Preterm infants exposed to supplemental oxygen are predisposed to the development of bronchopulmonary dysplasia [BPD] which is associated with increased airway resistance and subsequent airway hyperreactivity. The current proposal is to extend our earlier studies on regulation of airways by characterizing maturation of airway relaxant responses during normal development and in response to hyperoxic exposure. We will initially test the hypothesis that there is upregulation of airway smooth muscle relaxant mechanisms during early postnatal life, secondary to increased production of nitric oxide and relaxant prostaglandins [PGE2 and PGI2] from airway epithelium. Our preliminary data demonstrate that administration of substance P [SP] and cholinergic stimulation elicit a relaxant response of preconstricted tracheal smooth muscle which declines with postnatal maturation, is mediated by release of endogenous NO and PGE2, and is impaired after hyperoxic exposure. We will therefore additionally test the hypothesis that hyperoxic stress impairs NO and PGE2-mediated airway smooth muscle relaxation secondary to impaired NO and PG-mediated signaling pathways in airway smooth muscle. Physiologic relaxant responses of preconstricted airways will be characterized in maturing rat pups under normoxic and hyperoxic conditions. These findings will be correlated with expression and activity of nitric oxide synthase (NOS) and cyclooxygenase (COX) isoforms in airway epithelium. In airway smooth muscle we will determine developmental and hyperoxia-induced changes in prostaglandin (PGE2) receptor subtypes, Gi protein expression and cAMP production. Maturational and hyperoxia-induced effects on NO/cGMP signaling pathways including expression and activation of cGMP dependent protein kinase (PKG) will be assayed. Physiologic responses will then be correlated with levels of free intracellular Ca2++ and myosin light chain dephosphorylation in airway smooth muscle in normoxic and hyperoxic tissues. Characterization of the mechanisms underlying deficient airway smooth muscle relaxation will help to elucidate the pathologic mechanisms underlying airway hyperreactivity secondary to hyperoxia-induced lung injury, as in preterm infants who develop bronchopulmonary dysplasia. This should lead to the design of new therapeutic approaches for such disorders.
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