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Molecular Characterization of Trimellitic Anhydride–induced Respiratory Allergy in Brown Norway Rats

¹ TNO Quality of Life, Zeist, the Netherlands
² DSM Food Specialties, R&D Genetics, Delft, the Netherlands
³ Akzo Nobel, Technology & Engineering, Arnhem, the Netherlands

Correspondence: Address correspondence to: C. Frieke Kuper, TNO Quality of Life, Department of Toxicology and Applied Pharmacology, P.O. Box 360, 3700 AJ, the Netherlands; Phone: +31 30 69 44 478; e-mail:frieke.kuper{at}tno.nl.

To contribute to the hazard identification of low molecular weight (LMW) respiratory allergens, respiratory allergy induced by trimellitic anhydride (TMA) was characterized by whole genome analysis of lung tissue and blood proteomics in Brown Norway rats. Dermal sensitization (50% and 25% w/v) with TMA and an inhalation challenge of 15 mg/m³ TMA-induced apneas, laryngeal inflammation, increased numbers of eosinophils, neutrophils and macrophages in bronchoalveolar lavage (BAL), and increased immunoglobulin E levels in serum and lung tissue. Whole genome analysis of lung, sampled 24 hours after challenge, showed expression changes of not only genes belonging to several Gene Ontology groups with up-regulation of inflammatory-associated genes and those associated with lung remodeling but also genes involved in downsizing these processes. Blood proteomics reflected activation of inflammation-inhibiting pathways. Unsensitized animals challenged with TMA exhibited also an increased number of macrophages in BAL, but gene expression in the above-mentioned gene pathways was unchanged or down-regulated. The authors conclude that parameters for lung remodeling can be a valuable tool in hazard identification of LMW respiratory allergens.

Key Words: trimellitic anhydride • respiratory allergy • genes • lung remodeling • inflammation downsizing mechanisms • toll-like receptor pathway

Abbreviations: BN, Brown Norway • BAL, bronchoalveolar lavage • BHR, bronchial hyperresponsiveness • DNCB, dinitrochlorobenzene • ELISA, Enzyme-Linked-Immuno-Sorbent Assay • ECM, extracellular matrix components • HMW, high molecular weight • IgE, immunoglobulin E • LMW, low molecular weight • TMA, trimellitic anhydride

Toxicologic Pathology, Vol. 36, No. 7, 985-998 (2008)
DOI: 10.1177/0192623308327410


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