Enviornmental and Occupational Disorders
A novel mouse model of diisocyanate-induced asthma showing allergic-type inflammation in the lung after inhaled antigen challenge,☆☆

https://doi.org/10.1067/mai.2002.123533Get rights and content

Abstract

Background: Exposure to diisocyanates, a group of highly reactive, low-molecular-weight compounds, is a major cause of occupational asthma. In contrast to mouse models of atopic asthma, previous mouse models of diisocyanate-induced asthma have failed to show lung inflammation with characteristics of human disease. Objective: Our goal was to establish a novel mouse model of diisocyanate-induced asthma in which lung inflammation reminiscent of that seen in human asthma is generated after inhaled antigen challenge. Methods: BALB/c mice were epicutaneously sensitized to hexamethylene diisocyanate (HDI) and then challenged with an HDI-protein conjugate administered by means of an intranasal droplet. Results: HDI sensitization resulted in development of contact hypersensitivity and HDI-specific antibody production. Most importantly, however, vigorous inflammatory responses with characteristics of human asthma were generated in the lung after inhaled HDI challenge. Challenge of sensitized, but not unsensitized, mice resulted in airway eosinophilia, mucus hypersecretion, and production of TH1-type (IFN-γ) and TH2-type (IL-4, IL-5, and IL-13) cytokines by lung inflammatory cells. Despite the mixed TH1/TH2 response induced by HDI sensitization, use of cytokine-deficient mice revealed that airway eosinophilia was mediated by TH2 cytokines and not by IFN-γ. Conclusion: We report a novel mouse model of diisocyanate-induced asthma that, in contrast to previous models, demonstrates antigen-induced lung inflammation with characteristics of human disease. This model will allow investigation of the immunopathogenesis of diisocyanate-induced asthma and should provide insight into this common form of occupational disease. (J Allergy Clin Immunol 2002;109:873–8.)

Section snippets

Animals and epicutaneous sensitization

BALB/c mice were purchased from The National Cancer Institute (Frederick, Md). BALB/c-Il4tm2Nnt (IL-4-/-) mice were purchased from The Jackson Laboratory (Bar Harbor, Me). BALB/c IL-13-/- mice were provided by A. McKenzie. IFN-γ receptor-deficient (IFN-γR-/-) mice were provided by J. Aguet and backcrossed onto BALB/c. Female mice 9 to 12 weeks of age were used in all experiments. Backs of mice were shaved with electric clippers 1 to 2 days before exposure to HDI (0.01%–10%) diluted in a 4:1

CHS and antibody responses in HDI-sensitized mice

As shown in Fig 1, A , mice exposed to either 0.1% or 1.0% HDI on days 0 and 7 had significant ear-swelling responses after challenge on day 12.

. CHS, serum antibody, and airway inflammatory responses in HDI-sensitized mice. A, Ears of sensitized mice were challenged with HDI, and peak swelling at 24 hours is shown. Data are reported as means ± SEM of 4 to 5 mice per group (representative experiment, 1 of 3). B and C, HDI-sensitized or unsensitized mice were challenged with inhaled HDI-MSA.

Discussion

In the present study we describe a novel mouse model of diisocyanate-induced asthma. To our knowledge, this is the first such model to demonstrate lung inflammation with characteristics of human asthma, including eosinophilia and mucus hypersecretion. The lung inflammation in our model was present specifically in sensitized animals. Scheerens et al7, 8 have reported increased airway reactivity after intratracheal challenge of toluene diisocyanate-sensitized mice. However, only nonspecific,

Acknowledgements

We thank Ms Heather MacLeod for technical assistance and Dr Robert Homer for his input regarding the histologic appearance of lung inflammatory infiltrates.

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  • Cited by (0)

    Supported by National Institutes of Health grants R01-HL65209 (K. Bottomly and C. Herrick), P50-HL56389 and K24-ES00355 (C. Redlich), and RO1-HL62622 (A. Wisnewski). C. Herrick was supported by a Dermatology Foundation Clinical Career Development Award.

    ☆☆

    Reprint requests: Christina A. Herrick, MD, PhD, Department of Dermatology, Yale University School of Medicine, 333 Cedar St, PO Box 208059, New Haven, CT 06520-8059.

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