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NEUROTROPHIN MEDIATION OF ALLERGIC AIRWAYS RESPONSES TO INHALED DIESEL PARTICLES IN MICE
FARRAJ, A., N. HAYKAL-COATES, A. D. LEDBETTER, P. A. EVANSKY, AND S. H. GAVETT. NEUROTROPHIN MEDIATION OF ALLERGIC AIRWAYS RESPONSES TO INHALED DIESEL PARTICLES IN MICE. TOXICOLOGICAL SCIENCES. Society of Toxicology, RESTON, VA, 94(1):183-92, (2006).
We tested the hypothesis that DEP-induced enhancement of allergic airways disease in a murine model is dependent on normal function of the low affinity pan-neurotrophin receptor p75NTR, or trkA, the primary receptor for NGF
Neurotrophins, including nerve growth factor (NGF) partially mediate many features of allergic airways disease including airway hyper-responsiveness. Diesel exhaust particulates (DEP) associated with the combustion of diesel fuel exacerbate many of these allergic airways responses in humans. We tested the hypothesis that DEP-induced enhancement of allergic airways disease in a murine model is dependent on normal function of the low affinity pan-neurotrophin receptor p75NTR, or trkA, the primary receptor for NGF. Ovalbumin (OVA)-sensitized and nonallergic BALB/C mice were intranasally instilled with anti-p75NTR, anti-trkA, or vehicle, 1 hour before OVA aerosol challenge, and then exposed nose-only to the PM2.5 fraction of SRM2975 DEP (2.0 mg/m3) or filtered air for 5 hours. Two days later, DEP-exposed OVA-allergic mice had significantly greater increases in ventilatory responses to methacholine, but not increased lung resistance, suggesting that the airflow changes originated in the nasal passages. DEP-exposed OVA-allergic mice also had increased lung IL-4 levels relative to all other groups. The instillation of anti-p75NTR or anti-trkA completely reversed the DEP-induced increases in ventilatory responses and lung IL-4 levels to levels similar to control mice. OVA-allergic DEP exposed mice treated with anti-p75NTR had significantly less lung resistance in response to methacholine relative to OVA-allergic DEP exposed mice treated with anti-trkA. NGF and potentially other neurotrophins may be involved in DEP induced exacerbation of ventilatory responses and IL-4 levels. Neurotrophins other than NGF may be involved in pulmonary central airways and tissue resistance responses to allergen and DEP exposure.
Record Details:Record Type: DOCUMENT (JOURNAL/PEER REVIEWED JOURNAL)
Organization:U.S. ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF RESEARCH AND DEVELOPMENT
NATIONAL HEALTH AND ENVIRONMENTAL EFFECTS RESEARCH LABORATORY
EXPERIMENTAL TOXICOLOGY DIVISION
PULMONARY TOXICOLOGY BRANCH