The overall objective of this proposal is to characterize the reflex and local mechanisms that regulate airway smooth muscle (ASM) tone during postnatal development. We hypothesize that important maturational changes characterize the ability of ASM to respond to neurochemical reflex stimuli in early life. These studies will employ a piglet model in which isometric contraction of an isolated tracheal segment, pulmonary resistance, and phrenic nerve activity will be recorded at each of three postnatal ages. Preliminary data with this piglet model indicate that ASM responses to some mechano- and chemoreceptor stimuli are weak over the first three weeks of life when compared to ten week old animals. The current proposal will allow evaluation of the mechanisms underlying these feeble responses of ASM to reflex stimulation during early postnatal development. Preliminary data in the youngest tracheal smooth muscle. These findings, if confirmed, implicate failure of neural transmission to ASM at a point beyond the afferent segment of the reflex pathway; otherwise, phrenic responses would also be weak. In this proposal the uniformity of ASM reflex responses will be characterized throughout the tracheobronchial tree by comparing responses of tracheal tension and pulmonary resistance at various postnatal ages. Since preliminary experiments provide extensive evidence for immaturity of many elements that comprise the efferent innervation to ASM, both in vivo and in vitro studies will be performed to characterize the maturation of cholinergic and adrenergic pathways to ASM, and their modulation by tachykinins. We will identify the mechanisms underlying this asynchrony in maturation of cholinergic function by correlating the development of physiologic responses of ASM with structural and biochemical development of tracheal efferent innervation, and with maturation of muscarinic receptors on ASM. The diminished physiologic responses of ASM observed in response to exogenously administered tachykinins in the youngest piglets will be correlated with the development of the various tachykinin receptor subtypes during postnatal maturation. Biochemical analyses of ASM will be performed for tachykinins and their degrading enzymes at comparable postnatal ages. Finally the physiologic role of alpha1-adrenergic excitation and beta-adrenergic inhibition of ASM will be evaluated during postnatal maturation in relation to the development of alpha1- and beta-adrenergic receptors on ASM. Such a detailed approach will allow us to construct a clear picture of the maturation of distinct but interacting neurochemical pathways to ASM in the developing animal and begin to understand the mechanisms leading to excessive bronchospasm in the face of neonatal lung injury.
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