AIRWAY PHARMACOLOGY DURING ONTOGENESIS

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The long-term objective of this proposal is to determine those factors which are responsible for the reduction of in vivo airway reactivity at a specific time during ontogenesis. This reduction is more pronounced in female than in male animals and shows obvious familial trends. Our hypothesis is that maturation and familial factors (a) alter the binding and/or efficacy of humoral agents (b) alter membrane potential and electrogenic pump activity and (c) alter the translocation of calcium. Measurements of airway reactivity will be made in animals of known age and sex in various physiological states e.g. immature, mature, old, in estrus and pregnant. Whole body plethysmography with the aid of a computer will be used to determine pulmonary mechanics and, in conjunction with morphometric measurements of airway diameter and smooth muscle, will be related to airway reactivity during maturation. Determination of sex hormones and thyroid function using radioimmunoassays will be used to monitor maturation. These assays will also be used to verify our success in manipulating hormone levels by surgical or pharmacological interventions. In vitro airway responses also show age related changes. The mechanism(s) for these changes will be assessed in animals of known age, sex and physiological status. Dose response to (a) partial agonists or (b) to full agonists before and after receptor antagonism or functional antagonism will allow an assessment of receptor affinities and drug affinities. These results will be correlated with receptor properties determined from ligand binding assays of membrane fractions of airway smooth muscle. Membrane properties will also be assessed by determining membrane potentials and the contribution of the electrogenic pump to potential in tissues from animals in various physiological states. These parameters will be determined using standard electrophysiological techniques. The membrane transport of calcium will be determined using radiolabeled calcium. Our longitudinal study of airway reactivity in guinea pigs has many characteristics of childhood bronchial asthma and its remission at puberty and has provided the basis of this proposal.