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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL028274-04
Application #
3339691
Study Section
Respiratory and Applied Physiology Study Section (RAP)
Project Start
1982-01-01
Project End
1987-12-31
Budget Start
1985-01-01
Budget End
1985-12-31
Support Year
4
Fiscal Year
1985
Total Cost
Indirect Cost
Name
John B. Pierce Laboratory, Inc.
Department
Type
DUNS #
City
New Haven
State
CT
Country
United States
Zip Code
Roux, F J; Rhoden, K J; Douglas, J S (1998) Binding of guanine nucleotides to bronchial membranes: effect of maturation. Exp Lung Res 24:675-84
Rhoden, K J; Souhrada, M; Douglas, J S (1997) Maturational changes in Na(+)-K+ pump activity in guinea pig airway smooth muscle. Exp Lung Res 23:333-45
Roux, F J; Grandordy, B; Douglas, J S (1996) Functional and binding characteristics of long-acting beta 2-agonists in lung and heart. Am J Respir Crit Care Med 153:1489-95
Rhoden, K J; Douglas, J S (1995) Evidence of Na-K-Cl cotransport in airway smooth muscle. Am J Physiol 268:L551-7
Rasmussen, H; Kelley, G; Douglas, J S (1990) Interactions between Ca2+ and cAMP messenger system in regulation of airway smooth muscle contraction. Am J Physiol 258:L279-88
Douglas, J S (1990) Receptors on target cells. Receptors on airway smooth muscle. Am Rev Respir Dis 141:S123-6
Wills, M; Douglas, J S (1988) Aging and cholinergic responses in bovine trachealis muscle. Br J Pharmacol 93:918-24
Souhrada, M; Rothberg, K G; Douglas, J S (1988) Membrane properties of bovine airway smooth muscle cells: effects of maturation. Pulm Pharmacol 1:47-52
Rothberg, K G; Morris, P L; Douglas, J S (1987) Characterization of cholinergic muscarinic receptors in cow tracheal muscle membranes. Effect of maturation. Biochem Pharmacol 36:1687-95
Douglas, J S; Brink, C (1987) Airway smooth muscle and disease workshop: histamine and prostanoids. Am Rev Respir Dis 136:S21-4

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