Emerging pharmacological tools to control hydrogen sulfide signaling in critical illness

Hydrogen sulfide (H₂S) has long been known as a toxic environmental hazard. Discovery of physiological roles of H₂S as a neurotransmitter by Kimura and colleagues triggered an intensive research in the biological roles of H₂S in the past decades. Manipulation of H₂S levels by inhibiting H₂S synthesis or administration of H₂S-releasing molecules revealed beneficial as well as harmful effects of H₂S. As a result, it is now established that H₂S levels are tightly controlled and too much or too little H₂S levels cause harm. Nonetheless, translation of sulfide-based therapy to clinical practice has been stymied due to the very low therapeutic index of sulfide and the incomplete understanding of endogenous sulfide metabolism. One potential strategy to circumvent this problem is to use a safe and stable sulfide metabolite that may mediate effects of H₂S. Alternatively, endogenous sulfide levels may be controlled using specific sulfide scavengers. In this review article, the role of endogenous H₂S production and catabolism will be briefly reviewed followed by an introduction of thiosulfate and H₂S scavengers as novel pharmacological tools to control H₂S-dependent signaling.