This proposal is designed to elucidate the in vivo activity of IgE antibody in a rabbit model and to elucidate the specific mediators, cells and physiologic mechanisms by which this antibody leads to the alterations in respiratory and circulatory function which are characteristic of acute allergic reactions. Two types of responses will be studied and compared: systemic anaphylaxis as a result of intravenous antigen challenge and asthma-like bronchoconstriction induced by aerosolized antigen. Roles for histamine, AGEPC, basophils, and platelets in the aerosol antigen response will be compared with those already established for anaphylaxis. We will determine if prostaglandins and/or leukotrienes are important mediators of any of the individual alterations in either response by a) comparing the circulatory and respiratory alterations induced by these agents to those induced by antigen and/or b) demonstrating their in vivo release following antigen challenge and c) determining the effects of agents which block their synthesis (ibuprofin, imidazole, ETYA) or activity (FPL55712) on the antigen-induced response. In vitro correlative studies will include use of isolated pulmonary arteries, bronchi and lung parenchyma to establish mechanisms of alterations in right ventricular pressure and lung mechanics. Effects of in vivo neutrophil depletion will be examined as will in vitro involvement of neutrophils (as secondarily stimulated cells) in mediator release. Purified IgE will be given to normal rabbits to examine our contention that IgE alone is necessary and sufficient to confer sensitivity to anaphylaxis and/or response to aerosolized antigen. We will establish threshold levels for IgE and determine the effects of various levels of specifi IgG. Finally, physiologic and histologic evidence of the occurrence of an IgE-induced late phase reaction (LPR) will be sought. If LPRs occur, their dependence on IgE level prostaglandin-synthesis, and circulating neutrophils will be determined.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL022582-08
Application #
3336986
Study Section
Immunological Sciences Study Section (IMS)
Project Start
1977-12-01
Project End
1986-11-30
Budget Start
1984-12-01
Budget End
1985-11-30
Support Year
8
Fiscal Year
1985
Total Cost
Indirect Cost
Name
University of Arizona
Department
Type
Schools of Medicine
DUNS #
City
Tucson
State
AZ
Country
United States
Zip Code
85722
Lohman, I C; Halonen, M (1993) The effects of combined histamine and platelet-activating factor antagonism on systemic anaphylaxis induced by immunoglobulin E in the rabbit. Am Rev Respir Dis 147:1223-8
Hamawy, M M; Pinnas, J L; Palmer, J D et al. (1992) Antigen enhances neuronally induced contraction of intrapulmonary bronchi from IgE-producing rabbits. J Neuroimmunol 37:105-14
Halonen, M; Dunn, A M; Palmer, J D et al. (1990) Anatomic basis for species differences in peripheral lung strip contraction to PAF. Am J Physiol 259:L81-6
Lohman, I; Halonen, M (1990) Effects of the PAF antagonist WEB 2086 on PAF-induced physiologic alterations and on IgE anaphylaxis in the rabbit. Am Rev Respir Dis 142:390-7
Gomez, J; Bloom, J W; Yamamura, H I et al. (1990) Characterization of receptors for platelet-activating factor in guinea pig lung membranes. Am J Respir Cell Mol Biol 3:259-64
Bloom, J W; Baumgartener-Folkerts, C; Palmer, J D et al. (1988) A muscarinic receptor subtype modulates vagally stimulated bronchial contraction. J Appl Physiol 65:2144-50
Bloom, J W; Baumgartener-Folkerts, C; Palmer, J D et al. (1988) Airway cholinergic responsiveness in rabbits in relation to antigen sensitization and challenge. Immunopharmacology 15:157-67
Habib, M P; Dunn, A M; Sobonya, R E et al. (1988) Immunoglobulin E anaphylaxis in rabbits: mechanisms of pulmonary resistance and compliance changes. J Appl Physiol 64:1009-16
Smith, P F; Palmer, J D; Holmes, T et al. (1986) The responsiveness of rabbit bronchial rings to antigen, AGEPC and histamine. Immunopharmacology 12:89-96
Smith, P F; Thompson, W J; de Haen, C et al. (1986) Bronchodilator activity of a nonxanthine phosphodiesterase inhibitor;2,4-diamino-5-cyano-6-bromopyridine (compound I). J Pharmacol Exp Ther 237:114-9

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