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

Jae Seok Jeong, Yeogha Yoon, Wankyu Kim, Hee Jung Kim, Hae Jin Park, Kyung Hwa Park, Kyung Bae Lee, So Ri Kim, Soon Ha Kim, Yang Soon Park, Sang Bum Hong, Soo Jong Hong, Dong Im Kim, Geum Hwa Lee, Han Jung Chae, Yong Chul Lee

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


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.

Original languageEnglish
Pages (from-to)57-72
Number of pages16
JournalAmerican Journal of Respiratory Cell and Molecular Biology
Issue number1
StatePublished - 1 Jul 2023


  • ER stress
  • NecroX
  • PHMG
  • lung injury
  • mitochondria


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