sepsis-induced ARDS/ALI by protecting TJs. MATERIAL AND METHODS: Rat sepsis-induced lung injury was induced by cecal ligation and puncture and treated with UFH. Hematoxylin and eosin staining, lung wet/dry weight (W/D) ratio, and pulmonary microvascular leakage were evaluated to assess lung injury. Cytokines in bronchoalveolar lavage fluid were detected to determine lung inflammation. A transendothelial electrical resistance assay, a Transwell permeability assay, and transmission electron microscopy were used to study endothelial TJs in human lung microvascular endothelial cells. TJ protein expression was measured by western blotting or immunohistochemistry. RESULTS: UFH treatment alleviated lung injury in vivo by reducing IL-6 in bronchoalveolar lavage fluid and protecting TJs in LMVECs. UFH also protected TJs against lipopolysaccharide-stimulated damage and functioned upstream by inhibiting the ERK1/2 MAPK pathway to attenuate endothelial hyperpermeability and downregulating the expression of TJ proteins such as claudin-5, occludin, and ZO-1. CONCLUSIONS: These findings suggested that UFH has therapeutic potential for sepsis-induced ARDS or ALI through protecting TJs in LMVECs.
BACKGROUND: Unfractionated heparin (UFH) has been shown to ameliorate lung edema and lung vascular leakage in lipopolysaccharide-induced lung injury. Impaired tight junction (TJ) function is a sign of sepsis-induced acute respiratory distress syndrome (ARDS) and acute lung injury (ALI), which is closely related to the downregulated expression of TJ-specific proteins or the upregulated expression of inflammatory cytokines. Because UFH has been intensively studied in modulating inflammation, we hypothesize that UFH may play a positive role in treating sepsis-induced ARDS/ALI by protecting TJs. MATERIAL AND METHODS:Rat sepsis-induced lung injury was induced by cecal ligation and puncture and treated with UFH. Hematoxylin and eosin staining, lung wet/dry weight (W/D) ratio, and pulmonary microvascular leakage were evaluated to assess lung injury. Cytokines in bronchoalveolar lavage fluid were detected to determine lung inflammation. A transendothelial electrical resistance assay, a Transwell permeability assay, and transmission electron microscopy were used to study endothelial TJs in human lung microvascular endothelial cells. TJ protein expression was measured by western blotting or immunohistochemistry. RESULTS:UFH treatment alleviated lung injury in vivo by reducing IL-6 in bronchoalveolar lavage fluid and protecting TJs in LMVECs. UFH also protected TJs against lipopolysaccharide-stimulated damage and functioned upstream by inhibiting the ERK1/2MAPK pathway to attenuate endothelial hyperpermeability and downregulating the expression of TJ proteins such as claudin-5, occludin, and ZO-1. CONCLUSIONS: These findings suggested that UFH has therapeutic potential for sepsis-induced ARDS or ALI through protecting TJs in LMVECs.
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