Clinical evidence supports the notion of age-dependent differences in the acquisition of airways hyperreactivity in response to pro-asthmatic conditions such as atopy, allergen exposure, and viral respiratory infections. Based on our recent evidence that under certain conditions of airway sensitization the smooth muscle (ASM) itself is induced to express proinflammatory cytokines that autologously elicit changes in its constrictor and relaxant responsiveness, the interrelated hypotheses are raised that: I: The induction of altered ASM responsiveness under pro-asthmatic conditions of airway sensitization varies in an age-dependent manner; II: Maturational differences in induced altered ASM responsiveness are attributed to age-related changes in intrinsic Fc receptor-mediated proinflammatory cytokine release and autocrine action; and III: Age-dependent differences in induction of altered ASM responsiveness reflect maturational differences in induced perturbations of the receptor/G protein-coupled transmembrane signaling mechanisms that regulate ASM contraction and relaxation. In addressing these hypotheses, experiments are proposed to examine age dependent mechanisms of induction of altered agonist responsiveness in sensitized maturing rabbit ASM tissues. A: To investigate the maturation of mechanisms regulating induction of altered ASM responsiveness in the sensitized state, we will examine whether ontogenetic differences exist in: 1) the effects of ASM sensitization under atopic (IgE-mediated) conditions alone and in the presence of either viral pathogen inoculation with RV and RSV, or exposure to the dust mite allergens, Der p1 and Der p3; 2) the evoked release and autocrine actions of specific proinflammatory cytokines under these sensitizing conditions; and 3) the expression and activation of specific Fc receptors, cellular adhesion molecules (CAMs) and proteaseactivated receptors (PARs) in the sensitized ASM. B: To investigate age-related mechanisms of altered receptor/G protein-coupled transmembrane signaling in sensitized ASM, we will examine whether induced changes in ASM responsiveness are attributed to: 1) altered constrictor agonist-mediated receptor/G protein coupled accumulation, metabolism, and receptor binding of the key calcium-mobilizing second messenger, inositol 1,4,5-trisphosphate (Ins(1,4,5)P3 in ASM; and 2) altered beta-adrenoceptor-mediated modulation of constrictor agonist-induced accumulation, metabolism, and receptor binding of Ins(1,4,5)P3. It is anticipated that the results generated by these proposed studies will yield significant new insights into the maturation of interplaying mechanisms regulating the acquisition of pro-asthmatic changes in ASM responsiveness in sensitized airways.
Showing the most recent 10 out of 44 publications
