Clinical and Experimental Allergy, 2001, Volume 31, pages 1067±1076 Importance of inflammatory and immune components in a mouse model of airway reactivity to toluene diisocyanate (TDI) J. M. MATHESON*, R. W. LANGE², R. LEMUS³, M. H. KAROL³ and M. I. LUSTER* *Toxicology and Molecular Biology Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, West Virginia, ²Pathology and Toxicology, 3M Pharmaceuticals, St Paul, Minnesota, ³Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA Summary Background Nearly 9 million individuals are exposed to agents in the workplace associated with asthma, and isocyanates represent the most common cause of occupationally induced asthma. Objectives Nonetheless, the immunological mechanisms responsible for isocyanate- induced asthma are not clear. A murine model for toluene diisocyanate (TDI) asthma is described and employed to examine inflammatory and immune components that may be involved in the disease. Methods Groups (n  6) of C57BL/6J and athymic mice were sensitized by subcutaneous injection (20 ml on day 1, 5 ml on days 4 and 11), and 7 days later challenged by inhalation (100 p.p.b., days 20, 22 and 24) with TDI. Twenty-four hours following the last challenge the tracheae and lungs were examined for histological changes as well as for the expression of Th1, Th2 and pro-inflammatory cytokines. Mice were also examined for airway reactivity to methacholine challenge and for specific and total IgE and IgG antibodies. Results TDI sensitization resulted in increased reactivity to methacholine challenge as well as a significant inflammatory response in the trachea and nares of wild-type mice, but not in the athymic mice nor in the lungs of the C57BL/6J mice. Airway inflammation was characterized by inflammatory cell influx, goblet cell metaplasia and epithelial damage. Histological changes in the trachea were accompanied by increased mRNA expression of interleukin (IL)-4, tumour necrosis factor a, lymphotoxin b, lymphotactin and Rantes, as well as TDI-specific IgG antibodies and elevated levels of total IgE. IgE-specific antibodies were not detected with this exposure regimen but were produced when the TDI concentrations were increased. Conclusions These studies provide a unique murine model for occupational asthma that generates both inflammatory and immune mediators similar to those occurring in TDI- induced asthma in humans. Keywords: airway hypersensitivity, occupational asthma, toluene diisocyanate Clinical and Experimental Allergy, Vol. 31, pp. 1067±1076. Submitted 1 August 2000; revised 24 November 2000; accepted 29 December 2000. Introduction Asthma is a chronic respiratory disease characterized by the presence of reversible airway constriction and airway hyper- responsiveness (AHR) to various stimuli. Isocyanates, such q 2001 Blackwell Science Ltd 1067 Correspondence: Joanna M. Matheson, Toxicology and Molecular Biology Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, WV 26505, USA.