Neglected role of hydrogen sulfide in sulfur mustard poisoning: Keap1 S-sulfhydration and subsequent Nrf2 pathway activation.

Abstract

Sulfur mustard (SM) is a chemical warfare agent and a terrorism choice that targets various organs and tissues, especially lung tissues. Its toxic effects are tightly associated with oxidative stress. The signaling molecule hydrogen sulfide (H2S) protects the lungs against oxidative stress and activates the NF-E2 p45-related factor 2 (Nrf2) pathway. Here, we sought to establish whether endogenous H2S plays a role in SM induced lesion in mouse lungs and lung cells and whether endogenous H2S plays the role through Nrf2 pathway to protect against SM-induced oxidative damage. Furthermore, we also explored whether activation of Nrf2 by H2S involves sulfhydration of Kelch-like ECH-associated protein-1 (Keap1). Using a mouse model of SM-induced lung injury, we demonstrated that SM-induced attenuation of the sulfide concentration was prevented by NaHS. Concomitantly, NaHS attenuates SM-induced oxidative stress. We also found that H2S enhanced Nrf2 nuclear translocation, and stimulated expression of Nrf2-targeted downstream protein and mRNA levels. Incubation of the lung cells with NaHS decreased SM-induced ROS production. Furthermore, we also found that H2S S-sulfhydrated Keap1, which induced Nrf2 dissociation from Keap1, and enhanced Nrf2 nuclear translocation. Our data indicate that H2S is a critical, however, being long neglected signal molecule in SM-induced lung injury.

• Authors: Wenqi Meng, Zhipeng Pei, Yongwei Feng, Jie Zhao, Yongchun Chen, Wenwen Shi, Qingqiang Xu, Fengwu Lin, Mingxue Sun, Kai Xiao
• Journal: Scientific reports (Sci Rep) Vol. 7 Issue 1 Pg. 9433 (08 25 2017) ISSN: 2045-2322 [Electronic] England
• PMID: 28842592 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Kelch-Like ECH-Associated Protein 1
• NF-E2-Related Factor 2
• Protective Agents
• Reactive Oxygen Species
• Sulfides
• Mustard Gas
• Hydrogen Sulfide

Topics

• Animals
• Disease Models, Animal
• Gene Expression
• Hydrogen Sulfide (pharmacology)
• Kelch-Like ECH-Associated Protein 1 (metabolism)
• Lung (drug effects, metabolism, pathology)
• Mice
• Mustard Gas (poisoning)
• NF-E2-Related Factor 2 (genetics, metabolism)
• Oxidative Stress
• Protective Agents (pharmacology)
• Protein Transport
• Reactive Oxygen Species (metabolism)
• Signal Transduction (drug effects)
• Sulfides (metabolism)