Surgical Intensive Care Unit, China-Japan Friendship Hospital, Beijing 100029, China.
Surgical Intensive Care Unit, China-Japan Friendship Hospital, Beijing 100029, China.
Mol Immunol. 2020 Apr;120:13-22. doi: 10.1016/j.molimm.2020.01.014. Epub 2020 Feb 8.
To investigate the impact of death-associated protein kinase 1 (Dapk1) on lipopolysaccharide (LPS)-induced acute lung injury (ALI) via p38MAPK/NF-κB pathway.
Dapk1 and Dapk1 mice were randomized into Control, LPS, SB203580 (a p38MAPK pathway inhibitor) + LPS, and PDTC (a NF-κB 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-κB pathway, mice were injected with TC-DAPK 6 (a Dapk1 inhibitor) with or without SB203580/PDTC before LPS administration.
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-κB 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-α, 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-κB pathway, which were reversed by SB203580 or PDTC.
Dapk1 improved oxidative stress, inhibited autophagy, and reduce inflammatory response of LPS-induced ALI mice by inhibiting p38MAPK/NF-κB pathway.
通过 p38MAPK/NF-κB 通路研究死亡相关蛋白激酶 1（Dapk1）对脂多糖（LPS）诱导的急性肺损伤（ALI）的影响。
Dapk1 和 Dapk1 小鼠随机分为对照组、LPS 组、SB203580（p38MAPK 通路抑制剂）+LPS 组和 PDTC（NF-κB 通路抑制剂）+LPS 组。通过 HE 染色、ELISA、qRT-PCR、Western blot 和免疫荧光检测，测定细胞计数、肺湿重与干重比（W/D 比值）以及氧化应激指标。此外，为了探讨 Dapk1 是否通过 p38MAPK/NF-κB 通路直接介导 ALI，在 LPS 给药前，用 TC-DAPK 6（Dapk1 抑制剂）和/或 SB203580/PDTC 对小鼠进行注射。
LPS 诱导的肺损伤导致肺 W/D 比值增加，在 LPS 诱导的小鼠中，p38MAPK/NF-κB 通路激活，SB203580 和 PDTC 可部分逆转这一作用，尤其是在 Dapk1 小鼠中。SB203580 和 PDTC 减少了 LPS 诱导的小鼠 BALF 中的总细胞和中性粒细胞，同时降低了 TNF-α、IL-6、MPO、LPO 和 MDA 的水平，以及 beclin-1、Atg5 和 LC3II 的表达，但上调了 SOD 和 GSH-Px 的活性，以及 p62 蛋白的表达。此外，TC-DAPK 6 加重了 LPS 诱导的 ALI 的病理损伤，导致更严重的炎症反应、氧化应激和自噬，以及 p38MAPK/NF-κB 通路的激活，这些作用可被 SB203580 或 PDTC 逆转。
Dapk1 通过抑制 p38MAPK/NF-κB 通路，改善 LPS 诱导的 ALI 小鼠的氧化应激、抑制自噬，减少炎症反应。
