Prenatal Exposure to Nicotine and Childhood Asthma: Role of Nicotine Acetylcholine Receptors, Neuropeptides and Fibronectin Expression in Lung

摘要

We hypothesized that prenatal exposure to nicotine, a major component of tobacco that transverses the placenta, is largely responsible for the development of asthma in children born of mothers who smoke. Specifically, we hypothesized that nicotine is recognized by specific cellular proteins called nicotinic acetylcholine receptors (nAChRs) that are expressed by lung cells termed fibroblasts and pulmonary neuroendocrine cells. In fibroblasts, this interaction triggers the exaggerated expression of a connective tissue protein called fibronectin. In PNECs, nicotine stimulates cell growth and the excessive secretion of neuropeptides that affect airway formation and lung growth, and that stimulate smooth muscle cells to contract. In this fashion, nicotine can affect airways development and promote disease during childhood. Studies were performed in primary lung fibroblasts, embryonic murine lungs, and in rodents to test the hypothesis. This work led to the discovery that nicotine stimulates lung branching morphogenesis thereby causing dysanatic lung growth. Of note, these events were found to be mediated by the alpha7 nAChRs as demonstrated using inhibitors and agonists of the receptor as well as genetically-engineered animals. In animals exposed to nicotine during the prenatal period, lung branching was enhanced based on morphometric analysis of tissues, and this was associated with airway hyperreactivity to methacholine in physiological studies. These studies led to two published original articles and 1 review article.