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

Research output: Contribution to journalArticle

Authors

  • 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

External Institution(s)

  • Cleveland Clinic Foundation
  • Rutgers Institute for Translational Medicine and Science
  • University of Würzburg
  • Bayer AG

Details

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

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.

    Research areas

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

Citation formats

APA

Ghosh, A., Koziol-White, C. J., Asosingh, K., Cheng, G., Ruple, L., Groneberg, D., ... 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

Harvard

Ghosh, A, Koziol-White, CJ, Asosingh, K, Cheng, G, Ruple, L, Groneberg, D, Friebe, A, Comhair, SA, Stasch, JP, Panettieri, RA, Aronica, MA, Erzurum, SC & Stuehr, DJ 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, vol. 113, no. 17, pp. E2355-E2362. https://doi.org/10.1073/pnas.1524398113