title: Damage to Olfactory Progenitor Cells Is Involved in Cigarette Smoke-Induced Olfactory Dysfunction in Mice.
abstract: 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). Immunohistological analyses and behavioral testing showed that CSS administration during 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 Ki-67(+) 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 after cessation of treatment with CSS, resulting in the subsequent restoration of mature ORN numbers and olfaction. These results suggest that SOX2(+) ORN progenitors are targets of CSS-induced impairment of the OE, and that by damaging the ORN progenitor population and increasing ORN death, CSS exposure eventually overwhelms the regenerative capacity of the epithelium, resulting in reduced numbers of mature ORNs and olfactory dysfunction.
authors.affiliation: Department of Otolaryngology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. Electronic address: ruu1025@yahoo.co.jp.
authors.forename: Rumi
authors.initials: R
authors.lastname: Ueha
authors.affiliation: Department of Molecular Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ueha
authors.affiliation: Department of Otolaryngology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Kondo
authors.affiliation: Department of Otolaryngology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Sakamoto
authors.affiliation: Department of Otolaryngology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Shu
authors.initials: S
authors.lastname: Kikuta
authors.affiliation: Department of Otolaryngology, Tokyo Teishin Hospital, Tokyo, Japan.
authors.forename: Kaori
authors.initials: K
authors.lastname: Kanaya
authors.affiliation: Department of Otolaryngology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Hironobu
authors.initials: H
authors.lastname: Nishijima
authors.affiliation: Department of Molecular Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Kouji
authors.initials: K
authors.lastname: Matsushima
authors.affiliation: Department of Otolaryngology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Yamasoba
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009831:Olfactory Mucosa / Q000187:drug effects / Q000503:physiopathology*; D018034:Olfactory Receptor Neurons / Q000187:drug effects / Q000502:physiology; D055748:SOXB1 Transcription Factors / Q000378:metabolism; D012907:Smoking / Q000009:adverse effects*; D013234:Stem Cells / Q000187:drug effects / Q000502:physiology*
chemical_list: D016207:Cytokines; D019394:Ki-67 Antigen; D055748:SOXB1 Transcription Factors; C527783:Sox2 protein, mouse; C505409:Casp3 protein, mouse; D053148:Caspase 3