title: Investigation of 5-HT4 receptors in bronchial hyperresponsiveness in cigarette smoke-exposed mice.
abstract: BACKGROUND
  Chronic obstructive pulmonary disease (COPD) arises from an interaction between genetic host factors and environmental exposures (mainly cigarette smoke (CS)). Genome Wide Association studies have demonstrated that genetic variations in the gene encoding 5-hydroxytryptamine 4 receptors (5-HT(4)R), HTR4, were associated with measures of airway obstruction and with COPD. We hypothesised that 5-HT(4) receptors, in addition to 5-HT2AR and muscarinic receptors, contribute to the pathogenesis of COPD by facilitating cholinergic bronchoconstriction.
  
  
  METHODS
  The levels of pulmonary 5-HT(4)R mRNA were measured in CS-exposed mice by qRT-PCR. We investigated the effect of CS exposure on bronchial hyperresponsiveness (BHR) to 5-HT and evaluated the contribution of 5-HT2AR, muscarinic receptors and 5-HT(4)R in the response to 5-HT by using the corresponding antagonists and 5-HT(4)R knockout (KO) mice.
  
  
  RESULTS
  The 5-HT(4)R mRNA levels were significantly elevated upon acute (3 days), subacute (4 weeks) and chronic (24 weeks) CS exposure. Both acute and subacute CS exposure significantly increased BHR to 5-HT. Antagonism of 5-HT2AR abolished the CS-induced BHR to 5-HT, and antagonism of muscarinic receptors significantly reduced the response to 5-HT. However, pre-treatment with GR113808, a specific 5-HT(4)R antagonist, did not alter the response to 5-HT in CS-exposed mice. Accordingly, the CS-induced BHR to 5-HT was not different between wild-type and 5-HT(4)R KO mice.
  
  
  CONCLUSIONS
  CS increased the levels of 5-HT(4)R mRNA in the lungs, concomitantly with bronchial responsiveness to 5-HT. Our in vivo data using pharmacologic and genetic approaches suggest that 5-HT(4) receptors are not involved in the BHR to 5-HT in CS-exposed mice.
authors.affiliation: Laboratory for Translational Research in Obstructive Pulmonary Diseases, Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium. Electronic address: lisa.dupont@ugent.be.
authors.forename: Lisa L
authors.initials: LL
authors.lastname: Dupont
authors.affiliation: Laboratory for Translational Research in Obstructive Pulmonary Diseases, Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium. Electronic address: ken.bracke@ugent.be.
authors.forename: Ken R
authors.initials: KR
authors.lastname: Bracke
authors.affiliation: Shire-Movetis NV, Turnhout, Belgium. Electronic address: joris.demaeyer@outlook.com.
authors.forename: Joris H
authors.initials: JH
authors.lastname: De Maeyer
authors.affiliation: CNRS, UMR-5203, Institut de Génomique Fonctionnelle, Montpellier, France; INSERM, U661, Montpellier, France; Universités de Montpellier 1 & 2, UMR-5203, Montpellier, France; Université de Nîmes, Nîmes, France. Electronic address: valerie.compan@igf.cnrs.fr.
authors.forename: Valérie
authors.initials: V
authors.lastname: Compan
authors.affiliation: Laboratory for Translational Research in Obstructive Pulmonary Diseases, Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium. Electronic address: guy.joos@ugent.be.
authors.forename: Guy F
authors.initials: GF
authors.lastname: Joos
authors.affiliation: Heymans Institute of Pharmacology, Ghent University, Ghent, Belgium. Electronic address: romain.lefebvre@ugent.be.
authors.forename: Romain A
authors.initials: RA
authors.lastname: Lefebvre
authors.affiliation: Laboratory for Translational Research in Obstructive Pulmonary Diseases, Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium. Electronic address: guy.brusselle@ugent.be.
authors.forename: Guy G
authors.initials: GG
authors.lastname: Brusselle
mesh_terms: D000818:Animals; D016535:Bronchial Hyperreactivity / Q000235:genetics / Q000503:physiopathology*; D016084:Bronchoconstriction / Q000235:genetics; D004195:Disease Models, Animal; D007211:Indoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D029424:Pulmonary Disease, Chronic Obstructive / Q000209:etiology / Q000235:genetics / Q000503:physiopathology*; D012333:RNA, Messenger / Q000378:metabolism; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism; D011976:Receptors, Muscarinic / Q000378:metabolism; D044422:Receptors, Serotonin, 5-HT4 / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013449:Sulfonamides / Q000494:pharmacology; D014028:Tobacco Smoke Pollution / Q000009:adverse effects*
chemical_list: D007211:Indoles; D012333:RNA, Messenger; D044402:Receptor, Serotonin, 5-HT2A; D011976:Receptors, Muscarinic; D013449:Sulfonamides; D014028:Tobacco Smoke Pollution; D044422:Receptors, Serotonin, 5-HT4; C082871:GR 113808
keywords: COPD; Cigarette smoke; Murine model; Serotonin 4 receptors