Basic Science Article | Published:

Cystathionine γ-lyase deficiency enhances airway reactivity and viral-induced disease in mice exposed to side-stream tobacco smoke

Abstract

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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Acknowledgements

We thank the Inhalation Toxicology Core (ITC) Facility, University of Texas Medical Branch, Galveston, TX, for their assistance with the cigarette TS exposure, Kimberly Palkowetz for technical assistance, and Cynthia Tribble for assistance in manuscript submission. This work was partially supported by NIH grants ES026782 (R.P.G.), AI125434 (A.C.), ES006676 (A.C., NIEHS), and AI062885 (R.P.G. and A.C.).

Author information

Each author listed on the paper have met the Pediatric Research authorship requirements.

Competing interests

The authors declare no competing interests.

Correspondence to Roberto P. Garofalo.

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