The long-range goal of this proposal is to identify mechanisms affecting airway neural development that are initiated by irritant exposures occurring during early postnatal life but result in enhanced airway responses as adolescents and adults. Infections or irritant exposures occurring during infancy and early childhood contribute to the pathogenesis of asthma in children and in adults. Airway nerves release potent mediators, such as substance P, that affect airway function and may contribute to abnormal airway diseases. However, there have been surprisingly few studies characterizing neural responses caused by irritant exposures during the early postnatal period. The goals of the experiments in this proposal are 1) to identify neural adaptations to ozone exposure that occur during early postnatal life and result in altered airway responses as adults and 2) determine the role of growth factors as mediators that regulate these responses. The overall hypotheses in the proposed studies are that animals in the early postnatal period are uniquely sensitive to the effects of environmental irritants, like ozone, and that exposure during the """"""""critical period"""""""" enhances neuronal and airway responses to subsequent exposures later in life. Innervation of the airways continues to develop during the early postnatal period, and our preliminary studies suggest that inhalation exposure to airway irritants during this period permanently alters normal development of airway innervation and inflammatory responsiveness. The proposed studies will examine the possibility that the neurotrophic factor Nerve Growth Factor (NGF) is upregulated by ozone exposures during early postnatal life and that increased NGF release alters normal innervation patterns and contributes to enhanced airway responses.
The specific aims are to 1) evaluate changes in the production of NGF, a neurotrophin known to regulate sensory neuron development, after early postnatal exposure ozone, 2) determine the long-range effects of early postnatal ozone exposure on airway innervation in rats, 3) measure message levels of NGF in airway epithelium and substance P in airway sensory neurons after ozone exposure in early life, 4) evaluate the effects of direct treatment with NGF during the """"""""critical period"""""""" on neural development and airway responses to ozone exposure on PD 28, and 5) evaluate the effect of NGF inhibitors (K252a, antibodies, siRNA) given prior to ozone exposure on PD 6 on neural development and airway responses to ozone exposure on PD 28. The effects of NGF on airway innervation may be permanent and explain both the immediate increase in airway responses to irritants in the neonatal period and also the persistent changes in airway responsiveness that occur in adolescents and adults after early life exposures to airway irritants. ? ? ?
