key: cord-0973595-o4mua03m authors: Datzmann, Thomas; Merz, Tamara; McCook, Oscar; Szabo, Csaba; Radermacher, Peter title: H(2)S as a Therapeutic Adjuvant Against COVID-19: Why and How? date: 2021-01-13 journal: Shock DOI: 10.1097/shk.0000000000001723 sha: e6693ed7ee8829e2614764fbe3d18e2242e89f5d doc_id: 973595 cord_uid: o4mua03m nan docking to the membrane-bound angiotensin-converting enzyme2 (ACE2) after cleavage of one of its surface proteins by the host's transmembrane protease serine 2 (TMPRSS2). In fact, both the severity (2) and extra-pulmonary manifestations (3) of the SARS-CoV-2 disease have been associated with variable ACE2 and/or TMPRSS2 activities. Consequently, H 2 S-related reduction of their activity could be therapeutically relevant (4). 2. Besides the blockade of virus entry into the cell, H 2 S may act via inhibition of virus replication as demonstrated in other RNA viruses (5): the slow-releasing H 2 S donor GYY4137 attenuated alveolar epithelial cell pro-inflammatory cytokine release due to reduced virus replication, while both genetic deletion (6) and pharmacological inhibition (7) of cystathionine-g-lyase (CSE), one of the major H 2 Sproducing enzymes, exerted the opposite effect. 3. Oxidative stress (8, 9) resulting from glutathione (GSH) deficiency (10) seems to be a key factor for the severity of the SARS-CoV-2 disease. An antioxidant effect of H 2 S may replenish GSH, thereby producing cytoprotective effects. 4. H 2 S could attenuate the SARS-CoV-2-related ''cytokine storm'' due to the downregulation of the production of various pro-inflammatory mediators (11) and/or via the inhibition of leukocyte activation (12). 5. Endothelial dysfunction is a significant part of SARS-CoV-2 disease (13) , and H 2 S donors have been demonstrated to exert significant endothelium-protective effects in various experimental models (14) . This point is especially pertinent, because the epidemiology of the SARS-CoV-2 disease clearly suggests a particular role of H 2 S: the majority of patients needing mechanical ventilation and extra-pulmonary organ support are older and/or suffer from underlying chronic cardiovascular, metabolic, and/or pulmonary comorbidity. All these conditions are well known to be associated with impaired endogenous H 2 S availability and/or reduced CSE expression (12). 6. In addition, H 2 S was found to potentiate T-cell activation and regulate T reg -cell-associated immune homeostasis, with the net effect being a stimulation of the immune response (15) . Such effects may be beneficial in the context of stimulation of anti-SARS-CoV-2 immune responses. 7. Finally, recently, Renieris et al. (16) demonstrated in this journal that high baseline concentrations of reactive sulfur species and/or their lacking decrease over time were associated with worse outcome of SARS-CoV-2. While the absolute concentrations reported clearly have to be questioned (17) , this observation nevertheless suggests investigating exogenous H 2 S as a therapeutic approach. It is self-evident that any potential therapeutic approach using H 2 S donation raises the question of the route of application. Theoretically, two possible strategies could be considered: boosting endogenous H 2 S formation, i.e., by supplementing upstream substrates and/or cofactors of the H 2 S-producing enzymes (e.g., taurine, vitamin B6, a-keto-glutarate), or exogenous H 2 S administration. The latter approach can either make direct use of the H 2 S molecule itself, i.e., by inhaling gaseous H 2 S, or use molecules that can ''release'' H 2 S (Fig. 1) . In this journal, Ali et al. (18) advocate a clinical trial to explore the use of inhaled H 2 S for the management of SARS-CoV-2-related ARDS. Albeit inhaling gaseous H 2 S has already been performed in small studies in healthy human volunteers (19) , for several reasons, we strongly recommend NOT to use this approach in SARS-CoV-2 patients (20): due to its potential toxicity, its use requires special equipment and personnel for storage and handling, as well as close monitoring of the environmental and delivered concentrations to protect any bystander; it is well established that gaseous H 2 S is an irritant of the airway mucosa; a direct comparison of inhaled H 2 S and infusion of the H 2 S-releasing salt Na 2 S in murine ventilatorinduced lung injury showed that in contrast to the protective effect of infusing Na 2 S, inhaling H 2 S dose-dependently had either no or even detrimental effects (21) . Injection of the rapidly H 2 S-''releasing'' salts (Na 2 S, NaHS) results in initially high concentrations that subsequently rapidly disappear, and, in addition, may have adverse properties, e.g., induce pro-rather than anti-inflammatory effects (20) . While at least under intensive care unit conditions, this inconvenient of bolus injection could theoretically be overcome by constant i.v., infusion, in clinically relevant large animal models, this approach had beneficial