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SUSCEPTIBILITY FACTORS FOR THE DEVELOPMENT OF ALLERGIC LUNG DISEASE AND ASTHMA
Citation:
Gilmour, M I., W. Dong, A. L. Lambert, P. Singh, AND MJK Selgrade. SUSCEPTIBILITY FACTORS FOR THE DEVELOPMENT OF ALLERGIC LUNG DISEASE AND ASTHMA. Presented at Asthma Workshop, RTP, NC, Oct 18-19, 2004.
Description:
Environmental Issue: More than 17 million people in the United States had asthma in 1998, which represents a doubling of the incidence in the previous 20 years. Since changes in the genetic makeup of the population take generations to occur, this increase must be related to changes in lifestyle and/or environment. Possible behavioral changes include altered diet and activity (i.e. more obesity and less exercise), changes in healthcare, (e.g. vaccination rate, antibiotic use) and different housing situations (e.g. urbanization, tight buildings, higher AC and daycare usage). Environmental factors include exposure to pesticides in food and water and a greater number of people being exposed to urban smog.
Scientific Approach: Although many of these factors have been implicated in the rise of asthma in epidemiological studies, the relative contribution of one component versus another can rarely be established. For this reason we have developed animal models of allergic lung disease to determine how behavioral or environmental changes may alter both the induction and the severity of the disease. Stressors that have been studied to date include exposure to a variety of air pollutants and model particulates, chronic exposure to oral pesticides, co-administration of vaccine components around the time of allergen sensitization, anti-oxidant status and level of food intake.
Methods: Allergen sensitization and challenge regimes have been established in rats and mice to assess both the induction and elicitation phase of lung disease. The stressors are applied around each phase and the kinetic development of a number of immunological and physiological endpoints of disease are assessed in both pulmonary and systemic tissue. These include the genetic expression and production of immune and pro-inflammatory cytokines; generation of total and antigen-specific antibodies; T lymphocyte proliferative responses; biochemical, cellular and histological markers of inflammation and injury; and pulmonary function changes in response to allergen and non-specific antagonists. Adoptive transfer experiments of serum and immune tissue from sensitized animals to naive recipients have demonstrated that different aspects of clinical disease can be transferred with different immunological components.
Results: These models have shown that exposure to a number of air pollutants including nitrogen dioxide, oil fly ash, metal sulfates, diesel exhaust, ambient PM samples and other particulates can enhance the development and/or increase the severity of disease endpoints associated with asthma. Mechanistic studies have demonstrated that pro-inflammatory cytokines such as TNF- can influence T cell polarization and that neutralization of this cytokine reduces the adjuvant effects of air-pollutants. We have also demonstrated that certain pesticide exposure regimens enhance aspects of the disease and that co-administration of the killed Bordetella pertussis vaccine augments sensitization to dust mite in juvenile rats which otherwise do not respond to allergen alone. Finally, rat strain comparison studies have shown that anti-oxidant status is associated with the potential to develop allergic lung disease, and that unrestricted diet in rats reduces the general anti-oxidant capacity and encourages the development of allergic immune responses and associated lung disease.
Future Directions Future work will determine the effect of acute and chronic vehicular exhaust exposure and emissions from coal combustion on the development of allergic lung disease. In depth investigations of signal transduction pathways in epithelial cells and macrophages during diesel exposure will identify chemical components of combustion emissions which drive the polarization of T lymphocytes to an allergic phenotype. In vitro systems with rodent and human lung cells will also be used to extrapolate dose response relationships in both species.
Impact: These animal models enable us to determine whether environmental factors have the potential to enhance the risk of developing asthma, or to exacerbate pre-existing disease. The understanding of these responses in whole animals and in human and rodent cells will allow extrapolation of health effects to humans and will provide a data base for the risk assessment of individual and mixed air pollutant atmospheres
Present address 2Food and Drug Administration, Washington D.C.; 3Southern Research Institute, Birmingham, AL