title: Nicotine impairs cyclooxygenase-2-dependent kinin-receptor-mediated murine airway relaxations.
abstract: BACKGROUND
  Cigarette smoke induces local inflammation and airway hyperreactivity. In asthmatics, it worsens the symptoms and increases the risk for exacerbation. The present study investigates the effects of nicotine on airway relaxations in isolated murine tracheal segments.
  
  
  METHODS
  Segments were cultured for 24h in the presence of vehicle, nicotine (10 μM) and/or dexamethasone (1 μM). Airway relaxations were assessed in myographs after pre-contraction with carbachol (1 μM). Kinin receptors, cyclooxygenase (COX) and inflammatory mediator expressions were assessed by real-time PCR and confocal-microscopy-based immunohistochemistry.
  
  
  RESULTS
  The organ culture procedure markedly increased bradykinin- (selective B₂ receptor agonist) and des-Arg⁹-bradykinin- (selective B₁ receptor agonist) induced relaxations, and slightly increased relaxation induced by isoprenaline, but not that induced by PGE₂. The kinin receptor mediated relaxations were epithelium-, COX-2- and EP2-receptor-dependent and accompanied by drastically enhanced mRNA levels of kinin receptors, as well as inflammatory mediators MCP-1 and iNOS. Increase in COX-2 and mPGES-1 was verified both at mRNA and protein levels. Nicotine selectively suppressed the organ-culture-enhanced relaxations induced by des-Arg⁹-bradykinin and bradykinin, at the same time reducing mPGES-1 mRNA and protein expressions. α7-nicotinic acetylcholine receptor inhibitors α-bungarotoxin and MG624 both blocked the nicotine effects on kinin B₂ receptors, but not those on B₁. Dexamethasone completely abolished kinin-induced relaxations.
  
  
  CONCLUSIONS
  It is tempting to conclude that a local inflammatory process per se could have a bronchoprotective component by increasing COX-2 mediated airway relaxations and that nicotine could impede this safety mechanism. Dexamethasone further reduced airway inflammation together with relaxations. This might contribute to the steroid resistance seen in some patients with asthma.
authors.affiliation: Division of Ear, Nose and Throat Diseases, Department of CLINTEC, Karolinska Institutet, Stockholm, Sweden. Electronic address: yuan.xu@ki.se.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Division of Ear, Nose and Throat Diseases, Department of CLINTEC, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Lars-Olaf
authors.initials: LO
authors.lastname: Cardell
mesh_terms: D000403:Airway Resistance / Q000187:drug effects*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D001920:Bradykinin / Q000031:analogs & derivatives / Q000378:metabolism; D065094:Bradykinin B2 Receptor Antagonists; D051546:Cyclooxygenase 2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects*; D018836:Inflammation Mediators / Q000819:agonists / Q000378:metabolism; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009213:Myography; D009538:Nicotine / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology*; D000071876:Prostaglandin-E Synthases; D043782:Receptor, Bradykinin B2 / Q000235:genetics / Q000378:metabolism; D020545:Respiratory Mucosa / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D046509:Tissue Culture Techniques; D014132:Trachea / Q000166:cytology / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D065094:Bradykinin B2 Receptor Antagonists; D018836:Inflammation Mediators; D018722:Nicotinic Agonists; D043782:Receptor, Bradykinin B2; D009538:Nicotine; D003907:Dexamethasone; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases; C000605865:Ptges protein, mouse; D001920:Bradykinin
keywords: Airway hyperreactivity; Airway relaxation; Bradykinin; Cyclooxygenase; Inflammation; Nicotine