Bench-to-bedside review: Hydrogen sulfide – the third gaseous transmitter: applications for critical care

Florian Wagner,Pierre Asfar,Enrico Calzia,Peter Radermacher,Csaba Szabó

doi:10.1186/cc7700

Abstract

Hydrogen sulfide (H2S), a gas with the characteristic odor of rotten eggs, is known for its toxicity and as an environmental hazard, inhibition of mitochondrial respiration resulting from blockade of cytochrome c oxidase being the main toxic mechanism. Recently, however, H2S has been recognized as a signaling molecule of the cardiovascular, inflammatory and nervous systems, and therefore, alongside nitric oxide and carbon monoxide, is referred to as the third endogenous gaseous transmitter. Inhalation of gaseous H2S as well as administration of inhibitors of its endogenous production and compounds that donate H2S have been studied in various models of shock. Based on the concept that multiorgan failure secondary to shock, inflammation and sepsis may represent an adaptive hypometabolic reponse to preserve ATP homoeostasis, particular interest has focused on the induction of a hibernation-like suspended animation with H2S. It must be underscored that currently only a limited number of data are available from clinically relevant large animal models. Moreover, several crucial issues warrant further investigation before the clinical application of this concept. First, the impact of hypothermia for any H2S-related organ protection remains a matter of debate. Second, similar to the friend and foe character of nitric oxide, no definitive conclusions can be made as to whether H2S exerts proinflammatory or anti-inflammatory properties. Finally, in addition to the question of dosing and timing (for example, bolus administration versus continuous intravenous infusion), the preferred route of H2S administration remains to be settled – that is, inhaling gaseous H2S versus intra-venous administration of injectable H2S preparations or H2S donors. To date, therefore, while H2S-induced suspended animation in humans may still be referred to as science fiction, there is ample promising preclinical data that this approach is a fascinating new therapeutic perspective for the management of shock states that merits further investigation.

Highlights

Hydrogen sulfide (H2S), a colorless, flammable and watersoluble gas with the characteristic odor of rotten eggs, has been known for decades because of its toxicity and as an environmental hazard [1,2]
Inhibitors of its endogenous production as well as compounds that donate H2S have been studied in various models of shock resulting from hemorrhage [7,8,9], ischemia/reperfusion [10,11,12,13,14,15,16,17,18], endotoxemia [19,20,21], bacterial sepsis [22,23,24,25] and nonmicrobial inflammation [26,27,28,29] – which, yielded rather controversial data with respect to the proinflammatory or anti-inflammatory properties of H2S
In mechanically ventilated mice instrumented with left ventricular pressure volume conductance catheters and assigned to 100 ppm inhaled H2S, we found that hypothermia alone (27°C) but not normothermic H2S inhalation (38°C) decreased the cardiac output due to a fall in heart rate, whereas both the stroke volume as

Summary

Introduction

Hydrogen sulfide (H2S), a colorless, flammable and watersoluble gas with the characteristic odor of rotten eggs, has been known for decades because of its toxicity and as an environmental hazard [1,2]. Owing to its SH group that allows reduction of disulfide bonds and radical scavenging, H2S exerts biological effects as an antioxidant [9], in particular as an endogenous peroxynitrite scavenger [58], which is consistent with its cytoprotective effects in various cell-based experiments [59,60] In this context the effect of H2S on intracellular signal pathways assumes particular importance: in LPS-stimulated macrophages, pretreatment with physically dissolved gaseous H2S or the H2S-donor NaHS was affiliated with diminished activation of the nuclear transcription factor NF-κB and inhibition of the inducible isoform of the NO synthase. While H2S did not affect the tissue concentrations of TNFα, combining hypothermia and inhaled H2S significantly decreased tissue IL-6 expression (Table 3) [91]

Conclusions

Szabó C