Clinical evidence supports the notion of age-related differences in the acquisition of airways hyperactivity following an acute inflammatory insult to the lungs. In view of the latter, two interrelated hypotheses are raised: I: That the transmembrane signaling mechanisms regulating non-specific airway smooth muscle responsiveness vary maturationally; and II: That acute pulmonary inflammation alters airways responsiveness in an age-dependent manner, secondary to maturational differences in perturbed transmembrane signaling. In addressing these hypotheses, in vivo and in vitro pharmacodynamic, biochemical, and molecular studies examining mechanisms of altered agonist-induced airways responsiveness will be conducted in rabbits of varying post-natal age. A: To assess the maturation of transmembrane signaling mechanisms regulating airways constrictor responsiveness, we will examine whether ontogenetic differences exist in: 1) the partitioned in vivo airway and lung tissue contributions to cholinergic-, endothelin-, and eicosanoid-induced changes in lung mechanics; 2) the expression, characteristics, and modulation by guanine nucleotide-binding (G) proteins of receptors coupled to the latter agonists; 3) the agonist-specific regulation of production, metabolism, and intracellular receptor binding of the key second messenger, inositol 1,4,5-triphosphate; and 4) the regulatory actions of protein kinase C activation on the latter processes. B: To assess the maturation of transmembrane signaling mechanisms regulating airway beta-adrenoceptor-mediated relaxant responsiveness, we will examine ontogenetic changes in: 1) the expression, characteristics, and G protein-coupled modulation of binding of the beta-adrenergic receptor in airway smooth muscle and lung tissue; and 2) the effects of beta-adrenergic stimulation on constrictor agonist-specific accumulation, metabolism, and receptor binding of inositol 1,4,5-triphosphate. To assess the age-related effects of acute pulmonary inflammation on airways responsiveness, separate experiments are designed to evaluate: 1) the airway and lung tissue responses to allergic/atopic-mediated and non-allergically-mediated pulmonary inflammation induced by ozone inhalation in maturing rabbits; 2) whether age-dependent, proinflammatory changes in airways responsiveness are attributed to maturational alterations in the contributions of the above signaling mechanisms (i.e., under A and B) regulating airway contraction and relaxation; and 3) the roles of specific cytokines in mediating age-dependent changes in airway responsiveness under the different proinflammatory conditions. It is anticipated that the above collection of proposed studies will provide significant new insights into the mechanistic interrelationship between maturation, altered airways responsiveness, and pulmonary inflammation.
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