Ketamine attenuates sepsis-induced acute lung injury via regulation of HMGB1-RAGE pathways

• Ketamine inhibits the development of CLP-induced ALI by negative modulation of HMGB1-RAGE pathway.
• CLP/HMGB1-induced release of inflammatory mediators in BALF and lung tissue was suppressed by anti-RAGE Ab and RAGE siRNA.
• Ketamine inhibited the phosphorylation of MAPK and the activation of NF-κB p65 in lung tissues.

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 HMGB1and 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 HMGB1and 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.