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

TY - JOUR

T1 - Stimulation of soluble guanylate cyclase prevents cigarette smoke-induced pulmonary hypertension and emphysema

AU - Weissmann, Norbert

AU - Lobo, Borja

AU - Pichl, Alexandra

AU - Parajuli, Nirmal

AU - Seimetz, Michael

AU - Puig-Pey, Raquel

AU - Ferrer, Elisabet

AU - Peinado, Víctor I

AU - Domínguez-Fandos, David

AU - Fysikopoulos, Athanasios

AU - Stasch, Johannes-Peter

AU - Ghofrani, Hossein A

AU - Coll-Bonfill, Núria

AU - Frey, Reiner

AU - Schermuly, Ralph T

AU - García-Lucio, Jéssica

AU - Blanco, Isabel

AU - Bednorz, Mariola

AU - Tura-Ceide, Olga

AU - Tadele, Elsa

AU - Brandes, Ralf P

AU - Grimminger, Jan

AU - Klepetko, Walter

AU - Jaksch, Peter

AU - Rodriguez-Roisin, Robert

AU - Seeger, Werner

AU - Grimminger, Friedrich

AU - Barberà, Joan A

PY - 2014/6/1

Y1 - 2014/6/1

N2 - 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.

AB - 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.

KW - Animals

KW - Biomarkers

KW - Blotting, Western

KW - Disease Models, Animal

KW - Down-Regulation

KW - Emphysema

KW - Guanylate Cyclase

KW - Guinea Pigs

KW - Humans

KW - Hypertension, Pulmonary

KW - In Vitro Techniques

KW - Mice

KW - Pulmonary Disease, Chronic Obstructive

KW - Real-Time Polymerase Chain Reaction

KW - Receptors, Cytoplasmic and Nuclear

KW - Smoking

U2 - 10.1164/rccm.201311-2037OC

DO - 10.1164/rccm.201311-2037OC

M3 - SCORING: Journal article

C2 - 24738736

VL - 189

SP - 1359

EP - 1373

JO - AM J RESP CRIT CARE

JF - AM J RESP CRIT CARE

SN - 1073-449X

IS - 11

ER -