A novel mouse model of diisocyanate-induced asthma showing allergic-type inflammation in the lung after inhaled antigen challenge.
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 T(H)1-type (IFN-gamma) and T(H)2-type (IL-4, IL-5, and IL-13) cytokines by lung inflammatory cells. Despite the mixed T(H)1/T(H)2 response induced by HDI sensitization, use of cytokine-deficient mice revealed that airway eosinophilia was mediated by T(H)2 cytokines and not by IFN-gamma.


CONCLUSIONS
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.
Herrick
Christina A
CA
Departments of Dermatology, Immunobiology, and Internal Medicine, Yale University School of Medicine, New Haven, Conn 06520-8059, USA.
Xu
Lan
L
Wisnewski
Adam V
AV
Das
Jyoti
J
Redlich
Carrie A
CA
Bottomly
Kim
K
D000280:Administration, Inhalation; D000818:Animals; D001249:Asthma / Q000276:immunology*; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002478:Cells, Cultured; D003485:Cyanates / Q000276:immunology*; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D003877:Dermatitis, Contact / Q000276:immunology; D004195:Disease Models, Animal; D004802:Eosinophilia / Q000276:immunology; D005260:Female; D007114:Immunization; D017953:Isocyanates; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D011014:Pneumonia / Q000276:immunology* / Q000473:pathology; D018418:Th2 Cells / Q000378:metabolism
D003485:Cyanates; D016207:Cytokines; D017953:Isocyanates; C015262:1,6-hexamethylene diisocyanate