title: Ketamine attenuates sepsis-induced acute lung injury via regulation of HMGB1-RAGE pathways.
abstract: High mobility group box protein 1 (HMGB1) and receptor for the advanced glycation end product (RAGE) play important roles in the development of sepsis-induced acute lung injury (ALI). Ketamine is considered to confer protective effects on ALI during sepsis. In this study, we investigated the effects of ketamine on HMGB1-RAGE activation in a rat model of sepsis-induced ALI. ALI was induced in wild type (WT) and RAGE deficient (RAGE(-/-)) rats by cecal ligation and puncture (CLP) or HMGB1 to mimic sepsis-induced ALI. Rats were randomly divided to six groups: sham-operation+normal saline (NS, 10 mL/kg), sham-operation+ketamine (10 mg/kg), CLP/HMGB1+NS (10 mL/kg), CLP/HMGB1+ketamine (5 mg/kg), CLP/HMGB1+ketamine (7.5 mg/kg), and CLP/HMGB1+ketamine (10 mg/kg) groups. NS and ketamine were administered at 3 and 12 h after CLP/HMGB1 via intraperitoneal injection. Pathological changes of lung, inflammatory cell counts, expression of HMGB1 and RAGE, and concentrations of various inflammatory mediators in bronchoalveolar lavage fluids (BALF) and lung tissue were then assessed. Nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinases (MAPK) signaling pathways in the lung were also evaluated. CLP/HMGB1 increased the wet to dry weight ratio and myeloperoxidase activity in lung, the number of total cells, neutrophils, and macrophages in the BALF, and inflammatory mediators in the BALF and lung tissues. Moreover, expression of HMGB1 and RAGE in lung tissues was increased after CLP. Ketamine inhibited all the above effects. It also inhibited the activation of IκB-α, NF-κB p65, and MAPK. Ketamine protects rats against HMGB1-RAGE activation in a rat model of sepsis-induced ALI. These effects may partially result from reductions in NF-κB and MAPK.
authors.affiliation: Department of Anesthesiology, The First Affiliated Hospital of Henan Science and Technology University, Luoyang, Henan, China. Electronic address: kehanli2015@outlook.com.
authors.forename: Kehan
authors.initials: K
authors.lastname: Li
authors.affiliation: Department of Neurology, The First Affiliated Hospital of Henan Science and Technology University, Luoyang, Henan, China.
authors.forename: Jianxue
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Anesthesiology, The First Affiliated Hospital of Henan Science and Technology University, Luoyang, Henan, China.
authors.forename: Xuechang
authors.initials: X
authors.lastname: Han
mesh_terms: D055371:Acute Lung Injury / Q000209:etiology / Q000517:prevention & control*; D000818:Animals; D030801:Animals, Genetically Modified; D019138:Antibodies, Blocking / Q000008:administration & dosage; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D055786:Gene Knockout Techniques; D024243:HMGB1 Protein / Q000008:administration & dosage* / Q000276:immunology*; D006801:Humans; D018836:Inflammation Mediators; D007649:Ketamine / Q000627:therapeutic use*; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D000067759:Receptor for Advanced Glycation End Products / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D018805:Sepsis / Q000150:complications / Q000188:drug therapy*; D015398:Signal Transduction
chemical_list: C000593874:Ager protein, rat; D019138:Antibodies, Blocking; D024243:HMGB1 Protein; C104200:Hbp1 protein, rat; D018836:Inflammation Mediators; D016328:NF-kappa B; D034741:RNA, Small Interfering; D000067759:Receptor for Advanced Glycation End Products; D007649:Ketamine; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: ALI; CLP; HMGB1; Ketamine; RAGE