title: Unfractionated heparin inhibits lipopolysaccharide-induced inflammatory response through blocking p38 MAPK and NF-κB activation on endothelial cell.
abstract: Heparins, including unfractionated heparin (UFH) and low-molecular-weight heparins (LMWH), are glycosaminoglycans that are largely used as anti-thrombotic drugs. While the mechanisms of their anticoagulant actions in blood have been extensively studied, their effects on the inflammation of the endothelium are still under investigation since the endothelium plays a central role in sepsis. Furthermore, UFH is much cheaper than LMWH. The aim of this study was to determine how UFH regulates lipopolysaccharide (LPS)-induced inflammatory response on endothelial cells in vitro, and define the role of p38 mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) in mediating this effect. Human pulmonary microvascular endothelial cells (HPMECs) were pretreated with UFH (0.01 U/ml-10 U/ml), prior to stimulation with LPS (10 μg/ml). Markers of systemic inflammation and endothelial activation were assessed. Interleukin (IL)-1β, IL-6, E-selectin, intercellular adhesion molecule (ICAM)-1 release were subsequently measured at 2h, 6h and 12h. Phosphorylation of p38 MAPK at 2h, 6h and nuclear translocation of the proinflammatory NF-κB at 2h were assessed. In HPMEC, UFH significantly attenuated LPS-induced production of IL-1β, IL-6, E-selectin and ICAM-1, as well as phosphorylation of p38 MAPK and NF-κB translocation, especially in 10 U/ml. In conclusion, UFH at high dose significantly protects against endothelial-cell-mediated immune response. The inhibition of p38 MAPK and NF-κB activation certainly represents one of the mechanisms by which UFH exerts its anti-inflammatory effect.
authors: Department of Intensive Care Unit, The First Affiliated Hospital, China Medical University, Bei-er Road 92, Shenyang 110001, Liaoning Province, PR China.
authors: Xu
authors: X
authors: Li
authors: Zhen
authors: Z
authors: Zheng
authors: Xin
authors: X
authors: Li
authors: Xiaochun
authors: X
authors: Ma
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D015153:Blotting, Western; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D019040:E-Selectin / Q000235:genetics / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006493:Heparin / Q000494:pharmacology*; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism*; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008168:Lung / Q000098:blood supply; D055806:Microvessels / Q000166:cytology; D000072000:NF-KappaB Inhibitor alpha; D010766:Phosphorylation / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051996:Transcription Factor RelA / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D016207:Cytokines; D019040:E-Selectin; D020672:I-kappa B Proteins; D018836:Inflammation Mediators; D053583:Interleukin-1beta; D015850:Interleukin-6; D008070:Lipopolysaccharides; C000606204:NFKBIA protein, human; D051996:Transcription Factor RelA; D018799:Intercellular Adhesion Molecule-1; D000072000:NF-KappaB Inhibitor alpha; D006493:Heparin; D048051:p38 Mitogen-Activated Protein Kinases