Bronchial hyperresponsiveness (BHR) is a feature of asthma which describes the exaggerated bronchoconstrictive response to a variety of inhaled stimuli. Neither the etiology nor the physiologic mechanisms of BHR are known. The studies proposed in this project focus on an animal model of BHR which shows a 10-fold increase in sensitivity to MCh compared to controls. This model in the rabbit will be studied in order to (1) establish optimal conditions for the development of BHR; (2) characterize the degree of similarity of the BHR model with the BHR associated with human asthma especially in terms of pathologic and physiologic manifestations; (3) demonstrate clearly the role for IgE and IgE-related mechanisms in inducing the BHR; (4) establish the pathophysiologic mechanism(s) responsible for the IgE-driven BHR; and (5) determine whether the preexisting level of innate bronchial responsiveness affects the degree of IgE-induced BHR. Methods for 1 and 2 (above) involve in vivo physiologic monitoring and histopathologic assessment of lungs which will be performed under varying conditions of BHR induction. In 3, purified IgE antibodies will be administered as a substitutive for active immunization; and purified IgG antibodies will be administered to assess their potential capacity to inhibit BHR. Allergic mediator inhibitors will be also be administered and assessed for inhibition of BHR. In each case, physiologic monitoring of bronchoconstriction will determine the effect. For 4, since preliminary data suggest that the pathophysiologic mechanism of BHR may be an inability of BHR smooth muscle to relax normally, both functional studies with relaxant agonists and biochemical studies of the intracellular process of relaxation (i.e., quantitating temporal alterations in phosphorylated myosin light chain) will be performed in isolated airways. Finally, in 5, advantage will be taken of the large variability in innate bronchial responsiveness among normal rabbits. By selecting for the extreme individual members in the normal population for sensitization studies, the effect of background level of responsiveness (i.e., innate or preexisting hyper- and hyporesponsiveness) on the IgE-driven BHR will be established. Also whether the same pathophysiologic mechanisms are responsible for innate and IgE-driven BHR will be determined.
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