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Asthma, gender, and ETS: pathogenic synergy

Institution: University of California, Davis
Investigator(s): Laurel Gershwin, D.V.M., Ph.D.
Award Cycle: 2005 (Cycle 14) Grant #: 14IT-0081 Award: $98,908
Subject Area: Pulmonary Disease
Award Type: Inno Dev & Exp Awards (IDEAS)

Initial Award Abstract
Epidemiological data on asthma shows it to be more prevalent in woman than men. This difference becomes apparent after puberty. It is reasonable to conclude that sex hormones are playing a vital role. It has been shown that progesterone elicits a T helper 2 (TH2) type response in regard to cytokine production during pregnancy. Both asthma and allergy are TH2 mediated diseases. In our previous studies supported by TRDRP we were the first to demonstrate that environmental tobacco smoke (ETS) has a strong adjuvant effect on induction of a TH2 response, IgE production, and development of allergic asthma in mouse models. Moreover, our studies on prenatal and neonatal exposure to ETS showed that in subsequent adulthood the female ETS exposed mice were significantly more allergic than either female in filtered air or males in ETS. Thus it is highly probably that the interaction of female hormones in the presence of an ETS exposure environment synergize in causing development of allergic asthma in the adult female humans. It has also been shown that there are progesterone receptors on mast cells of human airways. Mast cells release various mediators of allergic asthma. The hypothesis for this IDEA grant is that females are more susceptible to allergic asthma due to TH2 cytokine signals resulting from increased levels of progesterone that naturally occur in the luteal phase of the ovarian cycle, and that ETS exposure exacerbates this effect. This effect could be further modulated by exogenous progesterone in the form of hormonal birth control or hormone replacement therapy. The hypothesis will be addressed using a mouse model of allergic asthma. Specific Aim #1: examine how exogenously administered progesterone modulates the immune response to allergen in the presence and absence of ETS exposure, in a mouse model of allergic asthma. Specific Aim #2: determine if the effects of progesterone on the immunomodulation of allergic asthma can be reversed if the progesterone receptors are blocked. Experimental groups will include ovarectomized adult female mice implanted with progesterone pellets or placebo housed in either filtered air or ETS inhalation chambers. Mice will be sensitized IP and then exposed by aerosol to the house dust mite allergen, Progesterone, estrogen, and IgE, IgG1, and IgG2 will be monitored in serum and Interleukin (IL)-4, IL-10, IL-13 and IFN-g will be monitored in peripheral blood mononuclear cells (PBMC’s) stimulated with allergen or progesterone via ELISPOT. PBMC’s will also be used for flow cytometry to look at intracellular IL-4, IFN-g and progesterone receptors. Cell differentials will also be done on the cells harvested from BAL. Immunohistochemistry will be performed on formalin fixed lung sections from mice to evaluate expression of progesterone receptors and to quantitate IgE and IgG1 producing cells. The data from this study will provide critical information for women who suffer from asthma and those who take any kind of progesterone based hormone therapy. If we find a critical link between ETS exposure, asthma causation, and female hormones it will instigate further investigation into the mechanisms by which this synergy occurs. While recommendations for asthmatics to avoid ETS are currently operative, a ramification of this research may result in recommendations for alternative forms of birth control in young women unavoidably exposed to ETS.