title: TLR4-mediated NF-κB signaling pathway mediates HMGB1-induced pancreatic injury in mice with severe acute pancreatitis.
abstract: Severe acute pancreatitis (SAP) is an extremely dangerous acute abdominal disorder which causes multiple complications and has a high mortality rate. Previous research has suggested that high-mobility group box 1 (HMGB1) plays an important role in the pathogenesis of SAP; however, the mechanisms underlying this strong correlation remain unclear. In this study, to further investigate whether HMGB1 acts as a stimulating factor, and whether Toll-like receptor 4 (TLR4) acts as its major mediator in the development of pancreatic injury during SAP, recombinant human HMGB1 (rhHMGB1) and TLR4-deficient mice were used. We found that HMGB1 and TLR4 were highly expressed, and nuclear factor-κB (NF-κB) was activated in our mouse model of SAP. We noted that the rhHMGB1 pancreas-targeted injection activated the TLR4-mediated NF-κB signaling pathway and induced pancreatic injury in wild-type mice. In TLR4-deficient mice, the rhHMGB1-induced activation of NF-κB and pathological changes in the pancreas were less evident than in wild-type mice. Therefore, this study provides evidence that HMGB1 promotes the pathogenesis of pancreatitis, and its downstream TLR4-mediated NF-κB signaling pathway is a potential important mediator in the development of this form of pancreatic injury.
authors.affiliation: Department of Vascular Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China.
authors.forename: Gang
authors.initials: G
authors.lastname: Li
authors.affiliation: Department of Vascular Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China.
authors.forename: Xuejun
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Vascular Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China.
authors.forename: Le
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Vascular Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China.
authors.forename: Yuxiang
authors.initials: Y
authors.lastname: He
authors.affiliation: Department of Vascular Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Vascular Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China.
authors.forename: Xing
authors.initials: X
authors.lastname: Jin
authors.affiliation: Department of Vascular Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China.
authors.forename: Hai
authors.initials: H
authors.lastname: Yuan
mesh_terms: D000208:Acute Disease; D000818:Animals; D001120:Arginine; D004195:Disease Models, Animal; D024243:HMGB1 Protein / Q000276:immunology*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000276:immunology*; D010179:Pancreas / Q000276:immunology / Q000293:injuries / Q000473:pathology*; D010195:Pancreatitis / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology*; D011994:Recombinant Proteins / Q000276:immunology; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000276:immunology*
chemical_list: D024243:HMGB1 Protein; D016328:NF-kappa B; D011994:Recombinant Proteins; D051197:Toll-Like Receptor 4; D001120:Arginine