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.

H2S attenuates acute lung inflammation induced by administration of lipopolysaccharide in adult male rats

“…In contrast, PAG administration further exacerbated lung injuries. Moreover, Meng et al (2017) also documented that PAG has exacerbated lung damage through reduction of endogenous H 2 S level, CSE expression and Nrf2 nuclear translocation which was associated with increased oxidative stress markers. Zhao et al (2014) reported that H 2 S donors have been widely used in the field.…”

Oxidation of Hydrogen Sulfide by Quinones: How Polyphenols Initiate Their Cytoprotective Effects

“…The present experiments show that simple but specific hydroxybenzenes can oxidize H 2 S to polysulfides after the former are themselves autoxidized. These results help to explain the mechanism behind the health benefits of many nutraceutical polyphenols; polysulfides produced by the oxidation of H 2 S are potent antioxidants [ 17 ], they may scavenge superoxide [ 42 ], and through their ability to persulfidate Keap1, they free it from Nrf2, which can then activate nuclear antioxidant response elements [ 18 , 19 , 43 , 44 , 45 , 46 ]. Our experiments also show that the ability of hydroxybenzenes to oxidize H 2 S varies considerably with the location and distribution of these hydroxyl groups and that the addition of specific side groups can further alter the reactivity of these compounds.…”

Effects of Manganese Porphyrins on Cellular Sulfur Metabolism

“…Long-term benefits of polysulfides are also derived from their modulation of antioxidant response mechanisms. Polysulfides increase intracellular antioxidant activity via persulfidation of Keap1 which causes Keap1 to dissociate from Nrf2, similar to the proposed mechanism of Keap-1 peroxidation [34][35][36][37][38][39]. Nrf2 then translocates to the nucleus where it activates the suite of cytoprotective antioxidant response elements [40,41].…”