CYSTATHIONINE γ-LYASE DEFICIENCY ENHANCES AIRWAY REACTIVITY AND VIRAL-INDUCED DISEASE IN MICE EXPOSED TO SIDE-STREAM TOBACCO SMOKE

BACKGROUND: Environmental tobacco smoke (ETS) is a known risk factor for severe respiratory syncytial virus (RSV) infections, yet the mechanisms of ETS/RSV co-morbidity are largely unknown. Cystathionine γ-lyase regulates important physiological functions of the respiratory tract. METHODS: We used mice genetically deficient in the cystathionine γ-lyase enzyme (CSE), the major H(2)S-generating enzyme in the lung to determine the contribution of H(2)S to airway disease in response to side-stream tobacco smoke (TS), and to TS /RSV co-exposure. RESULTS: Following a two-week period of exposure to TS, CSE-deficient mice (KO) showed a dramatic increase in airway hyperresponsiveness (AHR) to methacholine challenge, and greater airway cellular inflammation, compared to wild type (WT) mice. TS-exposed CSE KO mice that were subsequently infected with RSV exhibited more severe clinical disease, airway obstruction and AHR, enhanced viral replication and lung inflammation, compared to TS-exposed RSV-infected WT mice. TS-exposed RSV-infected CSE KO mice had also a significant increase in the number of neutrophils in bronchoalveolar lavage (BAL) fluid and increased levels of inflammatory cytokines and chemokines. CONCLUSION: This study demonstrates the critical contribution of the H(2)S-generating pathway to airway reactivity and disease following exposure to ETS alone or in combination with RSV infection.