Investigations are proposed to define mechanisms accounting for the topographical and maturational changes in airway contractile response elucidated in the prior grant period. Those studies demonstrated a heterogeneous distribution of bronchoconstrictor responses in the major resistance airways of dogs that were related to intrinsic differences in 1) mechanical properties of airways in situ, 2) differences in force of smooth muscle contraction, and 3) intrinsic stability and Laplacian characteristics of the airways in vivo. Studies of isolated airway muscle in vitro revealed substantial differences among airway generations in the force of isometric contraction, which was not related solely to topographical distribution of airway receptors. In preliminary studies during the prior grant period, methods have been developed for computerized morphometric analysis of airway muscle that allow for quantitative determination and assessment of the geometric distribution of airway constrictor forces in vivo. Techniques were developed for radioligand assays permitting assessment of the distribution of receptors in the various airway generations. A major extension of the previous work has been the application of these techniques to the study of the maturational responses of airway smooth muscle in swine. Because of the rapid maturation of this species, major alterations in airway muscle function may be demonstrated in brief time. An in situ isometric preparation was developed that permitted the comparative assessment of tracheal smooth muscle contractile forces of infant (2 week) and juvenile (8-12 week) swine. Substantial alterations in the mechanical and pharmacological properties of this muscle appear to occur with age. In vitro study of tracheal muscle from the same animals suggests substantial alterations in the contractile properties of porcine airway muscle with maturation. We propose to extend these studies further to 1) describe the in situ distribution of airway contractile response in situ (using tantalum bronchography), 2) the morphometric and biochemical changes occurring with maturation, and 3) the biophysical changes that occur in the various airway generations with maturation (using recently developed techniques for measurement of force-velocity and isometric contractile properties in bronchial airways). These mechanisms accounting for topographical and maturation differences in force of, smooth muscle contraction further will be elucidated through in vitro studies of 1) specific receptor ligands (with autoradiographic localization). 2) myosin isoenzymes and content, 3) rate of ATPase-myosin cross bridge cycling These investigations will employ an intradisciplinary approach to elucidate the morphometric, biophysical and biochemical correlates of airway contractility as they are developed both topographically and during maturation. These data should suggest basic physiological and pathophysiological differences that occur in airways during maturation and possible essential differences in therapeutic approaches between adult and pediatric reactive airway disease.
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