Date of Graduation

2003

Document Type

Thesis

Abstract

Workers exposed to occupational irritants often develop symptoms of airway inflammation by unknown mechanisms. In laboratory animals, occupational irritants activate sensory nerves located in airway walls. Sensory nerves respond by increasing neuropeptide production. The neuropeptide, substance P (SP), is produced in trigeminal ganglia (TG) cell bodies and released from nasal mucosa nerve endings. Neurogenic inflammation results from the release of neuropeptides and is characterized by vasodilation, plasma extravasation, mucous secretion and neutrophil chemotaxis. The purpose of these studies was to characterize the regulation of neuropeptides in the upper airway after irritant exposure. Nasal irritation to asphalt fumes is a commonly reported symptom among road crew workers. In the first study, rats chronically exposed to asphalt fumes had increased levels of neuropeptides in TG neurons innervating the nasal epithelium and increased inflammatory cells in their nasal cavities. The enhanced neuropeptide production and subsequent neurogenic inflammation may cause symptoms of nasal irritation in road workers exposed to asphalt fumes. Since exposure to airway irritants has health implications that may be related to increased neuropeptide production, the remaining studies investigated mechanisms regulating SP production. Nerve growth factor is believed to mediate the irritant induced up-regulation of SP. Increased NGF levels in the nasal cavity preceded the up-regulation of SP in TG neurons innervating the nasal epithelium following TDI exposure. NGF binds receptors on sensory nerve terminals and travels to cell bodies where it regulates SP production. This temporal relationship suggests that irritant-induced SP expression in sensory neurons maybe mediated by NGF. To prove that NGF mediates SP production following irritant exposure, compounds were administered prior to TDI exposure to block NGF activity. K252a, a non-specific tyrosine-kinase inhibitor, prevented the increase in SP production and the inflammatory cell influx. The final study used an in vivo and ex vivo approach to demonstrate that NGF is synthesized and released from the nasal mucosa and the release of NGF increases following TDI exposure. Therefore, these studies support the concept that NGF release from the nasal mucosa following TDI correlates with SP production in TG cell bodies.

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