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 comorbidity 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 H₂S-generating enzyme in the lung to determine the contribution of H₂S to airway disease in response to side-stream tobacco smoke (TS), and to TS/RSV co-exposure. RESULTS:Following a 2-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 with wild-type (WT) mice. TS-exposed CSE KO mice that were subsequently infected with RSV exhibited a more severe clinical disease, airway obstruction and AHR, enhanced viral replication, and lung inflammation, compared with 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 fluid and increased levels of inflammatory cytokines and chemokines. CONCLUSION:This study demonstrates the critical contribution of the H₂S-generating pathway to airway reactivity and disease following exposure to ETS alone or in combination with RSV infection.

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