The mechanisms underlying the pathogenesis of late responses to inhaled antigen are unknown but are clinically important because the same mechanisms may determine the severity of asthma in patients. During the previous grant period we studied two groups of sheep with airway hypersensitivity to inhaled Ascaris suum antigen: one group with only acute responses to antigen (acute responders) and one group with both acute and late responses to antigen (dual responders). These studies led to the hypothesis that dual responders release greater amounts of 5-lipoxygenase (5-LO) metabolites of arachidonic acid during the acute allergic reaction. This increase in 5-LO metabolites causes a more severe airway inflammatory response, characterized by neutrophils and eosinophils; these inflammatory cells then release mediators which contribute to the late response. We also found evidence that the mechanisms leading to late responses and those leading to antigen-induced airway hyperresponsiveness (AHR) develop in parallel but may be independent of each other.
The specific aims of the present proposal are to determine: 1) the site, composition, and time course of antigen-induced inflammatory cell influx into the airways after antigen challenge, and if modifying these parameters pharmacologically, affects the late response; 2) that airway anaphylaxis results in a sequential release of mediators which is an important determinant of late responses; 3) the airway and cellular responses to bronchoactive and/or inflammatory metabolites (i.e. leukotrienes, prostaglandins, and platelet activating factor) in both acute and dual responders and if differences in sensitivity and/or cell recruitment patterns to these agents are related to the different airway responses in these groups; and 4) the mechanisms involved in antigen-induced AHR, and if mechanisms leading to AHR differ from those of late responses. We will measure airway mechanics (in vivo), tracheal smooth muscle contraction (in vitro), cell differentials and mediator contents (by RIA and HPLC) in bronchoalveolar lavages, and mediator generation from isolated sheep granulocytes and from sheep whole blood. Lung morphology will be used to confirm airway inflammation and to document sites of leukocyte influx. The roles of suspected mediators will be defined by selective pharmacologic intervention. These studies will help identify the mechanism(s) of late responses and antigen-induced AHR, and thus, 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 #
5R01HL033897-05
Application #
3346246
Study Section
Pathology A Study Section (PTHA)
Project Start
1985-04-01
Project End
1991-03-31
Budget Start
1989-04-01
Budget End
1990-03-31
Support Year
5
Fiscal Year
1989
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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