Stimulation of soluble guanylate cyclase prevents cigarette smoke-induced pulmonary hypertension and emphysema.

Abstract

RATIONALE:

Chronic obstructive pulmonary disease (COPD) is a major cause of death worldwide. No therapy stopping progress of the disease is available.

OBJECTIVES:

To investigate the role of the soluble guanylate cyclase (sGC)-cGMP axis in development of lung emphysema and pulmonary hypertension (PH) and to test whether the sGC-cGMP axis is a treatment target for these conditions.

METHODS:

Investigations were performed in human lung tissue from patients with COPD, healthy donors, mice, and guinea pigs. Mice were exposed to cigarette smoke (CS) for 6 hours per day, 5 days per week for up to 6 months and treated with BAY 63-2521. Guinea pigs were exposed to CS from six cigarettes per day for 3 months, 5 days per week and treated with BAY 41-2272. Both BAY compounds are sGC stimulators. Gene and protein expression analysis were performed by quantitative real-time polymerase chain reaction and Western blotting. Lung compliance, hemodynamics, right ventricular heart mass alterations, and alveolar and vascular morphometry were performed, as well as inflammatory cell infiltrate assessment. In vitro assays of cell adhesion, proliferation, and apoptosis have been done.

MEASUREMENTS AND MAIN RESULTS:

The functionally essential sGC β1-subunit was down-regulated in patients with COPD and in CS-exposed mice. sGC stimulators prevented the development of PH and emphysema in the two different CS-exposed animal models. sGC stimulation prevented peroxynitrite-induced apoptosis of alveolar and endothelial cells, reduced CS-induced inflammatory cell infiltrate in lung parenchyma, and inhibited adhesion of CS-stimulated neutrophils.

CONCLUSIONS:

The sGC-cGMP axis is perturbed by chronic exposure to CS. Treatment of COPD animal models with sGC stimulators can prevent CS-induced PH and emphysema.

• Authors: Norbert Weissmann, Borja Lobo, Alexandra Pichl, Nirmal Parajuli, Michael Seimetz, Raquel Puig-Pey, Elisabet Ferrer, Víctor I Peinado, David Domínguez-Fandos, Athanasios Fysikopoulos, Johannes-Peter Stasch, Hossein A Ghofrani, Núria Coll-Bonfill, Reiner Frey, Ralph T Schermuly, Jéssica García-Lucio, Isabel Blanco, Mariola Bednorz, Olga Tura-Ceide, Elsa Tadele, Ralf P Brandes, Jan Grimminger, Walter Klepetko, Peter Jaksch, Robert Rodriguez-Roisin, Werner Seeger, Friedrich Grimminger, Joan A Barberà
• Journal: American journal of respiratory and critical care medicine (Am J Respir Crit Care Med) Vol. 189 Issue 11 Pg. 1359-73 (Jun 01 2014) ISSN: 1535-4970 [Electronic] United States
• PMID: 24738736 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers
• Receptors, Cytoplasmic and Nuclear
• Guanylate Cyclase
• Soluble Guanylyl Cyclase

Topics

• Animals
• Biomarkers (metabolism)
• Blotting, Western
• Disease Models, Animal
• Down-Regulation
• Emphysema (enzymology, prevention & control)
• Guanylate Cyclase (metabolism)
• Guinea Pigs
• Humans
• Hypertension, Pulmonary (enzymology, prevention & control)
• In Vitro Techniques
• Mice
• Pulmonary Disease, Chronic Obstructive (enzymology, prevention & control)
• Real-Time Polymerase Chain Reaction
• Receptors, Cytoplasmic and Nuclear (metabolism)
• Smoking (adverse effects, metabolism)
• Soluble Guanylyl Cyclase