A strong association between prenatal exposure to environmental tobacco smoke (ETS) and postnatal obstructive airflow abnormalities exists, but the exact mechanisms responsible for this effect remain unelucidated. We hypothesize that this effect is related to ETS-induced dysanaptic lung growth causing disproportionate growth between developing airways and alveoli. Specifically, we hypothesize that prenatal exposure to nicotine, a major component of tobacco that traverses the placenta, leads to dysynaptic growth during lung development and increased airway reactivity. Nicotine acts through alpha7 nAChRs on fibroblasts leading to increased expression/deposition of the matrix glycoprotein fibronectin, and on pulmonary neuroendocrine cells (PNECs) causing hyperplasia/hyperfunction. Ultimately, these changes manifest as airflow limitation and bronchial hyperresponsiveness. We observed that developing lungs express alpha7 nAChRs and that nicotine stimulates the expression of fibronectin in lung fibroblasts both in vitro and in vivo. Also, nicotine was found to stimulate the development of primitive airways;this effect was blocked by inhibitors of alpha7 nAChRs. PNEC-derived neuropeptides also induce fibronectin expression, stimulate lung branching morphogenesis, and promote lung growth. Finally, we found that prenatal exposure to nicotine in mice is associated with airway wall thickening, and increased airway resistance and hyperresponsiveness. The hypothesis will be tested in specific aims designed to: 1) elucidate the mechanisms by which nicotine affects murine lung development using lung explants, and 2) examine the effects of prenatal nicotine exposure on postnatal airway structure and function in vivo, and study how this relates to fibronectin overexpression and PNEC hyperfunction. The proposed studies will test the hypothesis using both in vitro and in vivo methods to demonstrate how prenatal nicotine exposure alters normal lung development through fibronectin and PNECs to set the stage for postnatal airway dysfunction. The results are expected to enhance our understanding of the embryologic origins of airway diseases in humans. Through a comprehensive career development plan under the supervision of the mentor and an outstanding advisory committee, this project allows the applicant to obtain the necessary knowledge, skills and experience to develop into an independent physician-scientist in academia.
