The late pulmonary response (LPR) after antigen challenge in patients with asthma is poorly responsive to bronchodilators and often requires corticosteroids for resolution. The pathogenesis of these reactions is unclear with both IgE and non-IgE mediated mechanisms proposed to explain these reactions. The recent description of a model of LPPs in rabbits immunized from birth to produce antigen-specific IgE with or without antigen-specific IgG had demonstrated that IgE-allergen interactions can produce an LPR, and the IgG blunts rather than enhances this response (Am Pev Respir Dis 126:493, 1982). The LPR was also produced by passive transfer of the IgE, thus showing the response can occur in the absence of cellular immune mechanisms. This proposal will use this model to address 4 major questions: 1) What pathologic alterations occur within the lungs and airways during the development of an LPR? The pathology is anticipated to display cellular infiltrates (neutrophils and eosinophils) and edema without significant deposition of immune complexes and complement. 2) What are the detailed physiologic alterations that occur during the LPR? A central hypothesis is that allergen inhalation causes early alterations in small airway function that are not manifest in standard measurements of airway resistance until the dysfunction increases to involve large airways. In addition, increases in small airway resistance will correlate with the degree of small airway inflammation. 3) What mediators are responsible for the LPR in this animal model? The main hypothesis is that the LPR is an immunologically initiated (IgE) inflammatory response that involves mediators from various systems in the body. To study their relative contribution to ther LPRs, inhibitors or depletors of mediator systems will be used. Experiments will concentrate on mediators suggested by the medical literature to be of most importance to the LPR. Thus, the effects of cromolyn, corticosteroids, atropine, inhibitors of arachadonic acid metabolism, neutrophil depletion and repletion, platelet depletion, and complement depletion will be studied. 4) Will LPRs in rabbits lead to development of airway hyperreactivity to histamine? The hypotheses include the expectation that parenteral immunization will not lead to airway hyperreactivity while after an LPR, histamine responsiveness will increase and correlate with the inflammation (neutrophil infiltration) produced by the LPR in the airways. This animal model provides a new approach to these four basic questions about LPPs. The results should give insight into the human process, and aid clinical studies attempting to prevent these responses.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL031376-02
Application #
3342465
Study Section
Pathology A Study Section (PTHA)
Project Start
1983-12-01
Project End
1986-11-30
Budget Start
1984-12-01
Budget End
1985-11-30
Support Year
2
Fiscal Year
1985
Total Cost
Indirect Cost
Name
National Jewish Health
Department
Type
DUNS #
City
Denver
State
CO
Country
United States
Zip Code
80206
Larsen, G L; Presley, D M; Graves, J P et al. (1991) The effect of intravascular complement activation and brief episodes of hypoxia on protein in bronchoalveolar lavage fluid in C5 sufficient and deficient mice. Pediatr Pulmonol 11:302-9
Larsen, G L (1989) New concepts in the pathogenesis of asthma. Clin Immunol Immunopathol 53:S107-18
Larsen, G L (1988) The late asthmatic response. Chest 93:1287-9
Behrens, B L; Clark, R A; Presley, D M et al. (1987) Comparison of the evolving histopathology of early and late cutaneous and asthmatic responses in rabbits after a single antigen challenge. Lab Invest 56:101-13
Larsen, G L; Wilson, M C; Clark, R A et al. (1987) The inflammatory reaction in the airways in an animal model of the late asthmatic response. Fed Proc 46:105-12
Murphy, K R; Wilson, M C; Irvin, C G et al. (1986) The requirement for polymorphonuclear leukocytes in the late asthmatic response and heightened airways reactivity in an animal model. Am Rev Respir Dis 134:62-8
Murphy, K R; Marsh, W R; Glezen, L S et al. (1986) Inflammation and the late phase reaction in asthma: the effect of polymorphonuclear leukocyte depletion on airways obstruction and bronchial hyperreactivity in an animal model. Bull Eur Physiopathol Respir 22 Suppl 7:48-53
Larsen, G L; Webster, R O; Worthen, G S et al. (1985) Additive effect of intravascular complement activation and brief episodes of hypoxia in producing increased permeability in the rabbit lung. J Clin Invest 75:902-10
Bhagat, R G; Strunk, R C; Larsen, G L (1985) The late asthmatic response. Ann Allergy 54:272, 297-301
Larsen, G L (1985) Hypersensitivity lung disease. Annu Rev Immunol 3:59-85

Showing the most recent 10 out of 11 publications