Soluble guanylate cyclase as an alternative target for bronchodilator therapy in asthma

Arnab Ghosh, Cynthia J. Koziol-White, Kewal Asosingh, Georgina Cheng, Lisa Ruple, Dieter Groneberg, Andreas Friebe, Suzy A. Comhair, Johannes Peter Stasch, Reynold A. Panettieri, Mark A. Aronica, Serpil C. Erzurum, Dennis J. Stuehr

Research output: Contribution to journalArticle

22 Scopus citations

Abstract

Asthma is defined by airway inflammation and hyperresponsiveness, and contributes tomorbidity andmortalityworldwide. Although bronchodilation is a cornerstone of treatment, current bronchodilators become ineffective with worsening asthma severity. We investigated an alternative pathway that involves activating the airway smooth muscle enzyme, soluble guanylate cyclase (sGC). Activating sGC by its natural stimulant nitric oxide (NO), or by pharmacologic sGC agonists BAY 41-2272 and BAY 60-2770, triggered bronchodilation in normal human lung slices and in mouse airways. Both BAY 41-2272 and BAY 60-2770 reversed airway hyperresponsiveness in mice with allergic asthma and restored normal lung function. The sGC from mouse asthmatic lungs displayed three hallmarks of oxidative damage that render it NO-insensitive, and identical changes to sGC occurred in human lung slices or in human airway smooth muscle cells when given chronic NO exposure to mimic the high NO in asthmatic lung. Our findings show how allergic inflammation in asthma may impede NO-based bronchodilation, and reveal that pharmacologic sGC agonists can achieve bronchodilation despite this loss.

Original languageEnglish (US)
Pages (from-to)E2355-E2362
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number17
DOIs
StatePublished - Apr 26 2016

All Science Journal Classification (ASJC) codes

  • General

Keywords

  • Bronchoconstriction
  • Bronchodilation
  • Heme protein
  • Nitric oxide
  • S-nitrosylation

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    Ghosh, A., Koziol-White, C. J., Asosingh, K., Cheng, G., Ruple, L., Groneberg, D., Friebe, A., Comhair, S. A., Stasch, J. P., Panettieri, R. A., Aronica, M. A., Erzurum, S. C., & Stuehr, D. J. (2016). Soluble guanylate cyclase as an alternative target for bronchodilator therapy in asthma. Proceedings of the National Academy of Sciences of the United States of America, 113(17), E2355-E2362. https://doi.org/10.1073/pnas.1524398113