Dapk1 improves inflammation, oxidative stress and autophagy in LPS-induced acute lung injury via p38MAPK/NF-κB signaling pathway

• Published in: Molecular immunology Vol. 120; pp. 13 - 22
• Main Authors: Li, Tao, Wu, Yi-Na, Wang, Hui, Ma, Jun-Yu, Zhai, Shan-Shan, Duan, Jun
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.04.2020
• Subjects: Acute Lung Injury - chemically induced; Acute Lung Injury - metabolism; Acute Lung Injury - pathology; ALI; Animals; Autophagy; Dapk1; Death-Associated Protein Kinases - deficiency; Death-Associated Protein Kinases - genetics; Death-Associated Protein Kinases - metabolism; Imidazoles - pharmacology; Inflammation; Inflammation - metabolism; Inflammation - pathology; Lipopolysaccharides - toxicity; Lung - drug effects; Lung - metabolism; Lung - pathology; Male; MAP Kinase Signaling System - drug effects; Mice; Mice, Inbred C57BL; Mice, Knockout; NF-kappa B - antagonists & inhibitors; NF-kappa B - metabolism; Oxidative Stress; p38 Mitogen-Activated Protein Kinases - antagonists & inhibitors; p38 Mitogen-Activated Protein Kinases - metabolism; p38MAPK/NF-κB pathway; Pyridines - pharmacology; Pyrrolidines - pharmacology; Signal Transduction - drug effects; Thiocarbamates - pharmacology; Oxidative stress; p38MAPK/NF-κB pathway; Inflammation; Dapk1; Autophagy; ALI
• ISSN: 0161-5890; 1872-9142
• DOI: 10.1016/j.molimm.2020.01.014

•LPS-induced ALI mice had decreased Dapk1 and activated p38MAPK/NF-κB pathway.•No changes were found in p-p38 and nuclear p65 NF-κB in LPS-induced Dapk1-/- mice.•Inhibiting p38MAPK/NF-κB pathway improved lung injury of LPS-induced Dapk1-/- mice.•Inhibition of p38MAPK/NF-κB reduced the inflammation in LPS-induced Dapk1+/+ mice. 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.