Nicotine impairs cyclooxygenase-2-dependent kinin-receptor-mediated murine airway relaxations

作者：Xu Yuan^*; Cardell Lars Olaf

来源：Toxicology and Applied Pharmacology, 2014, 275(1): 12-21.

DOI：10.1016/j.taap2013.12.013

• Nicotine
• Inflammation
• Airway hyperreactivity
• Bradykinin
• Airway relaxation
• Cyclooxygenase

Introduction: 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 24 h in the presence of vehicle, nicotine (10 mu M) and/or dexamethasone (1 mu M). Airway relaxations were assessed in myographs after pre-contraction with carbachol (1 mu M). 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 B-2 receptor agonist) and des-Arg(9)-bradykinin- (selective B-1 receptor agonist) induced relaxations, and slightly increased relaxation induced by isoprenaline, but not that induced by PGE(2). 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-Arg(9)-bradykinin and bradykinin, at the same time reducing mPGES-1 mRNA and protein expressions. alpha 7-nicotinic acetylcholine receptor inhibitors alpha-bungarotoxin and MG624 both blocked the nicotine effects on kinin B-2 receptors, but not those on B-1. Dexamethasone completely abolished kinin-induced relaxations.
Conclusion: 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.

• 出版日期2014-2-15