The outbreak of COVID-19 pneumonia caused by a new coronavirus (severe acute respiratory syndrome coronavirus 2, SARS-CoV-2) is posing a global health emergency and has led to more than 380,000 deaths worldwide. The cell entry of SARS-CoV-2 depends on two host proteins angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2). There is currently no vaccine available and also no effective drug for the treatment of COVID-19. Hydrogen sulfide (H2S) as a novel gasotransmitter has been shown to protect against lung damage via its anti-inflammation, antioxidative stress, antiviral, prosurvival, and antiaging effects. In light of the research advances on H2S signaling in biology and medicine, this review proposed H2S as a potential defense against COVID-19. It is suggested that H2S may block SARS-CoV-2 entry into host cells by interfering with ACE2 and TMPRSS2, inhibit SARS-CoV-2 replication by attenuating virus assembly/release, and protect SARS-CoV-2-induced lung damage by suppressing immune response and inflammation development. Preclinical studies and clinical trials with slow-releasing H2S donor(s) or the activators of endogenous H2S-generating enzymes should be considered as a preventative treatment or therapy for COVID-19.
CAN H2S BE A POTENTIAL REMEDY FOR COVID-19 BY REVERSING LUNG DAMAGE? Accumulated evidence indicated that H2S is essential for normal lung functions, regulating airway tone, epithelial cell survival and death, alveolar development, secretion of extracellular matrix, inflammation, and oxidative stress . Endogenously H2S can be mostly generated by CSE with cysteine as the main substrate. Lower H2S levels were often observed in lungs when responding to stress conditions (13). Exogenously applied H2S donors protected various lung damages, including acute and chronic lung injury, asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, and hypoxia-induced pulmonary hypertension. H2S was effective in reversing lung inflammation and improving pulmonary function in various animal models of lung injury induced by cigarette smoke, lipopolysaccharide, cerulein, hypoxia, ozone, burn, resuscitated hemorrhagic shock, and infrarenal aortic cross-clamping. Often, CSE blockage by PPG further aggravated the severity of lung injury in some of these models. N-acetyl cysteine (NAC) is a potential H2S-releasing donor and a strong antioxidant. The application of NAC to patients with pneumonia reduced oxidative stress and inflammatory response. It is proposed that NAC may protect COVID-19-asscoiated cytokine storm and acute respiration distress syndrome. Moreover, prolonged mechanical ventilation often causes lung injury; however, one study observed that intravenous administration of H2S donor increased the tension of oxygen in blood and improved lung function in a rat model of mechanical ventilation injury. The inflation of rat donor lungs with H2S during the warm ischemia phase improved mitochondrial functions and attenuated graft ischemic-reperfusion injury after lung transplantation. Not only providing protection against lung damage, H2S is also involved in amelioration of the functions of other organs, such as heart and kidney. COVID-19 is often manifested as pneumonia with a prominent incidence of cardiovascular complications and also kidney failure (14, 73). In consideration of these findings, H2S may be a potential remedy for COVID-19 by relieving the damage in lungs and other organs.
PERSPECTIVE According to the research advances on H2S signaling in biology and medicine, it is suggested that H2S may be effective in management of COVID-19, especially in high-risk populations with underlying conditions including cardiovascular diseases, diabetes, and kidney disorders. H2S may fight COVID-19 in multiple ways. First, H2S may block SARS-CoV-2 entry into host cells by interfering with ACE2 and TMPRSS2. Second, H2S can inhibit SARS-CoV-2 replication by attenuating syncytium formation and virus assembly and release. Third, H2S can protect SARS-CoV-2-induced lung damage by suppressing immune response and inflammation development (Fig. 1). It is worth noting here that although our knowledge on H2S signaling in biology and medicine have been advanced in the last decades, there are still some gaps for translating to clinical applications, and many practical limitations need to be further addressed. Developing stable and slow-releasing H2S donors or enzyme-specific activator for boosting H2S production with improved organ specificity has always been a challenge. Identification of the molecular targets of H2S and also the downstream signals are vital for drug development. By knowing the real-time change and enzymatic regulation for H2S production in different types of cells under normal and disease conditions, we can definitely compose new therapeutic strategies for combatting a wide spectrum of diseases. Taking all these into consideration, further preclinical investigations with animals and clinical trials with humans are required to validate H2S signaling as a preventive treatment or therapy for COVID-19
Reference & Source information: https://journals.physiology.org/
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