Hydrogen Sulfide as a Potential Therapeutic Approach for Lung Endothelial Barrier Dysfunction in COVID-19

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As of May 2023, the global impact of the Coronavirus Disease 2019 (COVID-19) pandemic remains significant, with millions of deaths and a rising number of infections worldwide.

While COVID-19 was initially considered a respiratory disease, emerging evidence suggests that endothelial dysfunction plays a critical role in both acute cases and long-term post-COVID conditions.

This article explores the pathophysiology of COVID-19-associated endotheliopathy, with a specific focus on lung endothelial barrier dysfunction, and discusses the therapeutic potential of hydrogen sulfide (H2S) in mitigating these effects.

Hydrogen sulfide (H2S) is a gaseous signaling molecule that has gained significant attention in the field of biomedical research due to its diverse physiological functions and therapeutic potential. In recent years, numerous studies have highlighted the role of H2S in various physiological and pathological processes, leading to the exploration of its therapeutic applications.

This comprehensive review aims to provide an overview of the therapeutic potential of H2S, focusing on its therapeutic uses, mechanisms of action, and potential applications in various diseases and conditions.

  1. Hydrogen sulfide (H2S) is a colorless gas with a distinctive smell, often associated with rotten eggs. Despite its pungent odor, H2S has emerged as a critical signaling molecule in various biological processes. It has been implicated in the regulation of cardiovascular function, modulation of inflammatory responses, and neuroprotection, among other functions. In recent years, there has been growing interest in exploring the therapeutic applications of H2S due to its potential to target multiple disease pathways.
  2. Biological Functions of Hydrogen Sulfide – H2S exerts its effects through multiple mechanisms and interacts with various molecular targets. It plays a crucial role in cardiovascular regulation, promoting vasodilation, and protecting against ischemic injury. Additionally, H2S exhibits anti-inflammatory properties by modulating cytokine production and inhibiting pro-inflammatory signaling pathways. It also influences neuronal signaling and provides neuroprotection in various neurological disorders. Furthermore, H2S is involved in metabolic processes, redox balance, and cellular signaling cascades.
  3. Therapeutic Uses of Hydrogen Sulfide – Researchers have explored different approaches to harness the therapeutic potential of H2S. Inhalation of H2S gas and administration of H2S-releasing compounds have shown promise in various preclinical and clinical studies. These approaches aim to supplement endogenous H2S levels or enhance its effects through controlled release. Modulating endogenous H2S production is another strategy to harness its therapeutic benefits.
  4. Mechanisms of Action of Hydrogen Sulfide – H2S exerts its effects by interacting with various molecular targets and signaling pathways. It can modulate enzyme activity, receptor function, and gene expression. H2S also regulates redox balance and oxidative stress, contributing to its cytoprotective effects. Furthermore, it influences cellular processes such as apoptosis, autophagy, and metabolism, contributing to its therapeutic potential.
  5. Potential Applications of Hydrogen Sulfide Therapy

5.1 Cardiovascular Diseases: H2S has shown promising effects in cardiovascular disorders such as hypertension, atherosclerosis, myocardial infarction, heart failure, and ischemia-reperfusion injury.

5.2 Inflammatory and Immune Disorders: H2S exhibits anti-inflammatory properties and holds potential in conditions such as arthritis, colitis, and immune-related disorders.

5.3 Neurological Disorders: H2S provides neuroprotection in stroke, neurodegenerative diseases, and neuroinflammation, and it modulates neuronal signaling and synaptic plasticity.

5.4 Respiratory Diseases: H2S has implications in acute lung injury, chronic obstructive pulmonary disease (COPD), asthma, and airway smooth muscle contraction and inflammation.

5.5 Metabolic Disorders: H2S affects glucose and lipid metabolism and may have therapeutic applications in obesity, diabetes, and metabolic syndrome.

6. Challenges and Future Directions While H2S therapy holds great promise, there are challenges that need to be addressed. Safety considerations, potential toxicities, and the development of targeted delivery systems for H2S therapy are important areas of future research. Clinical trials investigating the efficacy and safety of H2S-based interventions in various diseases are necessary to validate its therapeutic potential. Additionally, there is a need for translational research to bridge the gap between preclinical studies and clinical applications.

Emerging areas of investigation include exploring the role of H2S in cancer, wound healing, organ transplantation, and age-related diseases. The development of H2S-based combination therapies and the identification of specific H2S-responsive biomarkers are also areas of interest. Furthermore, the potential of H2S as a diagnostic tool and its use in targeted imaging techniques are exciting avenues for future exploration.

Endothelial Dysfunction in COVID-19: Severe manifestations of COVID-19 are characterized by respiratory failure due to alveolar damage, inflammation, coagulopathy, and endothelialitis.

Lung endothelial barrier damage and dysfunction contribute to the development of acute respiratory distress syndrome (ARDS) and other complications. Pathological findings in COVID-19 lungs include disruption of intercellular junctions, basal membrane contact loss, and thrombotic events. While the exact factors contributing to COVID-19-related endotheliopathy are still under investigation, pro-inflammatory cytokines, platelet activation, and interactions with the SARS-CoV-2 spike protein are thought to play a role.

Hydrogen Sulfide and Endothelial Barrier Function: Hydrogen sulfide (H2S) is a gaseous signaling molecule produced in various cell types, including endothelial cells (ECs). H2S is involved in vascular homeostasis, modulating inflammatory responses, and reducing vascular leakage. Previous studies have demonstrated that H2S can improve endothelial barrier function in various experimental conditions. H2S treatment has shown beneficial effects in reducing blood-brain barrier permeability, protecting against lung injury, and attenuating vascular hyperpermeability.

H2S in COVID-19 Therapy: Recent research has indicated the therapeutic potential of H2S in COVID-19. H2S has been shown to inhibit the replication of respiratory viruses, including SARS-CoV-2, and reduce virus-induced inflammation. Impaired endogenous H2S availability is associated with cardiovascular, metabolic, and pulmonary diseases, all of which are risk factors for severe COVID-19. Furthermore, studies have suggested that H2S may interfere with SARS-CoV-2 entry into host cells by affecting ACE2 and TMPRSS2 expression.

Investigating the Therapeutic Potential of H2S in Lung Endothelial Barrier Dysfunction: This study aimed to evaluate the effects of the slow-releasing H2S donor GYY4137 on the barrier function of human lung microvascular ECs. The ECs were challenged with plasma samples from COVID-19 patients or inactivated SARS-CoV-2 virus. The researchers examined the impact of H2S on endothelial barrier integrity and assessed inflammatory cytokine levels in patients’ plasma, correlating them with disease severity and their influence on the endothelial barrier function.

Conclusion: COVID-19-associated endothelial dysfunction, particularly in the lung endothelial barrier, is a crucial factor in the pathophysiology of severe cases and long COVID. The therapeutic potential of H2S in mitigating endothelial barrier disruption and reducing the severity of COVID-19 complications is an exciting area of research.

Further investigations into the effects of H2S on lung endothelial barrier function and its potential application in COVID-19 therapy are warranted. Harnessing the beneficial properties of H2S may provide new avenues for improving outcomes in COVID-19 patients and addressing the global health and economic challenges posed by this ongoing pandemic.

reference link: https://www.preprints.org/manuscript/202305.1639/v1

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