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 physiologic and pathologic processes. It is primarily synthesised 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 anti-viral, and to ameliorate cell metabolism and protect from oxidative stress. H2Sinteracts with transcription factors, ion channels and a multitude of proteins via post-translational modifications through S-persulfidation ('sulfhydration'). Perturbation of endogenous H2Ssynthesis 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 indicate that persulfidation is decreased with aging. Here we review the use of H2Sas 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 H2Sconcentration in biological samples and discuss the challenges of characterising physiological and pathological levels. Considerations and caveats of using H2S delivery molecules, the choice of generating molecules and concentrations are also reviewed.