Objectives: Exposure to cigarette smoke is a major cause of olfactory dysfunction. However, the underlying mechanisms by which cigarette smoke interferes with the highly regenerative olfactory nerve system remain unclear. To investigate whether cigarette smoke induces olfactory dysfunction by disrupting cell proliferation and cell survival in the olfactory epithelium (OE), we developed a mouse model of smoking that involved intranasal administration of a cigarette smoke solution (CSS).

Methods: Firstly, we explored the effects of CS on olfactory populations and olfactory sensitivity using histological analyses and behavioral testing with time. Secondly, we investigated the effects of CS on pro-inflammatory responses using histological analyses and quantitative real-time PCR analyses.

Results: Immunohistological analyses andbehavioral testing showed that CSSadministration over a period of 24 days reduced the number of olfactory marker protein-positive mature olfactory receptor neurons (ORNs) in the OE and induced olfactory dysfunction. These changes coincided with a reduction in the number of SOX2+ ORN progenitors and Ki67+ proliferating cells in the basal layer of the OE, an increase in the number of caspase-3+ apoptotic cells, and an increase in the expression of mRNA for the inflammatory cytokines IL-1β and IL-6. Notably, the proliferating ORN progenitor population recovered following cessation of treatment with CSS, resulting in the subsequent restoration of mature ORN numbers and olfaction.