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Mechanism of nicotine action in developing lung

Institution: University of Southern California
Investigator(s): Carol Wuenschell, Ph.D.
Award Cycle: 2000 (Cycle 9) Grant #: 9RT-0238 Award: $720,281
Subject Area: Pulmonary Disease
Award Type: Research Project Awards

Initial Award Abstract
Evidence indicates that maternal smoking during pregnancy can lead to increased wheezing, decreased lung capacity, and increased respiratory infections in infants and children even in the absence of passive tobacco smoke exposure after birth. Further evidence suggests that it is the nicotine in tobacco smoke that is responsible for these effects. We have recently shown that nicotine can directly affect the development of embryonic mouse lungs isolated in a culture dish by interacting with some type of nicotine receptor similar to those found in the brain. We have also been able to detect the presence in embryonic, fetal, and adult lung tissue of a number of the subunit proteins that make up the various subtypes of nicotine receptor. It is not known, however, exactly where the receptors are located within the lung, or which subtype of nicotine receptor is responsible for the effects on lung development. The mechanism by which activation of nicotine receptors would bring about these effects is also unknown. The recent finding that the level the 7 nicotine receptor subunit was increased in lungs exposed to maternally administered nicotine suggests involvement of the 7 nicotine receptor subtype. A similar study showed increased levels in fetal lung of a hormone called gastrin releasing peptide (GRP). GRP has also been shown in other studies to affect lung development and many of the effects are similar to those of nicotine.

This project will explore the mechanism underlying the developmental effects of nicotine in the lung by comparing four strains of mice that differ in nicotine response or in the presence or absence of a functional 7 nicotine receptor. We will examine the hypothesis that nicotine acts through 7 receptors located on the cells that line the developing airways causing these cells to make more GRP. The increased GRP would then cause the effects associated with nicotine exposure. Locations and levels of 7 receptors and GRP in developing lungs will be compared in the four mouse strains. Isolated embryonic mouse lungs grown in culture will be used to test whether blocking the action of GRP will also block the effect of nicotine. Elements of our proposed mechanism will also be examined in embryonic and fetal mouse lungs exposed to nicotine via the maternal drinking water.

Insights gained from this study will contribute to our understanding of how nicotine exerts its adverse effects on fetal lung development. Since we know that nicotine receptors and GRP are also present in adult lungs, the information gained about mechanisms of nicotine action in developing lung may also contribute to our understanding of tobacco-related lung diseases in adult smokers. It is hoped that increased understanding of underlying disease mechanisms may help identify new treatments and new methods of prevention.

Nicotine-responsive genes in cultured embryonic mouse lung buds: Interaction of nicotine and superoxide dismutase.
Periodical: Pharmacology Research Index Medicus:
Authors: Wuenschell C, Kunimi M, Castillo C, Marjoram P ART
Yr: 2004 Vol: 50 Nbr: 3 Abs: Pg: 341-350

Nicotinic acetylcholine receptor expression in airway smooth muscle of fetal mouse lung: Switch to postnatal epithelial expression.
Periodical: American Journal of Critical Care Medicine Index Medicus:
Authors: Cheong H. Kunimi M, Wuenschell CW ABS
Yr: 2002 Vol: 165 Nbr: Abs: B36 Pg:

Nicotine effects on gene expression in embryonic mouse lung buds in culture.
Periodical: American Journal of Critical Care Medicine Index Medicus:
Authors: Wuenschell CW, Kunimi M, Castillo C, Marjoram P ABS
Yr: 2003 Vol: 167 Nbr: Abs: A381 Pg: