Investigation of 5-HT4 receptors in bronchial hyperresponsiveness in cigarette smoke-exposed mice

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-HT4R), HTR4, were associated with measures of airway obstruction and with COPD. We hypothesised that 5-HT4 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-HT4R 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-HT4R in the response to 5-HT by using the corresponding antagonists and 5-HT4R knockout (KO) mice. Results: The 5-HT4R 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-HT4R 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-HT4R KO mice. Conclusion: CS increased the levels of 5-HT4R mRNA in the lungs, concomitantly with bronchial responsiveness to 5-HT. Our in vivo data using pharmacologic and genetic approaches suggest that 5-HT4 receptors are not involved in the BHR to 5-HT in CS-exposed mice. (C) 2013 Elsevier Ltd. All rights reserved.