Postnatal Exposure History and Airways Oxidant Stress Responses in Airway Explants

Postnatally, the lung continues to grow and differentiate while interacting with the environment. Exposure to ozone (O-3) and allergens during postnatal lung development alters structural elements of conducting airways, including innervation and neurokinin abundance. These changes have been linked with development of asthma in a rhesus monkey model. We hypothesized that O-3 exposure resets the ability of the airways to respond to oxidant stress and that this is mediated by changes in the neurokinin-1 receptor (NK-1R). Infant rhesus monkeys received episodic exposure to O-3 biweekly with or without house dust mite antigen (HDMA) from 6 to 12 months of age. Age-matched monkeys were exposed to filtered air (FA). Microdissected airway explants from midlevel airways (intrapulmonary generations 5-8) for four to six animals in each of four groups (FA, O-3, HDMA, and HDMA+O-3) were tested for NK-1R gene responses to acute oxidant stress using exposure to hydrogen peroxide (1.2 mM), a lipid ozonide (10 mu M), or sham treatment for 4 hours in vitro. Airway responses were measured using real-time quantitative RT-PCR of NK-1R and IL-8 gene expression. Basal NK-1R gene expression levels were not different between the exposure groups. Treatment with ozonide or hydrogen peroxide did not change NK-1R gene expression in animals exposed to FA, HDMA, or HDMA+O-3. However, treatment in vitro with lipid ozonide significantly increased NK-1R gene expression in explants from O-3-exposed animals. We conclude that a history of prior O-3 exposure resets the steady state of the airways to increase the NK-1R response to subsequent acute oxidant stresses.