title: Stimulation of soluble guanylate cyclase prevents cigarette smoke-induced pulmonary hypertension and emphysema.
abstract: BACKGROUND
  Chronic obstructive pulmonary disease (COPD) is a major cause of death worldwide. No therapy stopping progress of the disease is available.
  
  
  OBJECTIVE
  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.
  
  
  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.affiliation: 1 Justus-Liebig University, Excellence Cluster Cardiopulmonary System, Universities of Giessen and Marburg Lung Center (UGMLC), DZL, Giessen, Marburg, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Weissmann
authors.forename: Borja
authors.initials: B
authors.lastname: Lobo
authors.forename: Alexandra
authors.initials: A
authors.lastname: Pichl
authors.forename: Nirmal
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authors.lastname: Parajuli
authors.forename: Michael
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authors.lastname: Seimetz
authors.forename: Raquel
authors.initials: R
authors.lastname: Puig-Pey
authors.forename: Elisabet
authors.initials: E
authors.lastname: Ferrer
authors.forename: Víctor I
authors.initials: VI
authors.lastname: Peinado
authors.forename: David
authors.initials: D
authors.lastname: Domínguez-Fandos
authors.forename: Athanasios
authors.initials: A
authors.lastname: Fysikopoulos
authors.forename: Johannes-Peter
authors.initials: JP
authors.lastname: Stasch
authors.forename: Hossein A
authors.initials: HA
authors.lastname: Ghofrani
authors.forename: Núria
authors.initials: N
authors.lastname: Coll-Bonfill
authors.forename: Reiner
authors.initials: R
authors.lastname: Frey
authors.forename: Ralph T
authors.initials: RT
authors.lastname: Schermuly
authors.forename: Jéssica
authors.initials: J
authors.lastname: García-Lucio
authors.forename: Isabel
authors.initials: I
authors.lastname: Blanco
authors.forename: Mariola
authors.initials: M
authors.lastname: Bednorz
authors.forename: Olga
authors.initials: O
authors.lastname: Tura-Ceide
authors.forename: Elsa
authors.initials: E
authors.lastname: Tadele
authors.forename: Ralf P
authors.initials: RP
authors.lastname: Brandes
authors.forename: Jan
authors.initials: J
authors.lastname: Grimminger
authors.forename: Walter
authors.initials: W
authors.lastname: Klepetko
authors.forename: Peter
authors.initials: P
authors.lastname: Jaksch
authors.forename: Robert
authors.initials: R
authors.lastname: Rodriguez-Roisin
authors.forename: Werner
authors.initials: W
authors.lastname: Seeger
authors.forename: Friedrich
authors.initials: F
authors.lastname: Grimminger
authors.forename: Joan A
authors.initials: JA
authors.lastname: Barberà
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D004195:Disease Models, Animal; D015536:Down-Regulation; D004646:Emphysema / Q000201:enzymology / Q000517:prevention & control*; D006162:Guanylate Cyclase / Q000378:metabolism*; D006168:Guinea Pigs; D006801:Humans; D006976:Hypertension, Pulmonary / Q000201:enzymology / Q000517:prevention & control*; D066298:In Vitro Techniques; D051379:Mice; D029424:Pulmonary Disease, Chronic Obstructive / Q000201:enzymology / Q000517:prevention & control*; D060888:Real-Time Polymerase Chain Reaction; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D012907:Smoking / Q000009:adverse effects* / Q000378:metabolism; D000071756:Soluble Guanylyl Cyclase
chemical_list: D015415:Biomarkers; D018160:Receptors, Cytoplasmic and Nuclear; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase