Stimulation of soluble guanylate cyclase prevents cigarette smoke-induced pulmonary hypertension and emphysema
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Stimulation of soluble guanylate cyclase prevents cigarette smoke-induced pulmonary hypertension and emphysema. / Weissmann, Norbert; Lobo, Borja; Pichl, Alexandra; Parajuli, Nirmal; Seimetz, Michael; Puig-Pey, Raquel; Ferrer, Elisabet; Peinado, Víctor I; Domínguez-Fandos, David; Fysikopoulos, Athanasios; Stasch, Johannes-Peter; Ghofrani, Hossein A; Coll-Bonfill, Núria; Frey, Reiner; Schermuly, Ralph T; García-Lucio, Jéssica; 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; Barberà, Joan A.
In: AM J RESP CRIT CARE, Vol. 189, No. 11, 01.06.2014, p. 1359-73.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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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 -