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  3. Repurposing the anesthetic dexmedetomidine: a novel antidote for sulfur mustard analog-induced acute lung injury via multi-mechanism modulation

Repurposing the anesthetic dexmedetomidine: a novel antidote for sulfur mustard analog-induced acute lung injury via multi-mechanism modulation

  • Int Immunopharmacol. 2026 Feb 1:170:116069. doi: 10.1016/j.intimp.2025.116069.
Min-Jie Shi 1,  Jiang-Zheng Liu 1,  Wei-Hua Yu 1,  Rui Liu 1,  Lu-Yao Li 2,  Meng Cao 1,  Yun-Ze Tian 2,  Xiao-Di Zhang 1,  Hao Wu 1,  Jian-Zhong Li 2,  Chun-Xu Hai 1,  Wen-Li Li 3,  Jia Li 4,  De-Qin Kong 5
Affiliations

Affiliations

  • 1 Department of Toxicology, The Shaanxi Provincial Key Laboratory of Free Radical Biology and Medicine, The Shaanxi Provincial Key Laboratory of Environmental Health Hazard Assessment and Protection, The Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, The Fourth Military Medical University, Shaanxi Province 710032, China.
  • 2 Department of Thoracic Surgery, The Second Affiliated Hospital of Xi'an Jiao Tong University, Shaanxi Province 710004, China.
  • 3 Department of Toxicology, The Shaanxi Provincial Key Laboratory of Free Radical Biology and Medicine, The Shaanxi Provincial Key Laboratory of Environmental Health Hazard Assessment and Protection, The Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, The Fourth Military Medical University, Shaanxi Province 710032, China. Electronic address: [email protected].
  • 4 Department of Toxicology, The Shaanxi Provincial Key Laboratory of Free Radical Biology and Medicine, The Shaanxi Provincial Key Laboratory of Environmental Health Hazard Assessment and Protection, The Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, The Fourth Military Medical University, Shaanxi Province 710032, China; The Ministry of Education Key Laboratory of Aerospace Medicine, School of Aerospace Medicine, The Fourth Military Medical University, Shaanxi Province 710032, China. Electronic address: [email protected].
  • 5 Department of Toxicology, The Shaanxi Provincial Key Laboratory of Free Radical Biology and Medicine, The Shaanxi Provincial Key Laboratory of Environmental Health Hazard Assessment and Protection, The Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, The Fourth Military Medical University, Shaanxi Province 710032, China. Electronic address: [email protected].
PMID: 41421231 DOI: 10.1016/j.intimp.2025.116069
Abstract

Sulfur mustard (SM), a typical alkylating agent, poses significant threats. Inhalational SM exposure causes acute lung injury (ALI) with complex mechanisms and no effective antidotes. we established a murine inhalation model and an in vitro alveolar epithelial cell (MLE-12) model using chloroethyl ethyl sulfide (CEES), a well-characterized SM analog, to explore therapeutic interventions. We found that dexmedetomidine (DEX), a clinically anesthetic with multi-mechanistic properties, effectively mitigated CEES-induced pulmonary histopathological and functional damage, enhancing survival rates in vivo. Transcriptomic profiling revealed that DEX reversed CEES-mediated downregulation of genes involved in hematopoietic lineage differentiation in lung tissues. Further histopathological and hematological analyses revealed that DEX mitigated CEES-triggered bone marrow suppression, splenic white pulp atrophy, peripheral neutrophilia, and serum inflammatory cytokine elevation. DEX also suppressed pulmonary infiltration of neutrophils and monocyte-macrophages, along with reduced inflammatory mediators. Mechanistically, DEX inhibited mitochondria-mediated Apoptosis in both lung tissues and MLE-12 cells. Additionally, DEX reduced Reactive Oxygen Species (ROS) and mitochondrial ROS levels, while enhancing SOD1 and glutathione content. Finally, DEX reversed CEES-induced mitochondrial structural damage in type II alveolar epithelial cells and the increase in mtDNA content in lung tissue, ameliorated the decline of mitochondrial membrane potential in MLE-12 cells, and inhibited the downregulation of the mitochondrial Mfn1 in both in vivo and in vitro models. Collectively, our findings underscore DEX's multifaceted protective mechanisms, including modulation of inflammation, Apoptosis, oxidative stress, and mitochondrial homeostasis against SM analog-induced ALI.

Keywords

Acute lung injury; Apoptosis; Dexmedetomidine; Inflammation; Oxidative stress; Sulfur mustard.

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