Environmental tobacco smoke (ETS) is a complex mixture of gases and particles that include smoke from the burning cigarette, cigar, or pipe tip (side-stream smoke, SS) and exhaled mainstream smoke (MS). It is involuntarily inhaled by nonsmokers, lingers in the air for hours after cigarettes have been extinguished, and can induce or exacerbate a wide range of lung diseases, from cancer to respiratory infections, chronic obstructive pulmonary disease (COPD) and asthma (4;5). Exposure to ETS continues to be common despite a decline in smoking in developed countries and despite evidence of serious health effects. Respiratory syncytial virus (RSV) is the single most important viral pathogen causing acute lower respiratory-tract infections (bronchiolitis) in children and predisposing to th development of childhood asthma. Exposure to ETS is a known risk factor for the development of severe RSV infections, yet the mechanisms that determine ETS/RSV infection co-morbidity are largely unknown. Severity of bronchiolitis is driven by higher level of viral replication in th airways, as shown in studies of neonatal mice exposed to SHTS prior to RSV infection. Hydrogen sulfide (H2S) is a gasotransmitter which is endogenously generated from cysteine metabolism mainly by the activity of two enzymes, cystathionine gamma-lyase (CSE) and cystathionine-beta-synthase (CBS), with CSE being the main H2S-forming enzyme in lung tissue. Lower levels of H2S have been demonstrated in serum of smokers, and negatively correlate with the severity of airway obstruction in patients with COPD. Recent investigations in our laboratory have discovered a previously unrecognized function of H2S as antiviral mediator in airway epithelial cells and in the lung. We propose the hypothesis that exposure to ETS inhibits the expression of the endogenous H2S-generating enzyme CSE, causing a relative defect in H2S levels in the lung, resulting in enhanced viral replication.
Two Aims will be pursued in this exploratory project.
Aim 1 will test the hypothesis that the endogenous H2S-generating CSE enzyme is a critical determinant of severe bronchiolitis in children exposed to ETS. Specifically, we will test the primary hypothesis that expression of CSE is reduced in RSV- infected subjects who are exposed to ETS, resulting in lower H2S production, enhanced viral replication and greater severity of illness.
In Aim 2 will test the hypothesis that CSE overexpression or direct H2S increased production in lungs of mice will blunt RSV replication and affect antiviral responses. To test this hypothesis, we will increase H2S production by CSE overexpression in the lung by replication deficient recombinant adenovirus-mediated gene transfer or by the use of GYY4137, a novel water-soluble H2S donor. Our experience with translational studies of RSV and ETS is ideal to pursue this innovative project. The results should have important therapeutic implications by identifying new strategies to treat primary respiratory viral infections or exacerbations of chronic underlying lung diseases that are associated with exposure to ETS.
The results of this project will provide a better understanding of the molecular mechanisms by which exposure to environmental tobacco smoke affects the severity of viral bronchiolitis in infants. These findings should have important therapeutic implications by identifying new strategies to treat viral bronchiolitis or exacerbations of chronic lung diseases that are associated with exposure to tobacco smoke.
| Bazhanov, Nikolay; Ansar, Maria; Ivanciuc, Teodora et al. (2017) Hydrogen Sulfide: A Novel Player in Airway Development, Pathophysiology of Respiratory Diseases, and Antiviral Defenses. Am J Respir Cell Mol Biol 57:403-410 |
| Komaravelli, Narayana; Ansar, Maria; Garofalo, Roberto P et al. (2017) Respiratory syncytial virus induces NRF2 degradation through a promyelocytic leukemia protein - ring finger protein 4 dependent pathway. Free Radic Biol Med 113:494-504 |
