Scientists From University Of Texas Discover That Hydrogen Sulfide Can Be Used To Treat COVID-19-Associated Lung Endothelial Barrier Disruption
: The ongoing SARS-CoV-2 onslaughts continue to present significant challenges to global health and economies worldwide. As new variants of the SARS-CoV-2 virus emerge and the long-term consequences of the infection and the issues of viral persistence become evident, the need for effective therapies remains crucial.
Recent studies have shed light on the critical role of lung microvascular endothelial injury in the pathophysiology of COVID-19. In this context, hydrogen sulfide (H2S) has emerged as a promising therapeutic agent. Researchers from the University of Texas Medical Branch in Galveston, USA, have evaluated the effects of H2S in ameliorating SARS-CoV-2-associated lung endothelial barrier disruption. Their study findings provide valuable insights into the potential therapeutic implications of H2S in COVID-19 treatment.
The lung endothelial barrier plays a pivotal role in maintaining tissue homeostasis and preventing the leakage of fluid and plasma proteins into the surrounding tissue. However, in severe cases of COVID-19, endothelial barrier disruption occurs, leading to increased vascular permeability and the development of acute respiratory distress syndrome (ARDS) and multiorgan failure. The study team aimed to investigate whether H2S could mitigate endothelial barrier disruption caused by plasma samples from COVID-19 patients or inactivated SARS-CoV-2 virus.
Previous studies have demonstrated the beneficial effects of H2S in various pathological conditions, including its ability to improve endothelial barrier function.
H2S is a gaseous signaling molecule produced in mammalian cells, including endothelial cells (ECs), and has been shown to modulate inflammatory responses and reduce vascular leakage. However, its specific role in the context of SARS-CoV-2-mediated lung endothelial barrier disruption had not been explored until now.
The study team used a slow-releasing H2S donor, GYY4137, to treat a human lung microvascular EC monolayer in vitro after exposing the cells to plasma samples from COVID-19 patients or inactivated SARS-CoV-2 virus. They assessed the barrier permeability using electrical impedance measurements in real-time and correlated the cytokine/chemokine profile of the patients' plasma with disease severity and its impact on endothelial barrier function.
Corresponding author, Dr Katalin Módis from the Department of Surgery, University of Texas Medical Branch told COVID-19 News
reporters at TMN, “The results of the study were remarkable. Our study showed that treatment with GYY4137 significantly reduced endothelial barrier permeability after plasma challenge, regardless of disease severity. Moreover, GYY4137 completely reversed the endothelial barrier disruption caused by inactivated SARS-CoV-2 virus particles. These study findings suggest that H2S-releasing compounds have the potential to ameliorate SARS-CoV-2-associated lung endothelial barrier disruption.”
The study team also investigated the correlation between disease severity, the cytokine/chemokine profile of the patients' plasma, and endothelial barrier permeability. They found that disease severity correlated with the concentration of certain biomolec
ules, particularly IL-8 and IP-10, in the plasma. These biomarkers reflected disease severity more accurately than routinely used clinical markers such as LDH, CRP, and D-dimer. However, the cytokine and chemokine levels did not demonstrate a direct correlation with the endothelial barrier function assay results. This suggests that other factors, in addition to cytokines and chemokines, contribute to endothelial barrier disruption in COVID-19.
The study's findings provide valuable insights into the potential therapeutic implications of H2S in COVID-19 treatment. H2S has previously demonstrated anti-inflammatory, vasculoprotective, and antiviral effects, making it a promising candidate for combating COVID-19. Impaired H2S availability has been implicated in various cardiovascular, metabolic, and pulmonary diseases, all of which are risk factors for severe COVID-19.
It has been suggested that the reduced availability of H2S contributes to COVID-19-associated endotheliopathy and worsens the outcome of the disease.
Interestingly, the inhalation of sodium thiosulfate, an H2S donor, has shown protective effects in COVID-19 patients by reducing symptoms and accelerating recovery.
All these study findings suggest that H2S may have beneficial effects in the pathogenesis of COVID-19.
Interestingly in the study, the researchers observed that patient plasma induced barrier damage comparable to that caused by a known cytokine, TNF-α, which is known to disrupt endothelial junctions. However, the plasma-induced barrier disruption did not correlate with disease severity based on the patients' oxygen requirement. Plasma from some patients with mild disease caused as much or even more damage than plasma from some critical patients. On the other hand, plasma from certain individuals did not lead to an increase in endothelial barrier permeability. These results indicate that the impact of plasma on endothelial barrier function is highly variable and independent of disease severity.
Additionally, the researchers investigated the effect of inactivated SARS-CoV-2 Omicron BA.1 virus particles on endothelial barrier disruption and found that it caused a significant disruption. However, the addition of GYY4137 completely reversed the barrier disruption caused by the virus particles.
The study highlights the critical role of endothelial dysfunction in the pathophysiology of COVID-19. Severe cases of COVID-19 are characterized by progressive respiratory failure, which is caused by various factors, including endothelial barrier disruption. The findings suggest that H2S, as a gaseous signaling molecule, plays a fundamental role in vascular homeostasis and can modulate inflammatory responses and reduce vascular leakage.
Further research is needed to elucidate the precise mechanisms by which H2S regulates endothelial barrier function and its specific effects on SARS-CoV-2 infection. Additionally, clinical studies are warranted to evaluate the potential benefits of H2S-releasing compounds in COVID-19 patients. It is important to note that while the results of this study are promising, they are based on in vitro experiments using a specific H2S donor compound and patient plasma samples. Therefore, the translation of these findings into clinical practice requires careful consideration and rigorous investigation.
The study team concluded that impaired H2S availability and endothelial barrier dysfunction have emerged as important factors in the pathogenesis of severe COVID-19. The study discussed here sheds light on the potential therapeutic role of H2S-releasing compounds in ameliorating endothelial barrier disruption associated with SARS-CoV-2 infection. By targeting H2S availability and its effects on endothelial function, it may be possible to mitigate the severe outcomes of COVID-19 and improve patient outcomes.
The study findings were published on a preprint server and are currently being peer reviewed.
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