Environmental tobacco smoke (ETS) is a major indoor air pollutant. ETS has been implicated in human airway hypersensitivity, a prominent feature of bronchial asthma. The mechanisms by which ETS produces airway hyper-reactivity are poorly understood, but current evidence suggests that a defect in the beta-adrenergic system could be a contributory factor. The objective of the proposed study is to confirm whether ETS causes airway hyper-responsiveness and whether there is a concurrent presence of beta-adrenergic dysfunction in airway epithelial and smooth muscle cells. Furthermore, we will determine the mechanism by which ETS desensitizes beta-adrenoreceptors. For the study of the mechanism, we will focus on (a) the phosphorylation-inactivation of beta-adrenergic receptors, and (b) the mutation of the gene for the beta-adrenergic receptors. Guinea pigs will be chosen as the animal model because (i) ETS-induced airway hyper-responsiveness has been well characterized in guinea pigs, and (ii) a link has been established between beta-adrenoreceptors desensitization and bronchial hyper-reactivity in guinea pig airway epithelial and smooth muscle cells. Data obtained from this study on the mechanism by which ETS weakens beta-adrenergic receptor function would translate into the possibility for new approaches to treatment of hyper-reactivity to ETS-pollution. Our future goal will be to clone the normal and mutated beta-adrenergic receptor cDNA in mammalian expression vectors, transfect these clones into ETS-exposed airway epithelial and smooth muscle cells, and study whether the function of beta-adrenoreceptors in ETS-exposed cells are improved. This may highlight an innovative control measure to develop future therapeutic strategies for ETS-effects in human.
NIH ExPorter
NIH ExPorter