Prenatal exposure to maternal smoking adversely affects the respiratory health of children even in the absence of postanatal passive smoking. Transplacental nicotine exerts developments effects on fetal lung in animals, including lung hypoplasia and hyperplasia of pulmonary neurodendocrine cells. Paradoxically, the lungs of smoking-exposed infants appear to be more mature at birth than those of unexposed infants. The cellular and molecular mechanisms underlying these prenatal effects of maternal smoking are presently unknown. The study will use culture of whole embryonic mouse lungs in chemically defined medium as a model system to study the mechanism of nicotine action in development lung. Preliminary data show stimulation of branching and expression of the genes encoding the peptide growth factor GRP and surfactant proteins SP-C and SP-A in nicotine-treated lungs. The effect on SP-C gene expression is blocked by the nicotinic antagonist d-tubocurarine. Further, the increase in SP-C gene expression is blocked an antibody directed against the reactive region of GRP. Thus, the effects of nicotine in this system are mediated by nicotinic acetycholine receptor (nAChR) subtype and GRP may be a mediator in the downstream pathway. The added observation that embryonic lung distal epithelial cells posses and partial neuroendocrine phenotype leads to his hypothesis; That nicotine alters the developmental program of the embryonic lung including expression of surfactant protein genes, through a mechanism involving nAChRs located on cells of the distal epithelium and stimulation of production of GRP by these name distal epithelial cells.
The specific Aims are: 1) To characterize the effects of added nicotine on development of embryonic lung with respect to growth, branching morphogenesis, specific gene expression and differentiation of epithelial cells. 2) To determine the nature and location of the nAChRs mediating the developmental effects of nicotine in embryonic lung. 3) To test the role of GRP as a downstream mediator of nicotine effects by blocking strategies. The results of this study will provide insights into an aspect of normal lung development that has not previously been explored, as well as increasing our understanding of the mechanism of nicotine toxicity in developing lung and possible cancer risks from prenatal nicotine exposure.
| Wuenschell, Carol; Kunimi, Masao; Castillo, Carmenza et al. (2004) Nicotine-responsive genes in cultured embryonic mouse lung buds: interaction of nicotine and superoxide dismutase. Pharmacol Res 50:341-50 |
