Dapk1 improves inflammation, oxidative stress and autophagy in LPS-induced acute lung injury via p38MAPK/NF-κB signaling pathway
Dapk1 improves inflammation, oxidative stress and autophagy in LPS-induced acute lung injury via p38MAPK/NF-κB signaling pathway
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Dapk1 通过 p38MAPK/NF-κB 信号通路改善 LPS 诱导的急性肺损伤中的炎症、氧化应激和自噬
DOI：
10.1016/j.molimm.2020.01.014
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发表时间：
2020-04-01
影响因子：
3.6
通讯作者：
Duan, Jun
中科院分区：
文献类型：
--
作者：
Li, Tao;Wu, Yi-Na;Duan, Jun
目的：探讨死亡相关蛋白激酶1(Dapk1)在脂多糖(LPS)诱导的急性肺损伤(ALI)中的作用。方法：将Dapk1(+/+)和Dapk1(-/-)小鼠随机分为对照组、内毒素组、p38MAPK途径抑制剂SB203580组和核因子-kappaB途径抑制剂PDTC组。检测肺组织细胞计数、肺湿重/干重比(W/D)和氧化应激指标，并用HE染色、ELISA、qRT-PCR、Western blotting和免疫荧光等方法进行检测。此外，为了探讨Dapk1在ALI中的作用是否通过p38MAPK/NF-kappa B途径直接介导，在给药前给小鼠注射Dapk1抑制剂TC-DAPK 6和加或不加SB203580/PDTC。结果：脂多糖诱导的肺损伤使肺湿/干重比值增加，SB203580和PDTC可部分逆转肺组织中p38MAPK/NF-kappa B通路的激活，尤其是Dapk1(-/-)小鼠。SB203580和PDTC可降低脂多糖诱导的小鼠肺泡灌洗液中的细胞总数和中性粒细胞数，降低肺泡灌洗液中肿瘤坏死因子-α、IL-6、MPO、LPO和丙二醛的水平，降低BALF中BECLIN-1、ATG5和LC3II的表达，但可上调SOD、GSH-Px的活性和p62蛋白的表达。此外，TC-DAPK6可加重内毒素诱导的ALI小鼠的炎症反应、氧化应激和自噬，并激活p38MAPK/NF-kappa B通路，而SB203580或PDTC可逆转这种作用。结论：DAPK1通过抑制p38MAPK/NF-kappa B通路，改善内毒素诱导的ALI小鼠的氧化应激，抑制自噬，减轻炎症反应。
Objective: To investigate the impact of death-associated protein kinase 1 (Dapk1) on lipopolysaccharide (LPS)induced acute lung injury (ALI) via p38MAPK/NF-kappa B pathway.Methods: Dapk1(+/+) and Dapk1(-/-) mice were randomized into Control, LPS, SB203580 (a p38MAPK pathway inhibitor) + LPS, and PDTC (a NF-kappa B pathway inhibitor) + LPS groups. Cell counts, lung wet to dry weight ratio (W/D weight ratio), as well as indicators of oxidative stress were determined followed by the detection with HE staining, ELISA, qRT-PCR, Western blotting and Immunofluorescence. Besides, to explore whether the effect of Dapk1 on ALI directly mediated via p38MAPK/NF-kappa B pathway, mice were injected with TC-DAPK 6 (a Dapk1 inhibitor) with or without SB203580/PDTC before LPS administration.Results: LPS induced lung injury with increased lung W/D weight ratio, which could be partly reversed by SB203580 and PDTC in LPS-induced mice with activated p38MAPK/NF-kappa B pathway in lung tissues, especially in Dapk1(-/-) mice. SB203580 and PDTC reduced total cells and neutrophils in BALF in LPS-induced mice, accompanying with decreased levels of TNF-alpha, IL-6, MPO, LPO and MDA and the expressions of beclin-1, Atg5 and LC3II, but with the up-regulated activities of SOD and GSH-Px, as well as p62 protein expression. Besides, TC-DAPK 6 aggravated the pathologic injury in LPS-induced ALI with more serious inflammatory response, oxidative stress and autophagy as well as the activated p38MAPK/NF-kappa B pathway, which were reversed by SB203580 or PDTC.Conclusion: Dapk1 improved oxidative stress, inhibited autophagy, and reduce inflammatory response of LPS-induced ALI mice by inhibiting p38MAPK/NF-kappa B pathway.