Reversible loss of neuronal marker protein expression in a transgenic mouse model for sinusitis-associated olfactory dysfunction.
BACKGROUND
Chronic rhinosinusitis (CRS) is among the most common causes of olfactory loss. The loss of the sense of smell is thought to result from structural and functional changes occurring in the olfactory epithelium caused by inflammation. However, the cellular mechanisms underlying CRS-associated olfactory loss remain incompletely understood.


METHODS
Transgenic mice expressing TNF-alpha specifically within the olfactory epithelium were used as a model for CRS-associated olfactory loss. TNF-alpha expression was induced over different time intervals, and olfactory epithelial tissue was assessed for the expression of neuronal markers by laser scanning confocal microscopy and Western blot.


RESULTS
TNF-alpha expression results in an inflammatory infiltrate in the olfactory epithelium, thinning of the olfactory neuron layer, and a progressive loss of olfactory function. Reduced expression of markers for neurons and mature olfactory neurons (neural cell adhesion molecule [NCAM] and olfactory marker protein [OMP], respectively) was observed in the neuroepithelium and in the subepithelial axon bundles. Expression of growth-associated protein (GAP) 43, a marker for immature neurons, was also reduced. These alterations were reversed when TNF-alpha expression was discontinued.


CONCLUSIONS
TNF-alpha expression in a transgenic model of CRS-associated olfactory loss results in progressive loss of olfactory neurons. Decreased GAP-43 expression suggests that TNF-alpha-associated inflammation inhibits differentiation of progenitor cells into immature olfactory neurons. Therefore, reduced regeneration of olfactory neurons may be an important mechanism underlying olfactory loss in CRS, in addition to neuronal loss or apoptosis. This mouse model represents a potential tool in the development of novel therapeutic strategies for the prevention of olfactory neuron loss in CRS.
Division of Rhinology and Sinus Surgery, Department of Otolaryngology-Head and Neck Surgery, The Johns Hopkins University, School of Medicine, 601 N. Caroline Street, Baltimore, MD 21287, USA.
Justin H
JH
Turner
Lindsey
L
May
Randall R
RR
Reed
Andrew P
AP
Lane
D000377:Agnosia / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism; D017209:Apoptosis; D002908:Chronic Disease; D003001:Cloning, Molecular; D019922:GAP-43 Protein / Q000378:metabolism; D007249:Inflammation; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D023421:Models, Animal; D019006:Neural Cell Adhesion Molecules / Q000378:metabolism; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D051842:Olfactory Marker Protein / Q000378:metabolism; D012220:Rhinitis / Q000150:complications / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D012852:Sinusitis / Q000150:complications / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
D000943:Antigens, Differentiation; D019922:GAP-43 Protein; D019006:Neural Cell Adhesion Molecules; D051842:Olfactory Marker Protein; D014409:Tumor Necrosis Factor-alpha