Li Kehan, Yang Jianxue, Han Xuechang
Department of Anesthesiology, The First Affiliated Hospital of Henan Science and Technology University, Luoyang, Henan, China.
Department of Neurology, The First Affiliated Hospital of Henan Science and Technology University, Luoyang, Henan, China.
Int Immunopharmacol. 2016 May;34:114-128. doi: 10.1016/j.intimp.2016.01.021. Epub 2016 Mar 2.
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.
高迁移率族蛋白1（HMGB1）和晚期糖基化终末产物受体（RAGE）在脓毒症诱导的急性肺损伤（ALI）的发生发展中起重要作用。氯胺酮被认为在脓毒症期间对ALI具有保护作用。在本研究中，我们在脓毒症诱导的ALI大鼠模型中研究了氯胺酮对HMGB1-RAGE激活的影响。通过盲肠结扎和穿刺（CLP）或HMGB1在野生型（WT）和RAGE缺陷型（RAGE(-/-)）大鼠中诱导ALI，以模拟脓毒症诱导的ALI。大鼠被随机分为六组：假手术+生理盐水（NS，10 mL/kg）、假手术+氯胺酮（10 mg/kg）、CLP/HMGB1+NS（10 mL/kg）、CLP/HMGB1+氯胺酮（5 mg/kg）、CLP/HMGB1+氯胺酮（7.5 mg/kg）和CLP/HMGB1+氯胺酮（10 mg/kg）组。在CLP/HMGB1后3小时和12小时通过腹腔注射给予NS和氯胺酮。然后评估肺的病理变化、炎症细胞计数、HMGB1和RAGE的表达以及支气管肺泡灌洗液（BALF）和肺组织中各种炎症介质的浓度。还评估了肺中的核因子-κB（NF-κB）和丝裂原活化蛋白激酶（MAPK）信号通路。CLP/HMGB1增加了肺的湿重与干重比和髓过氧化物酶活性、BALF中的总细胞数、中性粒细胞和巨噬细胞数以及BALF和肺组织中的炎症介质。此外，CLP后肺组织中HMGB1和RAGE的表达增加。氯胺酮抑制了上述所有作用。它还抑制了IκB-α、NF-κB p65和MAPK的激活。氯胺酮在脓毒症诱导的ALI大鼠模型中保护大鼠免受HMGB1-RAGE激活。这些作用可能部分源于NF-κB和MAPK的减少。
