The postnatal lung continues to grow and differentiate while interacting with the environment. Exposure to ozone and allergens during postnatal lung development alters structural and signaling elements of conducting airways including innervation, ligand distribution, ligand-receptor interaction and neuroimmune processes. These changes have been linked with the development of asthma in a rhesus monkey model. We subjected infant male monkeys, nonsensitized or sensitized to house dust mite (HDM), to filtered air, acute or episodic ozone, HDM or HDM in combination with ozone, during the first or second 6 months of postnatal development. We studied the impact of these exposures on the developmental pattern of two key nerve pathways in the lung: serotonin (5-HT) and neurokinin-1 receptor (NK-1R). Methods employed included microdissection, explant culture, immunohistochemistry, histopathology, compound and confocal microscopy, stereology and qRT-PCR. Serotonin (5-HT) is a neurotransmitter involved in several neurotrophic, signaling and immune-mediated lung processes during postnatal development. Postnatal ozone and/or allergen exposure can alter developmental 5-HT distribution and subsequent interaction with 5-HT 2AR/4R, receptors involved in neuronal excitation and smooth muscle contraction. We hypothesized that the 5-HT pattern in airway epithelia of postnatal male infant rhesus monkeys increases with age and decreases in a proximal to distal manner. Additionally, we hypothesized that postnatal months 1-6 represent a window of susceptibility and that 1) ozone and/or allergen exposure deviates the normal distribution of serotonin transporter (5-HTT), 5-HT and its proximity to 5-HT2AR/4R, 2) these changes persist beyond the period of exposure and 3) the degree to which these ligand-receptor distributions are altered is determined by airway compartment. Ozone, a pervasive environmental pollutant, adversely affects functional lung growth and exacerbates respiratory disease in children. Animal studies demonstrate that altered lung development is associated with modified signaling within the airway epithelial mesenchymal trophic unit, including neurokinin-driven processes that can change nerve growth and neuroimmune responses to oxidant stress. Neurokinin Substance P (TAC1), its receptor neurokinin-1 (NK-1R) and nuclear receptor Nur77 (NR4A1) comprise a pathway involved in neuronal excitation, inflammation and cell death. With respect to the neurokinin pathway, we hypothesized that postnatal O3 exposure alters the distribution of the NK-1 receptor cascade, neurokinin-mediated oxidative stress and the ability of the airways to respond to subsequent oxidant insult. Exposure responses are both intrinsic to the airway environment and systemic, such as in neurogenic inflammation. This is relevant to air pollution health effects in children, particularly asthma, as exposure to oxidant pollutants exacerbates asthma, and changes we describe in the 5-HT and NK-1R pathways may be mediators in this process. Ultimately, we concluded that 1) postnatal mos 1-6 represent a critically susceptible window where ozone alters the spatial distribution and exposure responses of 5-HT or NK-1R pathways, specifically in midlevel 2 mo and distal 6 mo airways, 2) changes persist beyond the exposure period, 3) allergen enhances overall 5-HT2AR/4R epithelial expression and proximity to 5-HT positive cells in distal airways, 4) O3 increases overall epithelial injury and inflammation, 5) these altered cellular processes correlate with the inflammatory infiltrate profile, and 6) a history of prior ozone exposure resets the steady state of the airways to increase the 5-HT or NK-1R pathway responses to subsequent acute oxidant stress.
|Advisor:||Winkle, Laura S. Van|
|Commitee:||Hyde, Dallas M., Lein, Pamela J., Schelegle, Edward S.|
|School:||University of California, Davis|
|Department:||Pharmacology and Toxicology|
|School Location:||United States -- California|
|Source:||DAI-B 75/01(E), Dissertation Abstracts International|
|Subjects:||Toxicology, Surgery, Pharmacology, Developmental biology|
|Keywords:||Air pollution, Airway epithelium, Asthma, Bronchial epithelium, House dust mites, Lung development, Neurokinin, Serotonin|
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