ONTOGENY OF AIRWAY SMOOTH MUSCLE FUNCTION

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Neonatal respiratory distress syndrome (RDS) may be complicated by a forma of unresolved lung injury referred to as bronchopulmonary dysplasia (BPD). Treatment of RDS is believed to be partially responsible for the emergence of BPD by mechanisms such as oxygen toxicity. Many studies suggest that BPD is characterized in part by reactive airway disease in addition to lung parenchymal damage. On the other hand, while bronchodilators are frequently employed in the routine management of these infants, other studies suggest that large-airway collapse may complicate BPD and that bronchodilators may at times worsen airway obstruction by promoting large airway relaxation. Thus, abnormal airway smooth muscle tone probably plays an important role in the symptoms of BPD. Herein are described studies on isolated airway smooth muscle from 6 groups of guinea pigs: 1) term newborns between 1-3 days of age, randomized to breathe room air for 2-3 days; 2) or to breathe 95% oxygen for 2-3 days; 3) 6 week old adults (controls); 4) 6 week old adults that have been exposed to 95% oxygen in the newborn period for 2-3 days; 5) preterm newborns delivered 3-6 days prior to term and allowed to breathe room air; and 6)preterm newborns exposed to 95% oxygen as described for groups #2. These experiments will first define the normal ontogeny of airway smooth muscle responses to physiologic and pharmacologic stimuli in order to test the overall hypothesis that exposure to high oxygen concentrations during the newborn period alters the normal developmental pregression of airway smooth muscle function. The technique of isometric force measurements on segments of tracheal and bronchial rings will be employed to determine the following specific aims: 1) Determine if the normal ontogeny of airway smooth muscle response sis altered after exposure to high oxygen concentrations during the newborn period to physiologic, pharmacologic and environmental stimuli; 2) Determine if the effect of airway epithelial function during normal development changes after high oxygen exposure during the newborn period; 3) Determine if gestational age at birth influences airway smooth muscle reactivity following exposure to high oxygen concentrations; and 4) Determine if relaxation responses mediated by cAMP and cGMP correlate with measurements of intracellular cAMP and cGMP accumulation. The importance of these studies is best expressed by a recent NHLBI workshop summary on "Postnatal lung development in health and disease" that recommended that the "sequence of events leading to the early development of chronic lung diseases in neonates, . . . needs to be defined. The relative importance of oxygen toxicity, . . . and airway reactivity as etiologic factors in this disease process must be examined." (30). Thus, results of studies proposed herein hold the promise of achieving new knowledge that the NHLBI feel should be "given the highest priority" (30).