The tachykinin peptides, substance P (SP) and neurokinin A (NKA), play an important role in enhancing airway smooth muscle contractile responses, and this role is well preserved across species. The objective of this proposal is to characterize developmental changes in tachykinin-mediated airway smooth muscle contraction, identify corresponding changes in tachykinin (NK1 and NK2) receptor function, localize these maturational changes between large airways and lung parenchyma, and examine the role of hyperoxic stress in modulating these phenomena. In the newborn piglet contractile responses to tachykinins are markedly attenuated over the first days of life. This animal model will be employed to test the hypothesis that immature receptor function contributes to the weak tachykinin-mediated physiologic responses observed in early postnatal life, possibly serving to minimize airway constriction and ensure adequate airway caliber at that time. Parallel in vitro studies will be performed on pig trachea and lung parenchyma at 3 postnatal ages to correlate physiologic responses to SP and NKA administration with receptor binding and autoradiography, G protein levels and measurements of phosphoinositide metabolism and intracellular Ca++. Hyperoxic stress, a common pathophysiologic perturbation, increases SP precursor gene expression and SP content in newborn lung, accompanied by an increase in NK1 and NK2 receptor density. The newborn rat model will be employed to test the hypothesis that hyperoxia-induced facilitation of SP content, release and signaling may compromise airway function by enhancing cholinergically- mediated airway contractile responses under these conditions. Physiologic in vitro and in vivo studies will be performed in rats at 2 postnatal ages, and responsiveness to cholinergic agonists compared after hyperoxic and normoxic exposure in the presence and absence of NK1 and NK2 receptor blockade, and after tachykinin depletion with capsaicin. Physiologic studies performed under hyperoxic and normoxic conditions will be combined with measurements of NK1 and NK2 receptor density and function, and the above signaling pathways. Localization of physiologic responses in rat trachea and lung parenchyma will be correlated with mapping of the corresponding receptors via autoradiography. These studies will allow us to characterize pharmacologic and cellular mechanisms underlying site- specific physiologic responses of developing respiratory structures to tachykinin peptides. The corresponding behavior of these phenomena during hyperoxia should delineate possible mechanisms underlying abnormal pulmonary function in diseases such as bronchopulmonary dysplasia.
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