title: HMGB1 Neutralizing Antibody Attenuates Cardiac Injury and Apoptosis Induced by Hemorrhagic Shock/Resuscitation in Rats.
abstract: High-mobility group box 1 (HMGB1) and its natural receptor, Toll-like receptor-4 (TLR4), are involved in various infectious or noninfectious diseases including hemorrhagic shock. HMGB1 neutralizing antibody (anti-HMGB1 monoclonal antibody (mAb)) treatment was shown to alleviate ischemia-reperfusion injury effectively. The aim of this study was to explore whether and by what mechanisms anti-HMGB1 mAb attenuates hemorrhagic shock and resuscitation (HS/R)-induced cardiac injury. Employing rat HS/R models, we found that anti-HMGB1 mAb treatment improved HS/R-induced cardiac function deterioration, attenuated cardiac enzyme elevation, improved ATP loss, and protected cardiac tissue. Anti-HMGB1 mAb also inhibited the production of inflammatory factors interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α). Moreover, anti-HMGB1 mAb reduced apoptotic responses by suppressing activated caspase-3 and reversing apoptotic gene expression of capase-3, Bax, and Bcl-2 in rat cardiac tissue. Moreover, anti-HMGB1 mAb decreased HS/R-induced HMGB1 and TLR4 expression elevation. We further confirmed that anti-HMGB1 mAb inhibited lipopolysaccharide-activated HGMB1 and TLR4 expression and decreased inflammatory factors IL-1β, IL-6, and TNF-α at the cellular level. It was concluded that anti-HMGB1 mAb treatment protects rats from cardiac injury induced by HS/R, and the beneficial effects may be related to its inhibitory effects on the HMGB1-TLR4 axis.
authors.affiliation: Department of Orthopedics, Beijing Chao-Yang Hospital, Capital Medical University.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhou
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Tong
authors.initials: T
authors.lastname: Mu
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D057134:Antibodies, Neutralizing / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D024243:HMGB1 Protein / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006331:Heart Diseases / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D007249:Inflammation / Q000097:blood / Q000188:drug therapy / Q000209:etiology; D053583:Interleukin-1beta / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D008070:Lipopolysaccharides; D051379:Mice; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D000067996:RAW 264.7 Cells; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D012151:Resuscitation; D012771:Shock, Hemorrhagic / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D024243:HMGB1 Protein; D053583:Interleukin-1beta; D015850:Interleukin-6; D008070:Lipopolysaccharides; C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D051028:bcl-2-Associated X Protein; D053148:Caspase 3