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Pharmacological differentiation of early and late phase asthma-like response in trimellitic anhydride (TMA) sensitized and challenged brown Norway rats.

Zhang-XD; Siegel-PD
Toxicologist 2007 Mar; 96(1):282
Trimellitic anhydride (TMA) is a low molecular weight chemical that may induce specific-IgE and occupational asthma. We have previously demonstrated that dermal exposure to dry TMA powder with subsequent TMA challenge produces asthma-like early (EAR) and late airway responses (LAR) in Brown Norway rats (BNR), as indicated by Penh (an index of airway resistance). Potential mediators involved in LAR or EAR were examined, using selective pharmacological inhibitors, in the present study. Eight BNR were sensitized by 4, weekly, 4 hr dermal exposures to 40 mg dry TMA powder. Two weeks following the final dermal exposure, BNR were given a 10 min, 40 mg/m3 TMA nose-only aerosol challenge. Pharmacological agents were administered either prior to and/or 1 hr after EAR, and Penh was recorded every 0.5 min for 16-20 hrs. Results: Dexamethasone (2 mg/kg, i.p.) inhibited TMA induced EAR or LAR in TMA sensitized and challenged BNR. Intranasal steroid, fluticasone, (10Ál/nostril, daily for 3 days before airway challenge) did not inhibit EAR and LAR, suggesting that the Penh changes were not due primarily to upper airway responses. An aerosol of 1% Salbutamol, a beta 2 agonist neither prevented or reversed the EAR or LAR. Both Ketanserin, (10 mg/kg, i.p.) a 5-HT2-receptor antagonist, and Cetirizin, a H1-blocker, (30 mg/kg, i.p.) administered 1 hr after TMA challenge inhibited the subsequent LAR. Montelukast (10 mg/kg, i.p.), a leukotriene receptor antagonist, inhibited EAR, but not LAR, when administered either before or 1 hr after challenge. The adenosine antagonist, aminophylline (30 mg/kg, i.p.) also inhibited LAR in some, but not all treated/challenged rats. Selective pharmacological inhibition of mediators demonstrates different pathophysiological mechanisms of EAR and LAR for the asthma-like responses in the BNR TMA model.
Animal-studies; Physical-reactions; Mathematical-models; Statistical-analysis; Physical-reactions; Risk-analysis; Risk-factors; Dose-response; Epidemiology; Bronchial-asthma; Inhalation-studies; Allergic-reactions; Allergic-disorders; Allergens; Allergies; Chemical-analysis; Chemical-composition; Chemical-hypersensitivity; Chemical-reactions; Pharmacodynamics; Dermatology; Skin-absorption; Skin-exposure; Skin-irritants
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The Toxicologist. Society of Toxicology 46th Annual Meeting and ToxExpo, March 25-29, 2007, Charlotte, North Carolina