DEFENSE FUNCTIONS IN THE DEVELOPING RESPIRATORY SYSTEM

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Epidemiologic and clinical studies suggest that acute airway injury during postnatal lung growth can lead to chronic bronchitis, asthma or recurrent respiratory infections extending into adulthood. However, the underlying mechanisms have not been identified. The overall objective of this proposal is therefore to establish a link between airway damage during early life and chronic airway disease by using an animal model with lung anatomy resembling that of man, and focusing on the role of mucociliary dysfunction in this sequence of events. The specific aims are to 1) establish a relationship between airway morphology and mucociliary function during postnasal lung growth, 2) investigate the possibility that mechanical and chemical mucosal damage shortly after birth produce permanent mucociliary dysfunction, and 3) determine if this defect leads to impaired bacterial clearance in, and thus bacterial colonization and possible recurrent infection of the airways. Lambs will be studied longitudinally between birth and six months of age (full maturation). Mucosal injury shortly after birth will be produced by O3, or airway manipulation simulating ventilatory support for respiratory insufficiency. Three aspects of the respiratory system will be investigated: Mucociliary function, airway function and airway morphology. For the first, in vivo tracheal mucous transport rates and lung mucociliary clearance will be measured by using a radiographic technique and an inhaled insoluble radioaerosol, respectively. In addition, the clearance of an inhaled bacterial aerosol will also be determined. The component functions of mucociliary clearance will be measured in vitro by determination of mucus secretion, ion and water transport as well as ciliary beat frequency. Airway function will be assessed by the measurement of pulmonary resistance and gas distribution by the single-breath nitrogen test. Routine light microscopy will be used for the histologic studies. These observations are expected to provide valuable new information on the pathogenesis of chronic airway disease occurring following acute airway injury in newborns.