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 (H ₂S) protects the lungs against oxidative stress and activates the NF-E2 p45-related factor 2 (Nrf2) pathway. Here, we sought to establish whether endogenous H ₂S plays a role in SM induced lesion in mouse lungs and lung cells and whether endogenous H ₂S plays the role through Nrf2 pathway to protect against SM-induced oxidative damage. Furthermore, we also explored whether activation of Nrf2 by H ₂S 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 H ₂S 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 H ₂S S-sulfhydrated Keap1, which induced Nrf2 dissociation from Keap1, and enhanced Nrf2 nuclear translocation. Our data indicate that H ₂S is a critical, however, being long neglected signal molecule in SM-induced lung injury.