Respiratory effects of hydrogen sulfide poisoning: dysfunction, damage, and diseases

Abstract

Hydrogen sulfide (H2S) has had a long history categorized as a major toxicant and was recently identified as a key gasotransmitter alongside nitric oxide and carbon monoxide and a therapeutic compound for several ailments. The toxicity profile of H2S remains incomplete and has centered around the inhibition of cytochrome C oxidase, a mitochondrial enzyme, and its link to neurotoxicity and cardiotoxicity. The cause of death also remains unknown, although respiratory depression has been identified as the main culprit. This dissertation challenges the current understanding of H2S toxicity in the respiratory center and brainstem. The natural history of H2S-induced lung injury and resolution was mapped out from onset of injury to resolution. Finally, the effects of ambient H2S were evaluated in combination with influenza A virus infection, a respiratory disease that affects animals and humankind. Neurological sequelae were identified in the brainstems of H2S-exposed mice, with an immediate increase in excitatory and inhibitory monoamines, alteration of the enzymatic activity responsible for monoamine metabolism, and neurodegeneration accompanied by a decrease in excitatory neurotransmitters. In the lungs, H2S caused immediate pulmonary edema in dead and surviving mice, pathways responsible for aerobic energy production were immediately dysregulated, pro-inflammatory cytokines were inhibited, markers of lung injury were increased, and increased nucleotide metabolism indicative of tissue repair following H2S poisoning were observed. Finally, we developed a novel large animal model for studying the interaction of occupationally relevant H2S concentrations with influenza A virus, a respiratory disease. Piglets exposed to H2S and infected with influenza A virus experienced the worst clinical scores, increased viral load, most severe microscopic lesion scores in the lungs, and increased oxidative stress markers. This dissertation offers novel mechanistic approaches for future studies of therapies counteracting H2S-induced sequelae in the brainstem and lungs. It will also serve to address the potential health issues in occupational settings and animal health pertaining to ambient H2S exposure. This dissertation offers a systemic view of the effects of acute and ambient H2S gas concerning breathing and respiratory system integrity.