title: Brown Norway rat asthma model of diphenylmethane-4,4'-diisocyanate (MDI): impact of vehicle for topical induction.
abstract: The development of this Brown Norway (BN) rat asthma model was focused on the duplication of at least some hallmarks of human diisocyanate asthma using the skin as the initial priming route of exposure. Equal total doses of polymeric diphenylmethane-diisocyanate (MDI) were applied to similar surface areas either dissolved in di-n-octyl sebacic acid ester (20%) (SEBA), in acetone:olive oil (20%) (AOO) or undiluted. The elicitation of respiratory allergy utilized four repeated nose-only inhalation challenges of 30 min with 39 mg/m(3) MDI-aerosol approximately every 2 weeks. Emphasis was directed towards the analysis of respiratory responses delayed in onset. Endpoints suggestive of an allergic inflammatory response were examined by bronchoalveolar lavage (BAL) 1 day after the last inhalation challenge and comprised protein, LDH, cytodifferentiation of BAL cells, MCP-1, and some Th1 and Th2 cytokines. MCP-1 and cytokines were comparatively determined in three compartments: BAL fluid, BAL cells, and lung-associated lymph nodes (LALN). In all groups sensitized topically to MDI typical delayed-onset respiratory responses occurred. The lung and LALN weights, BAL-protein and -LDH were significantly increased as compared to the naïve control group challenged identically. There was compelling evidence of a neutrophilic rather than an eosinophilic inflammatory response. The patterns of interleukin (IL) IL-1alpha, TNF-alpha, IFN-gamma, GM-CSF, and IL-4 differed appreciably from one compartment to another and were essentially maximal in BAL cells. In contrast, MCP-1 was increased to the same extent in all compartments measured. Collectively, changes were slightly, although consistently more pronounced when using SEBA as vehicle when compared with the vehicle AOO or undiluted MDI. Notable was a discordance of cytokine profiles and respiratory responses. In conclusion, the priming potency of topically administered MDI and subsequent asthma-like responses following repeated inhalation exposures appear to be dependent on multiple factors, one of them appears to be associated with the type of matrix used to dissolve MDI. This animal model provides a versatile and robust experimental tool to evaluate and assess at least some features of MDI-related asthma.
authors.affiliation: Institute of Toxicology, Bayer Schering Pharmaceuticals, Building No. 514, 42096 Wuppertal, Germany. juergen.pauluhn@bayerhealthcare.com
authors.forename: Jürgen
authors.initials: J
authors.lastname: Pauluhn
mesh_terms: D000096:Acetone / Q000008:administration & dosage*; D000280:Administration, Inhalation; D000287:Administration, Topical; D000818:Animals; D001249:Asthma / Q000139:chemically induced* / Q000276:immunology / Q000503:physiopathology; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000276:immunology; D016207:Cytokines / Q000276:immunology; D003652:Decanoic Acids / Q000008:administration & dosage*; D004195:Disease Models, Animal; D017953:Isocyanates / Q000008:administration & dosage*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D007958:Leukocyte Count; D008198:Lymph Nodes / Q000187:drug effects / Q000276:immunology; D008297:Male; D000069463:Olive Oil; D014677:Pharmaceutical Vehicles / Q000008:administration & dosage*; D010938:Plant Oils / Q000008:administration & dosage*; D051381:Rats; D011914:Rats, Inbred BN; D012869:Skin Absorption; D001559:Benzhydryl Compounds
chemical_list: D000096:Acetone; D016207:Cytokines; D003652:Decanoic Acids; D017953:Isocyanates; D007770:L-Lactate Dehydrogenase; D000069463:Olive Oil; D014677:Pharmaceutical Vehicles; D010938:Plant Oils; C005969:4,4'-diphenylmethane diisocyanate; D001559:Benzhydryl Compounds