DESCRIPTION (provided by applicant): Rhinosinusitis affects about 10% of the U.S. population and is the reason for approximately 12-million physician office visits annually. Obstruction to sinus drainage and immune dysregulation are believed to result in mucosal disruption and hypersecretion, nasal obstruction, postnasal discharge, cough, headache, and facial pressure. Our laboratory has successfully developed and described the first mouse model of chronic rhinosinusitis. Now in press, we plan to use this model to characterize this disease at its molecular and genetic levels. Since the discovery of its role in regulating vascular tone, nitric oxide (NO) and nitric oxide synthase (NOS) have been implicated in neurotransmission, ischemia-reperfusion syndromes, atopic diseases, and chronic inflammatory disorders. During health, it is known that the human paranasal sinuses are the dominant source of nitric oxide in the upper airways. However, the diseased state is not well characterized. While chemiluminescense measurements of NO in exhaled air indicate decreased levels during sinusitis, nasal secretions find increased NO metabolite concentrations. Although the literature implicates nitric oxide as a player, there is no consensus as to its precise role or its degree of importance. Further study is necessary. The in vivo analysis of nitric oxide's role in chronic sinonasal disease shall be investigated using 3 experimental groups of mice: C57BL/6 wild-type mice, NOS I, II, and III knockout mice, and C57BL/6 mice infused with aminoguanidine - a pan-NOS inhibitor. Each of these groups shall be further sub-divided into normal controls, sham-operated controls, and animals with surgically induced sinusitis. All groups and interventions shall be compared at the light microscope level. Histomorphometric analysis of en-bloc sinonasal tissue shall be used to quantify epithelial thickness, cell density, basement membrane thickness, and goblet cell number. Qualitative observations shall assess the presence or absence of inflammatory infiltrates and sinonasal fibrosis. With this approach of inhibiting nitric oxide production at multiple levels -- pharmacologically and with gene knockout -- we hope to better characterize the importance of NO in sinonasal pathophysiology.
|Effective start/end date||8/1/01 → 7/31/02|
- National Institutes of Health: $62,500.00