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NEUROTROPHINS OPERATE AT DIFFERENT LEVELS OF THE RESPIRATORY TRACT IN RESPONSES OF ALLERGIC MICE TO DIESEL EXHAUST PARTICLES (DEP)
Citation:
GAVETT, S. H., A. FARRAJ, N. HAYKAL-COATES, A. D. LEDBETTER, AND P. A. EVANSKY. NEUROTROPHINS OPERATE AT DIFFERENT LEVELS OF THE RESPIRATORY TRACT IN RESPONSES OF ALLERGIC MICE TO DIESEL EXHAUST PARTICLES (DEP). Presented at 45th Annual Society of Toxicology Meeting 2006, San Diego, CA, March 05 - 09, 2006.
Description:
Neurotrophins including NGF, NT-3, and BDNF are linked to allergic responses. Treatment with anti-p75 (pan-neurotrophin receptor) prevents the increase in airflow obstruction caused by exposure to DEP in ovalbumin (OVA)-allergic mice (Toxicol Sci 84(S1):91, 2005). Our present goals were to 1) compare responses to DEP in OVA-allergic mice using unrestrained whole body plethysmography (WBP; Buxco) vs. anesthetized ventilated system (flexivent; Scireq); 2) determine whether treatment with anti-p75 or anti-trkA (NGF-specific receptor) affects these responses; and 3) determine whether effects can be localized to distinct respiratory tract regions. One day after a 5 hr nose-only exposure to SRM2975 DEP (PM2.5 fraction; 2.0 mg/m3), airflow obstruction (Penh) induced by methacholine (Mch) aerosol in the WBP system was increased in allergic Balb/cJ mice vs. air-exposed allergic or nonallergic mice. Intranasal anti-p75 or anti-trkA blocked this increase in Penh. Therefore using WBP, neurotrophins in general and NGF specifically are involved in DEP-enhanced allergic airflow obstruction at some level (nasal / central / peripheral) of the respiratory tract. In the ventilated system, OVA-allergic (vs. nonallergic) mice had increases in i.v. Mch-induced total lung resistance (R), elastance (E), central airway resistance (Rn), and tissue resistance (G), but not tissue elastance. DEP exposure did not further enhance these responses to OVA. In contrast to WBP, only anti-p75 (not anti-trkA) reduced R, E, Rn, and G in DEP-exposed OVA-allergic mice to levels comparable to untreated air-exposed nonallergic mice. The ineffectiveness of DEP in enhancing lung responses to OVA in ventilated mice indicates that in this model DEP may enhance airflow obstruction only in nasal airways, which would be detected by WBP. Since only anti-p75 blocked the OVA-induced increase in responsiveness in ventilated mice, neurotrophins other than NGF may be involved in the lung response to OVA. (This abstract does not reflect EPA policy)