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Immunopathogenesis of Hypersensitivity Pneumonitis in the Mouse
EPA Grant Number: R825702C009Subproject: this is subproject number 009 , established and managed by the Center Director under grant R825702
(EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
Center: Environmental Lung Disease Center (National Jewish Medical and Research Center)
Center Director: Mason, Robert
Title: Immunopathogenesis of Hypersensitivity Pneumonitis in the Mouse
Investigators: Routes, John M. , Borish, Larry
Institution: National Jewish Medical and Research Center
EPA Project Officer: Katz, Stacey
Project Period: February 16, 1998 through February 28, 2003 (Extended to February 28, 2004)
RFA: Environmental Lung Disease Center (National Jewish Medical and Research Center) (1998)
Research Category: Targeted Research
Description:
Objective:Hypersensitivity pneumonitis results from inhalation of, and sensitization to, a large number of organic dusts and other antigens. The initial response appears to be a granulomatous pneumonitis, which resolves with cessation of exposure without structural sequelae. Repeated or continuous exposure, however, may result in chronic interstitial fibrosis. A role for activated T-cells in HSP has been suggested as broncho-alveolar lavage (BAL) reveals lymphocyte-enriched cellular recovery, often, though by no means universally, exhibiting a CD8+ predominance. The hypothesis has been advanced that acute HSP is associated with periodic high-level exposure, while chronic HSP results from low-level continuous exposure. While attractive, this hypothesis has not subject to rigorous test. Model systems reflecting hypersensitivity responses suggest that antigen exposure that results in generation of THl-type cytokines allows for resolution of granulomata without sequelae (consistent with early discrete exposure in HSP) while antigens that promote a TH2-type response lead to chronicity and fibrosis, as might occur with prolonged exposure to antigens. Using a new model of lymphocytic alveolitis induced by gene transfer of plasmids coding for expression of the staphlococcal superantigen SEA, we propose to test the hypothesis that repetitive exposures will lead to fibrotic disease. We will also determine the effect of expression of Thl and Th2 cytokines during defined periods in the evolutioon of the illness. These studies will reveal new mechanisms by which hypersensitivity pneumonitis is initiated and maintained in both mouse and human.
Supplemental Keywords:Scientific Discipline, Health, Toxicology, Biology, Risk Assessments, Disease & Cumulative Effects, Health Risk Assessment, Immunology, Biochemistry, Allergens/Asthma, exposure assessment, health effects, immune response, inhalation, lungs, respiratory problems, dust, cytokines, T cells, harmful environmental agents, human health risk, airborne pollutants, airway disease, effects assessment, response, lung disease, immunopathogenesis, exposure, immune system effects, lung dysfunction, allergic response, environmental stressors, human exposure, model, pulmonary disease, airway inflammation
Main Center Abstract and Reports:
R825702 Environmental Lung Disease Center (National Jewish Medical and Research Center)
Subprojects under this Center:
(EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
R825702C001 SP-A and SP-D in Environmental Lung Disease
R825702C003 Adaptation to Nitrogen Dioxide: Role of Altered Glycolytic Pathway Enzyme Expression and NF-κB-Dependent Cellular Defenses Against Apoptosis
R825702C005 Inhalation of Particulate Matter Alters the Allergic Airway Response to Inhaled Allergen
R825702C006 Particle-Induced Lung Inflammation and Extracellular EC-SOD
R825702C007 Indoor-Outdoor Relationships of Airborne Particle Count and Endotoxin Concentrations
R825702C008 The Role of Mitochondrial DNA Mutations in Oxidant-Mediated Lung Injury
R825702C009 Immunopathogenesis of Hypersensitivity Pneumonitis in the Mouse
R825702C010 Activation of Natural T Lymphocytes by Diesel Exhaust Particulates Leads to Their Production of Interleukin-4 and TH2 Lymphocyte Differentiation to Allergen
R825702C011 Latex Antigen Levels During Powdered and Powderless Glove Use
R825702C012 Adjuvant Effects of Ozone in a Model of Allergen-Induced Airway Inflammation and Hyperresponsiveness
R825702C013 Acute Exposure to Particulate Air Pollution in Childhood Asthma
R825702C014 Mechanisms of Ozone Toxicity to the Lung