An animal model for pulmonary hypersensitivity to airborne industrial chemicals has been developed using guinea pigs. Exposure conditions were designed to mimic those found in the industrial situation, i.e., exposure is via the inhalation route, animals are unrestrained being kept in whole body plethysmographs, assuring normal breathing patterns and thus normal distribution of chemical in the respiratory tract, and no immunologic adjuvants are used to artificially stimulate an immune response. Using the model, both immediate and late-onset pulmonary responses have been obtained to both an industrial protein allergen (subtilisin) and to a reactive industrial chemical, diphenylmethane diisocyanate (MDI). Further, the time of onset of the immediate and late-occurring reactions coincides with those reported for industrial workers. The objective of this proposal is to investigate the mechanism(s) of these pulmonary responses as well as of hypersensitivity pneumonitis. The hypothesis to be tested is that the ability of a sensitized animal to respond to inhalation challenge with specific allergen and display a pulmonary hypersensitivity reaction is dependent upon a combination of three factors: (a) airway hyperreactivity (b) specific cytophilic antibody (c) antigen-specific lymphocytes. Each of these components will be evaluated in inbred strain #2 guinea pigs sensitized to ovalbumin by inhalation exposure. Airway hyperreactivity will be artifically produced by exposure of animals to 1 ppm ozone. Hyperreactive airways will be assessed by dose-response reactions to increasing concentrations of carbamylcholine. Class-specific antibodies will be isolated by HPLC or affinity chromatography and antigen-specific lymphocytes by flow cytometry. Elucidation of the mechanism(s) underlying immediate- and late-onset pulmonary reactions, as well as hypersensitivity pneumonitis should enable recommendation of appropriate testing procedures to identify those sensitized individuals likely to experience adverse pulmonary hypersensitivity reactions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
2R01ES001532-10
Application #
3249545
Study Section
Pharmacology A Study Section (PHRA)
Project Start
1977-04-01
Project End
1991-11-30
Budget Start
1987-01-07
Budget End
1987-11-30
Support Year
10
Fiscal Year
1987
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Type
Schools of Public Health
DUNS #
053785812
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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Karol, M H; Hillebrand, J A; Thorne, P S (1989) Characteristics of weekly pulmonary hypersensitivity responses elicited in the guinea pig by inhalation of ovalbumin aerosols. Toxicol Appl Pharmacol 100:234-46
Thorne, P S; Karol, M H (1989) Association of fever with late-onset pulmonary hypersensitivity responses in the guinea pig. Toxicol Appl Pharmacol 100:247-58
Thorne, P S; Karol, M H (1988) Assessment of airway reactivity in guinea pigs: comparison of methods employing whole body plethysmography. Toxicology 52:141-63
Jin, R Z; Karol, M H (1988) Intra- and intermolecular reactions of 4,4'-diisocyanatodiphenylmethane with human serum albumin. Chem Res Toxicol 1:281-7
Jin, R Z; Karol, M H (1988) Diisocyanate antigens that detect specific antibodies in exposed workers and guinea pigs. Chem Res Toxicol 1:288-93

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