Hydrogen sulfide (H2S) is an endogenous gaseous transmitter that participates in the regulation of physiological functions of the respiratory system, including smooth muscle contractility, pulmonary circulation, cell proliferation/apoptosis, oxidative stress, and inflammation (1). Therefore, impaired H2S production in human and experimental animal models has been implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD), asthma, pulmonary fibrosis, and hypoxia-induced pulmonary hypertension. H2S is produced endogenously in mammals, including humans, by three enzymes: cystathionine γ-lyase (CSE), cystathionine-β-synthase (CBS), and 3-mercaptopyruvate sulfurtransferase (2-4). Sulfide salts such as sodium hydrosulfide and sodium sulfide have been used widely to study the biological effects of H2S in many cells, tissues, and animals. When used in cell culture, these salts generate a large burst of H2S over a short time period. GYY4137 is a novel water-soluble H2S donor that releases H2S slowly over a period of hours (5). H2S donors have been used to demonstrate how therapeutic H2S administration exerts significant effects in various animal models of inflammation, reperfusion injury, and circulatory shock (6); however, their role in the context of viral infections is largely unknown.
We have shown recently, we believe for the first time, that the modulation of intracellular H2S significantly affects cellular responses and viral replication in an in vitro model of respiratory viral infections caused by respiratory syncytial virus (RSV) and other paramyxoviruses (7). Treatment of both A549 cells and primary small alveolar epithelial cells with the H2S donor GYY4137 significantly reduced the viral-induced release of proinflammatory mediators and significantly inhibited replication not only of RSV but of other paramyxoviruses, such as human metapneumovirus and Nipah virus, as well (7). On the basis of the observations from our in vitro studies, we used an in vivo model of RSV infection to address the role of H2S in RSV-induced lung disease. In the current study, we found that GYY4137 administration significantly attenuated RSV-induced body weight loss, clinical illness, and airway hyperresponsiveness (AHR). H2S-donor treatment also significantly reduced pulmonary cytokine and chemokine production and neutrophil recruitment to the lung after RSV infection. To further explore the role of endogenous H2S production in an experimental model of RSV infection, we used C57BL/6J mice genetically deficient in CSE enzyme (CSE−/−), which exhibit a profound depletion of H2S in peripheral tissues including the lungs (8). We found that endogenous H2S modulates viral replication and disease severity in mice experimentally infected with RSV. These data suggest that endogenous H2S plays a central role in protection against RSV infection, and that treatment with slow-releasing H2S donors could provide a novel approach for the prevention and/or treatment of viral-induced pulmonary diseases.
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