Gasping for Sulfide: A Critical Appraisal of Hydrogen Sulfide in Lung Disease and Accelerated Aging

Hydrogen sulfide (H₂S) is a gaseous signaling molecule involved in a plethora of physiological and pathological processes. It is primarily synthesized by cystathionine-β-synthase, cystathionine-γ-lyase, and 3-mercaptopyruvate sulfurtransferase as a metabolite of the transsulfuration pathway. H₂S has been shown to exert beneficial roles in lung disease acting as an anti-inflammatory and antiviral and to ameliorate cell metabolism and protect from oxidative stress. H₂S interacts with transcription factors, ion channels, and a multitude of proteins via post-translational modifications through S-persulfidation ("sulfhydration"). Perturbation of endogenous H₂S synthesis and/or levels have been implicated in the development of accelerated lung aging and diseases, including asthma, chronic obstructive pulmonary disease, and fibrosis. Furthermore, evidence indicates that persulfidation is decreased with aging. Here, we review the use of H₂S as a biomarker of lung pathologies and discuss the potential of using H₂S-generating molecules and synthesis inhibitors to treat respiratory diseases. Furthermore, we provide a critical appraisal of methods of detection used to quantify H₂S concentration in biological samples and discuss the challenges of characterizing physiological and pathological levels. Considerations and caveats of using H₂S delivery molecules, the choice of generating molecules, and concentrations are also reviewed. Antioxid. Redox Signal. 35, 551-579.