effects only within a narrow dose and time window (22) . It is questionable as well, whether the recently developed ''slow-releasing'' H 2 S donors, e.g., GYY4137 or the mitochondria-targeted compound AP39, will find their way into clinical practice: despite abundant promising experimental studies both in vitro and in vivo, the available data from fully resuscitated animal models showed either hardly any protective properties or even detrimental side effects (23, 24) . Given the above-mentioned pitfalls of inhaling gaseous H 2 S or infusing Na 2 S-based i.v. solutions and the uncertainties of the newly developed compounds, interest has focused on the potential use of molecules, which are known sources of H 2 S and are already recognized drugs for other indications. GSH replenishment can be achieved using its precursor N-acetyl-cysteine (NAC), which, moreover, would also potentially attenuate SARS-CoV-2-related ''cytokine storm'' (25) as well as allow for ACE2 inhibition (8) . However, despite its promising pharmacological profile, in a single-center, double-blind, randomized, placebo-controlled trial in 135 patients, high-dose NAC ( 300 mg/kg over 20 h) did not beneficially affect the evolution of severe SARS-CoV-2 (26) . Other potential candidates are ammonium-tetrathiomolybdate, which is recognized for the treatment of Wilson's disease, and sodium thiosulfate (Na 2 S 2 O 3 ), which is well established for the treatment of cyanide intoxication, cis-platinum overdose, and calciphyllaxis. Ammonium-tetrathiomolybdate (ATTM) showed promising results in rat hemorrhage and cerebral and myocardial ischemia/reperfusion (27) . Na 2 S 2 O 3 not only was organ-protective in both murine endotoxin-and polymicrobial sepsis-induced acute lung injury (28) , but, in particular, also improved lung mechanics and gas exchange in a clinically relevant, resuscitated long-term model of hemorrhage-and resuscitation in chronically comorbid swine characterized by coronary arterial CSE deficiency due to underlying ubiquitous atherosclerosis (29) . It should be noted, however, that so far neither ATTM nor Na 2 S 2 O 3 have been investigated in patients with SARS-CoV-2. In conclusion, there is sound evidence that H 2 S bears the potential as a ''defense against COVID-19'' (4), in particular since currently there is no effective drug for the treatment of the disease. While inhalation of gaseous H 2 S cannot be recommended so far, its administration (either via inhalation as aerosols and/or i.v. infusion (30)) using already recognized drugs that are well-established sources of H 2 S in biological systems, warrants investigation in the clinical setting (31, 32) . Anti-inflammatory and antiviral roles of hydrogen sulfide: rationale for considering H 2 S donors in COVID-19 therapy ACE2 and TMPRSS2 variants and expression as candidates to sex and country differences in COVID-19 severity in Italy ACE 2, TMPRSS2 distribution and extrapulmonary organ injury in patients with COVID-19 H 2 S as a potential defense against COVID-19? 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Cardiovascular, metabolic, and biochemical responses International union of basic and clinical pharamcology. CII: pharmacological modulation of H 2 S Levels: H 2 S donors and H 2 S biosynthesis inhibitors Protective and detrimental effects of sodium sulfide and hydrogen sulfide in murine ventilatorinduced acute lung injury Is pharmacological, H 2 S-induced 'suspended animation' feasible in the ICU? Metabolic, cardiac, and renal effects of the slow hydrogen sulfide-releasing molecule GYY4137 during resuscitated septic shock in swine with pre-existing coronary artery disease The Mitochondria-Targeted H 2 S-donor ap39 in a murine model of combined hemorrhagic shock and blunt chest trauma The potential mechanism of N-acetylcysteine in treating COVID-19 Double-blind, randomized, placebo-controlled trial with N-acetylcysteine for treatment of severe acute respiratory syndrome caused by COVID-19 Ammonium tetrathiomolybdate following ischemia/reperfusion injury: chemistry, pharmacology, and impact of a new class of sulfide donor in preclinical injury models Sodium thiosulfate attenuates acute lung injury in mice Effects of sodium thiosulfate (Na 2 S 2 O 3 ) during resuscitation from hemorrhagic shock in swine with preexisting atherosclerosis Possible application of H 2 S-producing compounds in therapy of coronavirus (COVID-19) infection and pneumonia H 2 S in acute lung injury: a therapeutic dead end(?) The role of host defences in Covid 19 and treatments thereof 1 . Pharmacological approaches to strengthen antiviral activity via increased H 2 S availability in patients suffering from SARS-CoV-2 disease. 3-MST indicates 3-mercaptopyruvate sulfurtransferase; ATTM, ammonium-tetrathiomolybdate; CBS, cystathionine-b-synthase; CSE, cystathionine-g-lyase; Na 2 S, sodium sulfide; Na 2 S 2 O 3 , sodium thiosulfate; NaHS, sodium hydrogen sulfide. Adapted from (32) .