Journalartikel
Autorenliste: Weissmann, Norbert; Lobo, Borja; Pichl, Alexandra; Parajuli, Nirmal; Seimetz, Michael; Puig-Pey, Raquel; Ferrer, Elisabet; Peinado, Victor I.; Dominguez-Fandos, David; Fysikopoulos, Athanasios; Stasch, Johannes-Peter; Ghofrani, Hossein A.; Coll-Bonfill, Nuria; Frey, Reiner; Schermuly, Ralph T.; Garcia-Lucio, Jessica; Blanco, Isabel; Bednorz, Mariola; Tura-Ceide, Olga; Tadele, Elsa; Brandes, Ralf P.; Grimminger, Jan; Klepetko, Walter; Jaksch, Peter; Rodriguez-Roisin, Robert; Seeger, Werner; Grimminger, Friedrich; Barbera, Joan A.
Jahr der Veröffentlichung: 2014
Seiten: 1359-1373
Zeitschrift: American Journal of Respiratory and Critical Care Medicine
Bandnummer: 189
Heftnummer: 11
ISSN: 1073-449X
eISSN: 1535-4970
DOI Link: https://doi.org/10.1164/rccm.201311-2037OC
Verlag: American Thoracic Society
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 polyrnerase 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 beta 1-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.
Abstract:
Zitierstile
Harvard-Zitierstil: Weissmann, N., Lobo, B., Pichl, A., Parajuli, N., Seimetz, M., Puig-Pey, R., et al. (2014) Stimulation of Soluble Guanylate Cyclase Prevents Cigarette Smoke-induced Pulmonary Hypertension and Emphysema, American Journal of Respiratory and Critical Care Medicine, 189(11), pp. 1359-1373. https://doi.org/10.1164/rccm.201311-2037OC
APA-Zitierstil: Weissmann, N., Lobo, B., Pichl, A., Parajuli, N., Seimetz, M., Puig-Pey, R., Ferrer, E., Peinado, V., Dominguez-Fandos, D., Fysikopoulos, A., Stasch, J., Ghofrani, H., Coll-Bonfill, N., Frey, R., Schermuly, R., Garcia-Lucio, J., Blanco, I., Bednorz, M., Tura-Ceide, O., ...Barbera, J. (2014). Stimulation of Soluble Guanylate Cyclase Prevents Cigarette Smoke-induced Pulmonary Hypertension and Emphysema. American Journal of Respiratory and Critical Care Medicine. 189(11), 1359-1373. https://doi.org/10.1164/rccm.201311-2037OC
Schlagwörter
BAY 41-2272; EMPHYSEMA; ENDOTHELIAL GROWTH-FACTOR; pharmacology; P-SELECTIN; Pulmonary hypertension; RIOCIGUAT; soluble guanylate cyclase
