W3D通过调控TLR4/MD2-NF-κB p65信号通路改善LPS诱导的小鼠急性肺损伤  

W3D improves LPS-induced acute lung injury in mice by regulating TLR4/MD2-NF-κB p65 signaling pathway

作　　者：史新阳 高晓慧 赵蓓 唐莉[1] 李青山[1,2] SHI Xin-yang;GAO Xiao-hui;ZHAO Bei;TANG Li;LI Qing-shan(School of Pharmaceutical Science,Shanxi Medical University,Taiyuan 030001,China;Shanxi Key Laboratory of Innovative Drug for the Treatment of Serious Diseases Basing on the Chronic Inflammation,Shanxi University of Traditional Chinese Medicine,Taiyuan 030024,China)

机构地区：[1]山西医科大学药学院,山西太原030001 [2]基于炎性反应的重大疾病创新药物山西省重点实验室,山西中医药大学,山西太原030024

出　　处：《中国药理学通报》2021年第5期657-661,共5页Chinese Pharmacological Bulletin

基　　金：国家自然科学基金资助项目(No 81602976);山西省应用基础研究项目(No 201901D211350)。

摘　　要：目的研究4-(5′-二甲氨基)-萘磺酰氧基苯并噁唑酮(W3D)这一新型结构化合物对脂多糖(lipopolysaccharide,LPS)诱导的小鼠急性肺损伤(acute lung injury,ALI)的保护作用及其作用机制。方法ICR小鼠随机分为对照组、模型组、氯唑沙宗组(12.5 mg·kg^(-1))、W3D组(12.5、6.25和3.125 mg·kg^(-1)),气道滴入LPS造模。于造模4 h后给药,12 h后处死小鼠并取肺脏,计算肺湿干比(wwt/dw),HE染色观察肺组织病理变化,试剂盒检测MPO活性、iNOS和炎症因子IL-1β、IL-6、TNF-α的水平,Western blot检测肺组织TLR4、MD2、p-IRAK4、p65蛋白的表达。结果W3D可显著改善小鼠肺水肿状态,降低肺组织湿干比;减少炎性细胞浸润,减轻血管损伤及局部出血等现象;可剂量依赖性抑制MPO活性,降低iNOS、IL-1β、IL-6、TNF-α的表达水平,抑制TLR4、MD2、p-IRAK4、p65蛋白的表达。结论化合物W3D可通过调控TLR4/MD2-NF-κB p65信号通路改善LPS诱导的小鼠急性肺损伤。Aim To investigate the protective effect of new structure compound 4-(5′-dimethylamino)-naphthalenesulfonyl-2(3H)-benzoxazolone(W3D)on lipopolysaccharide(LPS)induced acute lung injury(ALI)and the underlying mechanism.Methods ICR mice were randomly divided into control group,LPS model group,chlorzoxazone(12.5 mg·kg^(-1))and W3D treated groups(12.5,6.25 and 3.125 mg·kg^(-1)),and the drug groups were treated orally with the test compounds after the instillation intratracheally of LPS(2.5 mg·kg^(-1))for 4 h.Twelve hours later,the lung tissues were collected to calculate the lung wet/dry ratio(wwt/dw)after the mice were anaesthetized to death,and then the pathological changes in lung tissues were evaluated by HE staining.Meanwhile,the myeloperoxidase(MPO)activity,the expression of iNOS and inflammatory factors IL-1β,IL-6,TNF-αin serum were measured,and the protein levels of TLR4,MD2,p-IRAK4 and p65 were determined by Western blot.Results W3D could significantly reduce the wet/dry ratio of lung tissue to improve the pulmonary edema in mice,and dose-dependently attenuate the pathological lesions,such as inflammatory cell infiltration,blood vessel damage and local bleeding.Meanwhile,the activity of MPO,the contents of iNOS,IL-1β,IL-6 and TNF-αwere also be obviously inhibited in a dose-dependent manner.In addition,the protein levels of TLR4,MD2,p-IRAK4,p65 were also reduced markedly after the treatment of compound W3D.Conclusion Compound W3D could protect LPS-induced ALI in mice by regulating the TLR4/MD2-NF-κB p65 inflammatory pathway.

关 键 词：4-(5′-二甲氨基)-萘磺酰氧基苯并噁唑酮(W3D) 急性肺损伤 湿干比 MPO 炎症因子 TLR4 MD2 

分 类 号：R-332[医药卫生] R322.35