Some asthmatic patients respond to inhalation of specific antigen with both early and late bronchial obstructions (late response). The mechanisms underlying the pathogenesis of late responses are unknown, but are of clinical interest because late responses are associated with prolonged airway hyperresponsiveness and a worsening of symptoms. Studies in this proposal use the disciplines of physiology, pharmacology, biochemistry and pathology to test the hypothesis that the late response is dependent upon lipoxygenase and/or cyclooxygenase metabolites of arachidonic acid. Two subgroups of sheep with airway hypersensitivity to Ascaris suum antigen will be used: those which have only an acute bronchoconstriction (acute responders) and those which have both acute and late bronchial obstructions (dual responders) following inhalation challenge with Ascaris suum.
The specific aims of this proposal with respect to the above hypothesis are to demonstrate that: 1) dual responders release increased levels of lipoxygenase metabolites of arachidonic acid during the acute response to antigen and that these metabolites stimulate pathways important for the expression of the late response; 2) the late response is a constrictor response to a secondary release of slow reacting substance of anaphylaxis; 3) dual responders are more responsive to inhalation challenge with leukotrienes C4 and D4 (major components of slow reacting substance of anaphylaxis) than are acute responders; and 4) inflammatory cells which appear in the bronchial wall at the time of the late response are the source of the mediator(s) inducing the late response, and/or contribute to the non-specific airway hyperresponsiveness observed in late responders. In these studies, antigen-induced changes in airway mechanics will be correlated with the appearance of mediators in the lung as measured by radioimmunoassay and bioassay of bronchoalveolar lavage fluid. These parameters will also be correlated with the inflammatory state of the bronchial wall as assessed by bronchial biopsies. The roles of suspected pathways and/or mediators involved in the late response will be confirmed by using selective pharmacologic intervention. Comparisons of these end-points between acute and dual responders will help to define the mechanism(s) of the late response and will contribute to a better understanding of the pathogenesis of asthma. This study could provide the basis for introducing new, more specific, and possibly more effective, therapies for bronchial asthma.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL033897-03
Application #
3346245
Study Section
Pathology A Study Section (PTHA)
Project Start
1985-04-01
Project End
1988-03-31
Budget Start
1987-04-01
Budget End
1988-03-31
Support Year
3
Fiscal Year
1987
Total Cost
Indirect Cost
Name
Mount Sinai Medical Center (Miami Beach)
Department
Type
DUNS #
046025144
City
Miami Beach
State
FL
Country
United States
Zip Code
33140
Abraham, W M (1993) Effect of nedocromil sodium on specific mediator- and antigen-induced airway responses in allergic sheep. J Allergy Clin Immunol 92:171-6
Ahmed, T; Abraham, W M; D'Brot, J (1992) Effects of inhaled heparin on immunologic and nonimmunologic bronchoconstrictor responses in sheep. Am Rev Respir Dis 145:566-70
Soler, M; Sielczak, M; Abraham, W M (1991) Separation of late bronchial responses from airway hyperresponsiveness in allergic sheep. J Appl Physiol 70:617-23
Lansing, M W; Mansour, E; Ahmed, A et al. (1991) Lipid mediators contribute to oxygen-radical-induced airway responses in sheep. Am Rev Respir Dis 144:1291-6
Abraham, W M; Ahmed, A; Cortes, A et al. (1991) Airway effects of inhaled bradykinin, substance P, and neurokinin A in sheep. J Allergy Clin Immunol 87:557-64
Soler, M; Mansour, E; Fernandez, A et al. (1990) PAF-induced airway responses in sheep: effects of a PAF antagonist and nedocromil sodium. J Allergy Clin Immunol 85:661-8
Long, W M; Yerger, L D; Abraham, W M et al. (1990) Late-phase bronchial vascular responses in allergic sheep. J Appl Physiol 69:584-90
Chapman, G A; Signoretti, F; Lauredo, I T et al. (1990) Cellular LTB4 production differs in allergic sheep with and without late airway responses. Am J Physiol 259:L136-43
Soler, M; Sielczak, M; Abraham, W M (1990) A bradykinin-antagonist blocks antigen-induced airway hyperresponsiveness and inflammation in sheep. Pulm Pharmacol 3:9-15
Abraham, W M (1989) Effect of picumast dihydrochloride on antigen-induced early and late airway responses in allergic sheep. Arzneimittelforschung 39:1328-31

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