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NEUROTROPHIN RECEPTOR BLOCKADE ATTENUATES DIESEL EXHAUST PARTICULATE MATTER (DEP) ENHANCEMENT OF ALLERGIC RESPONSES
Farraj, A., N. H. HaykalCoates, A. D. Ledbetter, P A. Evansky, AND S H. Gavett. NEUROTROPHIN RECEPTOR BLOCKADE ATTENUATES DIESEL EXHAUST PARTICULATE MATTER (DEP) ENHANCEMENT OF ALLERGIC RESPONSES. Presented at Society of Toxicology Annual Meeting, New Orleans, LA, March 06 - 10, 2005.
Recent investigations have linked neurotrophins including NGF, NT-3, and BDNF to allergic airways diseases. Antibody blockade of NGF attenuates airway resistance associated with allergic airway responses in mice. Mice administered an antibody against the low affinity pan-neurotrophin receptor p75, or p75 knockout mice have reduced pulmonary airway inflammation. DEP has been linked to asthma exacerbation in many cities with vehicular traffic congestion. Cell types affected by DEP, including eosinophils, macrophages, lymphocytes and the airway epithelium, also produce neurotrophins and/or express neurotrophin receptors. We tested the hypothesis that DEP-induced enhancement of the hallmark features of allergic airway disease in a murine model is dependent on p75 function. Nonallergic (NA) and ovalbumin (OVA)-allergic C57BL/6J mice were intranasally instilled with an antibody against the p75 receptor or saline alone 1 hour before OVA challenge. The mice were then exposed nose-only to the PM2.5 fraction of SRM2975 DEP (0.85 mg/m3) or air alone for five hours, 1 hour later (n=9/group). Two days later, air exposed OVA-allergic mice developed increased levels of bronchoalveolar lavage fluid eosinophils, macrophages, neutrophils and IL-4, enhanced serum OVA-specific IgE, and had a small but insignificant increase (22%) in methacholine (Mch)-induced airway obstruction (PenH; Buxco), relative to air-exposed NA mice. DEP-exposed OVA-allergic mice had a significantly greater degree of airway obstruction than all other groups (68% greater vs. air-exposed NA mice). Instillation of anti-p75 significantly reduced mean PenH values in DEP-exposed OVA-allergic mice to levels similar to NA mice. The data demonstrate that neurotrophins play a role in DEP exacerbation of allergic responses, particularly airway obstruction, and may be relevant to human DEP exposure (Supported by NCSU/USEPA CT829470. This abstract does not reflect EPA policy).
Record Details:Record Type: DOCUMENT (PRESENTATION/ABSTRACT)
Organization:U.S. ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF RESEARCH AND DEVELOPMENT
NATIONAL HEALTH AND ENVIRONMENTAL EFFECTS RESEARCH LABORATORY
EXPERIMENTAL TOXICOLOGY DIVISION
PULMONARY TOXICOLOGY BRANCH