HYDROGEN sulfide (H2S) is a potentially toxic gas with an obnoxious smell. It is a common cause of gas–related fatalities and is notorious for its use to commit suicide. Despite these properties, scientists have readily embraced H2S ever since its discovery as the third gaseous signaling molecule after carbon monoxide and nitric oxide. Exogenously H2S or H2S-donating compounds were reported to yield beneficial effects in numerous biologic systems. As such, H2S has been quickly targeted for its therapeutic potential in a variety of diseases.1However, concerns of toxicity remain. In particular, pulmonary toxicity is reported, underlining the need for a thorough analysis of this compound. In this issue of ANESTHESIOLOGY, Francis RC et al. shed light on this matter by comparing the route of administration of H2S in a murine model of ventilator-induced lung injury (VILI).2Although bolus injection of H2S-donating compound sodium sulfide exerted a protective effect, inhalation of high doses of H2S was found to aggravate lung injury. The mechanism of sodium sulfide-induced protection included a favorable balance in the antioxidant levels by up-regulation of genes involved in this process.
“… there is a continuing need for understanding mechanisms of toxicity of H2S before we can rejoice on potential clinical applications.”
Presumably, toxicity of H2S is because of inhibition of the respiratory complex in mitochondria, resulting in an inability of cells to use oxygen for oxidative metabolism. The authors hypothesize that because hypoxia (low arterial oxygen tension) is associated with pulmonary vasoconstriction and pulmonary edema, this may have been the mechanism underlying the detrimental effect of inhaling H2S in VILI. However, in their study there was no difference in arterial oxygenation between animals treated with a high dose of H2S compared with controls, while the fraction of inspired oxygen was unchanged. There may have been “functional hypoxia” after inhalation of H2S, i.e. , an inability to use available oxygen, but to our knowledge, there is no known association between cytopathic hypoxia and pulmonary vasoconstriction. In addition, beneficial effects of H2S inhalation on lung injury have previously been found in another model of VILI.3Thereby, the question remains what the mechanism is of the observed toxicity of inhaled H2S in the present study.
The dose is likely to be of importance. The toxicity of H2S is correlated with its concentration and depends less upon the duration of exposure,4suggesting that H2S is rapidly eliminated, with concomitant low levels of free H2S. This begs the questions as to what “physiologic” concentrations of H2S are. Measuring H2S concentrations is difficult, however, as the various techniques measure not only the biologic active form but also its intermediates. An explanation for discrepant results of routes of administration on toxicity could be that parenteral H2S is metabolized and exhaled within seconds, whereas continuous inhalation may expose the alveoli to high H2S concentrations. Also, the murine nasal cavity has an enormous surface area, thereby enabling deposition efficiency of inhaled H2S in the nose. Mechanical ventilation via a tracheotomy exposes the lungs to high H2S concentration as compared with spontaneously breathing animals. Of note is that only a high dose of H2S aggravated lung injury, whereas the low dose of inhaled H2S had no effect. This high dose nearly corresponds to a dose that has been shown to induce a “suspended animation like” state,5characterized by a reduction of oxygen consumption and a concomitant decrease in body temperature to ambient temperature. In their study, Francis RC et al. 2notably kept body temperature constant. If H2S exerts protection against VILI via reducing energy expenditure, it can be hypothesized that eliminating oxygen utilization with the use of “hibernating” doses of H2S, while preventing a drop in body temperature that lowers oxygen consumption, can be toxic.
Alternatively, H2S may have differential effects on endothelial and epithelial cells. The work by Francis RC et al. 2highlights that during VILI, injected sodium sulfide inhibited the expression of adhesion molecules needed for diapedesis and extravasation of neutrophils from the circulation into the alveoli. This may suggest a mechanism by which H2S exerts effects, which is less apparent in alveolar cells. Of note, chronic exposure to H2S induced bronchial epithelial hypertrophy.6
In conclusion, both beneficial as well as detrimental effects of H2S have been reported in various preclinical studies. Dose and route of administration are important factors related to H2S toxicity. The work by Francis RC et al. 2contributes to the hypothesis that H2S might protect the lung from damage caused by the mechanical ventilator. However, there is a continuing need for understanding mechanisms of toxicity of H2S before we can rejoice on potential clinical applications.