and Specific Aims.) In light of clinical evidence implying age-related differences in the acquisition of airways hyperreactivity following an acute inflammatory insult to the lungs, two interrelated hypotheses are raised: 1) that intrinsic mechanisms regulating non-specific airway smooth muscle responsiveness vary maturationally; and 2) that acute pulmonary inflammation alters airways responsiveness in an age-dependent manner. In addressing these hypotheses, in vivo and in vitro pharmacodynamic studies on agonist-induced airway and peripheral lung tissue constrictor responsiveness will be conducted in rabbits of varying post-natal age. To assess the maturation of mechanisms regulating pulmonary responsiveness, Specific Aim 1A will examine whether ontogenetic differences exist in: a) the partitioned in vivo airway and lung tissue contributions to cholinergic-, endothelin-, histamine-, and eicosanoid- induced changes in lung mechanics; b) the expression, characteristics, and modulation by guanine nucleotide-binding (G) proteins of receptors coupled to the latter agonists, determined by radioligand binding; c) the agonist-specific regulation of production, intracellular receptor binding, and metabolism of the key second messenger, inositol 1,4,5- trisphosphate, determined by radioreceptor and enzyme assays; and d) the regulatory actions of protein kinase C activation on the latter processes. To assess the maturation of mechanisms regulating airway beta-adrenergic relaxant responsiveness, Specific Aim 1B will examine ontogenetic differences in:a) the expression, characteristics, and G- protein-coupled modulation of binding of the beta- adrenergic receptor in airway smooth muscle and lung tissue; b) the effects of beta- adrenergic stimulation on constrictor agonist-specific accumulation, metabolism, and receptor binding of inositol 1,4,5-trisphosphate; and c) the contributions of the calcium- and ATP-dependent potassium channels in modulating beta-adrenergic-mediated airway relaxation. To assess the age- related effects of acute pulmonary inflammation on airways responsiveness, Specific Aim 2 is designed to evaluate: a) the airway and lung tissue responses to antigen-specific- and non-allergically- mediated pulmonary inflammation induced by endotoxin and ozone inhalation in maturing rabbits; and b) mechanisms of inflammation- induced changes in airways reactivity in the maturing lung as reflected by alterations in the contributions of the above mechanistic processes regulating pulmonary constrictor responsiveness and beta-adrenergic relaxation. The proposed studies may provide new insights into the interrelationship between maturation, airways responsiveness, and pulmonary inflammation.
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