Guanylyl cyclase activation reverses resistive breathing-induced lung injury and inflammation

Constantinos Glynos, Dimitris Toumpanakis, Konstantinos Loverdos, Vassiliki Karavana, Zongmin Zhou, Christina Magkou, Maria Dettoraki, Fotis Perlikos, Athanasia Pavlidou, Vasilis Kotsikoris, Stavros Topouzis, Stamatios E. Theocharis, Peter Brouckaert, Athanassios Giannis, Andreas Papapetropoulos, Theodoros Vassilakopoulos

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

Inspiratory resistive breathing (RB), encountered in obstructive lung diseases, induces lung injury. The soluble guanylyl cyclase (sGC)/cyclic guanosine monophosphate (cGMP) pathway is downregulated in chronic and acute animal models of RB, such as asthma, chronic obstructive pulmonary disease, and in endotoxin-induced acute lung injury. Our objectives were to: (1) characterize the effects of increased concurrent inspiratory and expiratory resistance in mice via tracheal banding; and (2) investigate the contribution of the sGC/cGMP pathway in RB-induced lung injury. Anesthetized C57BL/6 mice underwent RB achieved by restricting tracheal surface area to 50% (tracheal banding). RB for 24 hours resulted in increased bronchoalveolar lavage fluid cellularity and protein content, marked leukocyte infiltration in the lungs, and perturbed respiratory mechanics (increased tissue resistance and elasticity, shifted static pressure-volume curve right and downwards, decreased static compliance), consistent with the presence of acute lung injury. RB down-regulated sGC expression in the lung. All manifestations of lung injury caused by RB were exacerbated by the administration of the sGC inhibitor, 1H-[1,2,4]oxodiazolo[4,3-] quinoxalin-l-one, or when RB was performed using sGCα1 knockout mice. Conversely, restoration of sGC signaling by prior administration of the sGC activator BAY 58-2667 (Bayer, Leverkusen, Germany) prevented RB-induced lung injury. Strikingly, direct pharmacological activation of sGC with BAY 58-2667 24 hours after RB reversed, within 6 hours, the established lung injury. These findings raise the possibility that pharmacological targeting of the sGC-cGMP axis could be used to ameliorate lung dysfunction in obstructive lung diseases.

Original languageEnglish (US)
Pages (from-to)762-771
Number of pages10
JournalAmerican journal of respiratory cell and molecular biology
Volume52
Issue number6
DOIs
StatePublished - Jun 1 2015
Externally publishedYes

Keywords

  • Lung injury
  • Soluble guanylyl cyclase
  • Tracheal banding

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

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