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Date of Award

10-2000

Degree Type

Thesis

Degree Name

Doctor of Philosophy (PhD)

Department

Medical Sciences

Supervisor

Dr. Edwin E. Daniel

Abstract

A large number of studies have identified that bronchoconstricting agents have increased potency and effect following inhaled ozone, but the contribution of bronchodilatory mediators to attenuation of the airway hyperresponsiveness observed following inhaled ozone remains unclear. The purpose of this investigation was to identify the contribution of nitric oxide synthase (NOS) and cyclooxygenase (COX) to the regulation of ozone-induced airway hyperresponsiveness. These mediators are derived largely from the airway epithelium and ozone exposure is likely, through epithelial damage, to alter the effect of NOS and COX in the airway. Using an ozone exposed guinea pig model of airway hyperresponsiveness, the in vivo responses to inhaled histamine were compared to responses in sham treated animals. Administration of the NOS inhibitor L-NAME (5120 μg/mL) increased the histamine sensitivity after ozone treatment. The non-selective COX inhibitor indomethacin (10 mg/kg) also increased the histamine sensitivity after ozone treatment. The COX-2 selective inhibitor DFU (1 or 10 mg/kg) caused a 2-fold leftward shift after ozone exposure, similar to that observed with indomethacin. The thromboxane antagonist, SQ 29,548 (1 mg/kg i.p.) attenuated the histamine responsiveness in a time dependent manner. The combination of COX and NOS inhibition produced a histamine-induced airway hyperresponsiveness greater than that observed with either NOS or COX inhibition alone. Pre-administration of dexamethasone inhibited the ozone-induced histamine hyperresponsiveness at all time points. Biochemical measurements of NOS activity identified an increase in NOS enzyme activity following ozone. Bronchoalveolar lavage revealed an inflammatory cell profile that did not correlate to the in vivo airway hyperresponsiveness. In vitro tissue bath experiments identified the presence and biological activity of NOS in the guinea pig trachea. Liquid chromatographic detection of nitric oxide metabolites and Western blot detection of COX-2 and NOS isoforms did not provide reliable data. This thesis demonstrates that histamine airway responsiveness following ozone changes rapidly and that both NOS and COX are upregulated a few hours after ozone exposure and, through functional antagonism, modulate ozone-induced histamine airway hyperresponsiveness.

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