Chen Tong, Mou Yi, Tan Jiani, Wei Linlin, Qiao Yixue, Wei Tingting, Xiang Pengjun, Peng Sixun, Zhang Yihua, Huang Zhangjian, Ji Hui
State Key Laboratory of Natural Medicines, China Pharmaceutical University, No. 24 Tongjiaxiang, Nanjing 210009, Jiangsu, China.
School of Pharmacy, China Pharmaceutical University, No.24 Tongjiaxiang, Nanjing 210009, Jiangsu, China.
Int Immunopharmacol. 2015 Mar;25(1):55-64. doi: 10.1016/j.intimp.2015.01.011. Epub 2015 Jan 19.
CDDO-Me, initiated in a phase II clinical trial, is a potential useful therapeutic agent for cancer and inflammatory dysfunctions, whereas the therapeutic efficacy of CDDO-Me on LPS-induced acute lung injury (ALI) has not been reported as yet. The purpose of the present study was to explore the protective effect of CDDO-Me on LPS-induced ALI in mice and to investigate its possible mechanism. BalB/c mice received CDDO-Me (0.5mg/kg, 2mg/kg) or dexamethasone (5mg/kg) intraperitoneally 1h before LPS stimulation and were sacrificed 6h later. W/D ratio, lung MPO activity, number of total cells and neutrophils, pulmonary histopathology, IL-6, IL-1β, and TNF-α in the BALF were assessed. Furthermore, we estimated iNOS, IL-6, IL-1β, and TNF-α mRNA expression and NO production as well as the activation of the three main MAPKs, AkT, IκB-α and p65. Pretreatment with CDDO-Me significantly ameliorated W/D ratio, lung MPO activity, inflammatory cell infiltration, and inflammatory cytokine production in BALF from the in vivo study. Additionally, CDDO-Me had beneficial effects on the intervention for pathogenesis process at molecular, protein and transcriptional levels in vitro. These analytical results provided evidence that CDDO-Me could be a potential therapeutic candidate for treating LPS-induced ALI.
CDDO-Me已进入II期临床试验，是一种对癌症和炎症性功能障碍有潜在治疗作用的药物，然而，CDDO-Me对脂多糖诱导的急性肺损伤（ALI）的治疗效果尚未见报道。本研究的目的是探讨CDDO-Me对脂多糖诱导的小鼠ALI的保护作用，并研究其可能的机制。BalB/c小鼠在脂多糖刺激前1小时腹腔注射CDDO-Me（0.5mg/kg，2mg/kg）或地塞米松（5mg/kg），6小时后处死。评估肺组织湿干重比、肺髓过氧化物酶（MPO）活性、总细胞和中性粒细胞数量、肺组织病理学、支气管肺泡灌洗液（BALF）中的白细胞介素-6（IL-6）、白细胞介素-1β（IL-1β）和肿瘤坏死因子-α（TNF-α）。此外，我们还检测了诱导型一氧化氮合酶（iNOS）、IL-6、IL-1β和TNF-α的mRNA表达、一氧化氮（NO）生成以及三种主要丝裂原活化蛋白激酶（MAPKs）、蛋白激酶B（AkT）以及核转录因子κB抑制蛋白α（IκB-α）和核转录因子κB（p65）的激活情况。体内研究结果显示，CDDO-Me预处理可显著改善肺组织湿干重比、肺MPO活性、炎症细胞浸润以及BALF中炎症细胞因子的产生。此外，CDDO-Me在体外对分子、蛋白质和转录水平的发病机制干预具有有益作用。这些分析结果表明，CDDO-Me可能是治疗脂多糖诱导的ALI的潜在候选药物。
