Role of Nerve Growth Factor in Ozone-Induced Neural Responses in Early Postnatal Airway Development

Abstract

Airway neural plasticity contributes to the process of airway remodeling in response to airway irritants. However, the mechanisms of neural remodeling in the airways during the early postnatal period, when responses to airway irritation may be most sensitive, have not been characterized. This study used a rat model to examine a possible mechanism of ozone (O(3))-induced neural hyperresponsiveness during a critical period of developmental, postnatal day (PD) 6, that may be mediated by the neurotrophin nerve growth factor (NGF), resulting in an enhanced release of inflammatory neuropeptide substance P (SP) from airway nerves. Rat pups between PD6-PD28 were killed 24 hours after exposure to O(3) (2 ppm, 3 hours) or filtered air (FA), to establish a timeline of NGF synthesis, or else they were exposed to O(3) or NGF on PD6 or PD21 and re-exposed to O(3) on PD28, and killed on PD29. Measurement endpoints included NGF mRNA in tracheal epithelial cells, NGF protein in bronchoalveolar lavage fluid, airway SP-nerve fiber density (NFD), and SP-positive airway neurons in vagal ganglia. Acute exposure to O(3) increased NGF in bronchoalveolar lavage fluid on PD10 and PD15, and mRNA expression in epithelial cells on PD6, compared with FA controls. NGF protein and mRNA expression in the O(3)-PD6/O(3)-PD28 groups were significantly higher than in the O(3)-PD21/O(3)-PD28 and O(3)-PD6/FA-PD28 groups. NGF-PD6/O(3)-PD28 increased the SP innervation of airway smooth muscle and SP-positive sensory neurons, compared with the NGF-PD21/O(3)-PD28 or NGF-PD6/FA-PD28 groups. NGF enhanced sensory innervation, which may mediate acute responses or prolong sensitivity to O(3) during early life. The model may be relevant in O(3) responses during early childhood.