Volume 16 Supplement 1

Abstracts from the 7th International Conference on cGMP Generators, Effectors and Therapeutic Implications

Open Access

sGC redox regulation and asthma

  • Dennis J Stuehr1Email author,
  • Arnab Ghosh1,
  • Cynthia J Koziol-White2,
  • Kewal Asosingh1,
  • Georgina Cheng1,
  • Lisa Ruple1,
  • Jennifer Rodgers1,
  • Dieter Groneberg3,
  • Andreas Friebe3,
  • Johannes-Peter Stasch4,
  • Reynold A Panettieri2,
  • Mark A Aronical5 and
  • Serpil C Erzurum1, 5
BMC Pharmacology and Toxicology201516(Suppl 1):A26

DOI: 10.1186/2050-6511-16-S1-A26

Published: 2 September 2015

Asthma is defined by airway inflammation and hyper-responsiveness, and contributes to morbidity and mortality worldwide. Although bronchodilation is a cornerstone of asthma treatment, current bronchodilators become ineffective with time and with worsening asthma severity. We investigated an alternative pathway for bronchodilation that involves activating the airway smooth muscle enzyme, soluble guanylate cyclase (sGC).

The pharmacologic sGC stimulator BAY 41-2272 or a NO donor each triggered a dose-dependent bronchodilation in precision cut human lung slices from healthy donors and in mouse tracheal rings, whereas BAY 60-2770 was a less effective bronchodilator in these circumstances. Neither NO nor BAY 41-2272 relaxed tracheal rings obtained from sGC-/- mice. This established the NO-sGC pathway can trigger bronchodilation in healthy airway. In live animal studies, a single intra-tracheal administration of either BAY 41-2272 or BAY 60-2770 reversed the airway hyper-responsiveness that had developed in mice with allergic asthma and restored their normal lung function. The sGC recovered from the mouse asthmatic lungs displayed three hallmarks of oxidative damage that render it NO-insensitive, and identical changes were found to occur in sGC obtained from human lung slices or from cultured cells that had been exposed to low chronic NO. Our findings reveal how allergic inflammation in asthma, and its resulting airway inflammation and excessive NO production, impede the natural NO-sGC-based bronchodilation pathway, and suggest that pharmacologic sGC stimulants or activators can provide a novel therapeutic approach to achieve bronchodilation despite this loss.

Authors’ Affiliations

(1)
Department of Pathobiology, Lerner Research Institute, Cleveland Clinic
(2)
University of Pennsylvania Medical Center, Pulmonary, Allergy, and Critical Care Division
(3)
Institute of Vegetative Physiology, Universität Würzburg
(4)
Bayer Pharma AG
(5)
Respiratory Institute, Cleveland Clinic

Copyright

© Stuehr et al. 2015

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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