title: The role of soluble guanylyl cyclase in chronic obstructive pulmonary disease.
abstract: BACKGROUND
  Soluble guanylyl cyclase (sGC), a cyclic guanosine 5'-monophosphate-generating enzyme, regulates smooth muscle tone and exerts antiinflammatory effects in animal models of asthma and acute lung injury. In chronic obstructive pulmonary disease (COPD), primarily caused by cigarette smoke (CS), lung inflammation persists and smooth muscle tone remains elevated, despite ample amounts of nitric oxide that could activate sGC.
  
  
  OBJECTIVE
  To determine the expression and function of sGC in patients with COPD and in a murine model of COPD.
  
  
  METHODS
  Expression of sGCα1, α2, and β1 subunits was examined in lungs of never-smokers, smokers without airflow limitation, and patients with COPD; and in C57BL/6 mice after 3 days, 4 weeks, and 24 weeks of CS exposure. The functional role of sGC was investigated in vivo by measuring bronchial responsiveness to serotonin in mice using genetic and pharmacologic approaches.
  
  
  RESULTS
  Pulmonary expression of sGC, both at mRNA and protein level, was decreased in smokers without airflow limitation and in patients with COPD, and correlated with disease severity (FEV1%). In mice, exposure to CS reduced sGC, cyclic guanosine 5'-monophosphate levels, and protein kinase G activity. sGCα1(-/-) mice exposed to CS exhibited bronchial hyperresponsiveness to serotonin. Activation of sGC by BAY 58-2667 restored the sGC signaling and attenuated bronchial hyperresponsiveness in CS-exposed mice.
  
  
  CONCLUSIONS
  Down-regulation of sGC because of CS exposure might contribute to airflow limitation in COPD.
authors.affiliation: 1 Laboratory for Translational Research in Obstructive Pulmonary Diseases, Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium.
authors.forename: Constantinos
authors.initials: C
authors.lastname: Glynos
authors.forename: Lisa L
authors.initials: LL
authors.lastname: Dupont
authors.forename: Theodoros
authors.initials: T
authors.lastname: Vassilakopoulos
authors.forename: Andreas
authors.initials: A
authors.lastname: Papapetropoulos
authors.forename: Peter
authors.initials: P
authors.lastname: Brouckaert
authors.forename: Athanassios
authors.initials: A
authors.lastname: Giannis
authors.forename: Guy F
authors.initials: GF
authors.lastname: Joos
authors.forename: Ken R
authors.initials: KR
authors.lastname: Bracke
authors.forename: Guy G
authors.initials: GG
authors.lastname: Brusselle
mesh_terms: D000368:Aged; D000818:Animals; D016084:Bronchoconstriction / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D015536:Down-Regulation; D005260:Female; D006162:Guanylate Cyclase / Q000032:analysis / Q000172:deficiency / Q000502:physiology*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D029424:Pulmonary Disease, Chronic Obstructive / Q000503:physiopathology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000032:analysis / Q000172:deficiency / Q000502:physiology*; D020545:Respiratory Mucosa / Q000737:chemistry; D012701:Serotonin / Q000502:physiology*; D012907:Smoking / Q000009:adverse effects* / Q000503:physiopathology; D000071756:Soluble Guanylyl Cyclase; D014028:Tobacco Smoke Pollution / Q000009:adverse effects*
chemical_list: D018160:Receptors, Cytoplasmic and Nuclear; D014028:Tobacco Smoke Pollution; D012701:Serotonin; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase