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NecroX Improves Polyhexamethylene Guanidine-induced Lung Injury by Regulating Mitochondrial Oxidative Stress and Endoplasmic Reticulum Stress

Title
NecroX Improves Polyhexamethylene Guanidine-induced Lung Injury by Regulating Mitochondrial Oxidative Stress and Endoplasmic Reticulum Stress
Authors
Jeong J.S.Yoon Y.Kim W.Kim H.J.Park H.J.Park K.H.Lee K.B.Kim S.R.Kim S.H.Park Y.S.Hong S.-B.Hong S.-J.Kim D.I.Lee G.-H.Chae H.-J.Lee Y.C.
Ewha Authors
김완규
SCOPUS Author ID
김완규scopus
Issue Date
2023
Journal Title
American journal of respiratory cell and molecular biology
ISSN
1535-4989JCR Link
Citation
American journal of respiratory cell and molecular biology vol. 69, no. 1, pp. 57 - 72
Keywords
ER stresslung injurymitochondriaNecroXPHMG
Publisher
NLM (Medline)
Indexed
SCOPUS scopus
Document Type
Article
Abstract
Various environmental compounds are inducers of lung injury. Mitochondria are crucial organelles that can be affected by many lung diseases. NecroX is an indole-derived antioxidant that specifically targets mitochondria. We aimed to evaluate the therapeutic potential and related molecular mechanisms of NecroX in preclinical models of fatal lung injury. We investigated the therapeutic effects of NecroX on two different experimental models of lung injury induced by polyhexamethylene guanidine (PHMG) and bleomycin, respectively. We also performed transcriptome analysis of lung tissues from PHMG-exposed mice and compared the expression profiles with those from dozens of bleomycin-induced fibrosis public data sets. Respiratory exposure to PHMG and bleomycin led to fatal lung injury manifesting extensive inflammation followed by fibrosis. These specifically affected mitochondria regarding biogenesis, mitochondrial DNA integrity, and the generation of mitochondrial reactive oxygen species in various cell types. NecroX significantly improved the pathobiologic features of the PHMG- and bleomycin-induced lung injuries through regulation of mitochondrial oxidative stress. Endoplasmic reticulum stress was also implicated in PHMG-associated lung injuries of mice and humans, and NecroX alleviated PHMG-induced lung injury and the subsequent fibrosis, in part, via regulation of endoplasmic reticulum stress in mice. Gene expression profiles of PHMG-exposed mice were highly consistent with public data sets of bleomycin-induced lung injury models. Pathways related to mitochondrial activities, including oxidative stress, oxidative phosphorylation, and mitochondrial translation, were upregulated, and these patterns were significantly reversed by NecroX. These findings demonstrate that NecroX possesses therapeutic potential for fatal lung injury in humans.
DOI
10.1165/rcmb.2021-0459OC
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자연과학대학 > 생명과학전공 > Journal papers
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