Alarming increases in the incidence, morbidity and mortality from allergic asthma in children have been documented in the US over the last decade. The underlying cause(s) of this increase are unknown. Recent epidemiological studies have documented a positive association between levels of urban airborne particulate matter (PM) and exacerbations of asthma, although a causal relationship has not been established. Although virtually nothing is known about the mechanisms by which PM exposure may exacerbate asthma, PM exposure has been consistently shown to induce the production of the pro-inflammatory cytokine, interleukin-6 (IL-6). An immunopathogenic role for IL-6 in exacerbation of asthma may be hypothesized by the recent demonstration that it is critical in directing the development of allergin-driven pathogenic type-2 immune responses (IL- 4, IL-5) associated with asthma. The overall goal of this proposal is to establish a causal relationship between PM exposure and asthma morbidity and to determine the mechanisms by which PM elicits these effects. Thus, we plan to test the hypothesis that PM exposure exacerbates allergic asthma by inducing airway epithelial cell release of IL-6. To test this hypothesis, we have developed a unique murine model for susceptibility to allergic asthma. In this model, susceptible A/J mice develop antigen- dependent AHR eosinophilic inflammation and elevated IgE levels, concomitant with increases in lung levels of Th2 cytokine (IL-4), while resistant C3H/HeJ mice fail to develop these responses. Our preliminary data with this model, suggests that the asthmatic response in susceptible A/J mice is exacerbated by exposure to the reference emission source urban relationship between PM and allergic airway responses in genetically susceptible A/J mice. Secondly, we will determine the biological effects of PM exposure in non-allergic strains of mice. Thirdly, we will determine the role of IL-6 in mediating PM-induced inflammation and exacerbations of allergic asthmatic symptoms by neutralizing its activity in vivo and examining PM-induced effects on allergic airway responses. These studies will provide insight into the immunopathogenic mechanisms involved in PM- induced exacerbation of asthma and establish an exposure-response relationship upon which to base air quality standards to protect the health of asthmatic children living in urban environments.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Program Projects (P01)
Project #
5P01ES009606-02
Application #
6203529
Study Section
Project Start
1999-11-01
Project End
2000-10-31
Budget Start
1998-10-01
Budget End
1999-09-30
Support Year
2
Fiscal Year
2000
Total Cost
$109,361
Indirect Cost
Name
Johns Hopkins University
Department
Type
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Williams, D' Ann L; McCormack, Meredith C; Matsui, Elizabeth C et al. (2016) Cow allergen (Bos d2) and endotoxin concentrations are higher in the settled dust of homes proximate to industrial-scale dairy operations. J Expo Sci Environ Epidemiol 26:42-7
Bose, Sonali; Breysse, Patrick N; McCormack, Meredith C et al. (2013) Outdoor exposure and vitamin D levels in urban children with asthma. Nutr J 12:81
Levin, Albert M; Mathias, Rasika A; Huang, Lili et al. (2013) A meta-analysis of genome-wide association studies for serum total IgE in diverse study populations. J Allergy Clin Immunol 131:1176-84
Myers, Rachel A; Himes, Blanca E; Gignoux, Christopher R et al. (2012) Further replication studies of the EVE Consortium meta-analysis identifies 2 asthma risk loci in European Americans. J Allergy Clin Immunol 130:1294-301
Huang, Weiguo; Besar, Kalpana; Lecover, Rachel et al. (2012) Correction to Highly Sensitive NH(3) Detection Based on Organic Field-Effect Transistors with Tris(pentafluorophenyl)borane as Receptor. J Am Chem Soc 134:18149
Huang, Weiguo; Besar, Kalpana; LeCover, Rachel et al. (2012) Highly sensitive NH3 detection based on organic field-effect transistors with tris(pentafluorophenyl)borane as receptor. J Am Chem Soc 134:14650-3
Mazique, D; Diette, G B; Breysse, P N et al. (2011) Predictors of airborne endotoxin concentrations in inner city homes. Environ Res 111:614-7
Bezemer, Gillina F G; Bauer, Stephen M; Oberdorster, Gunter et al. (2011) Activation of pulmonary dendritic cells and Th2-type inflammatory responses on instillation of engineered, environmental diesel emission source or ambient air pollutant particles in vivo. J Innate Immun 3:150-66
Williams, D'Ann L; Breysse, Patrick N; McCormack, Meredith C et al. (2011) Airborne cow allergen, ammonia and particulate matter at homes vary with distance to industrial scale dairy operations: an exposure assessment. Environ Health 10:72
Wegmann, Daniel; Kessner, Darren E; Veeramah, Krishna R et al. (2011) Recombination rates in admixed individuals identified by ancestry-based inference. Nat Genet 43:847-53

Showing the most recent 10 out of 50 publications