title: Cigarette Smoke Delays Regeneration of the Olfactory Epithelium in Mice.
abstract: The olfactory system is a unique part of the mammalian nervous system due to its capacity for neurogenesis and the replacement of degenerating receptor neurons. Cigarette smoking is a major cause of olfactory dysfunction. However, the mechanisms by which cigarette smoke impairs the regenerative olfactory receptor neurons (ORNs) remain unclear. Here, we investigated the influence of cigarette smoke on ORN regeneration following methimazole-induced ORN injury. Administration of methimazole caused detachment of the olfactory epithelium from the basement membrane and induced olfactory dysfunction, thus enabling us to analyze the process of ORN regeneration. We found that intranasal administration of cigarette smoke solution (CSS) suppressed the recovery of ORNs and olfaction following ORN injury. Defective ORN recovery in CSS-treated mice was not associated with any change in the number of SOX2(+) ORN progenitor cells in the basal layer of the OE, but was associated with impaired recovery of GAP43(+) immature ORNs. In the nasal mucosa, mRNA expression levels of neurotrophic factors such as brain-derived neurotrophic factor, neurotrophin-3, neurotrophin-5, glial cell-derived neurotrophic factor, and insulin-like growth factor-1 (IGF-1) were increased following OE injury, whereas CSS administration decreased the ORN injury-induced IGF-1 expression. Administration of recombinant human IGF-1 prevented the CSS-induced suppression of ORN recovery following injury. These results suggest that CSS impairs regeneration of ORNs by suppressing the development of immature ORNs from ORN progenitors, at least partly by reducing IGF-1 in the nasal mucosa.
authors.affiliation: Department of Otolaryngology, The University of Tokyo, 7-3-1 Hongo Bunkyo-ku, Tokyo, 113-8655, Japan. 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, 7-3-1 Hongo Bunkyo-ku, Tokyo, 113-0033, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ueha
authors.affiliation: Department of Otolaryngology, The University of Tokyo, 7-3-1 Hongo Bunkyo-ku, Tokyo, 113-8655, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Sakamoto
authors.affiliation: Department of Otolaryngology, Tokyo Metropolitan Bokutoh Hospital, 4-23-15 Kotobashi Sumida-ku, Tokyo, 130-8575, Japan.
authors.forename: Kaori
authors.initials: K
authors.lastname: Kanaya
authors.affiliation: Department of Otolaryngology, Tokyo Metropolitan Bokutoh Hospital, 4-23-15 Kotobashi Sumida-ku, Tokyo, 130-8575, Japan.
authors.forename: Keigo
authors.initials: K
authors.lastname: Suzukawa
authors.affiliation: Department of Otolaryngology, The University of Tokyo, 7-3-1 Hongo Bunkyo-ku, Tokyo, 113-8655, Japan.
authors.forename: Hironobu
authors.initials: H
authors.lastname: Nishijima
authors.affiliation: Department of Otolaryngology, The University of Tokyo, 7-3-1 Hongo Bunkyo-ku, Tokyo, 113-8655, Japan.
authors.forename: Shu
authors.initials: S
authors.lastname: Kikuta
authors.affiliation: Department of Otolaryngology, The University of Tokyo, 7-3-1 Hongo Bunkyo-ku, Tokyo, 113-8655, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Kondo
authors.affiliation: Department of Molecular Preventive Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo Bunkyo-ku, Tokyo, 113-0033, Japan.
authors.forename: Kouji
authors.initials: K
authors.lastname: Matsushima
authors.affiliation: Department of Otolaryngology, The University of Tokyo, 7-3-1 Hongo Bunkyo-ku, Tokyo, 113-8655, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Yamasoba
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D004195:Disease Models, Animal; D007334:Insulin-Like Growth Factor I / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D008713:Methimazole; D008810:Mice, Inbred C57BL; D009416:Nerve Regeneration / Q000187:drug effects; D058953:Neural Stem Cells / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology; D000857:Olfaction Disorders / Q000188:drug therapy / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D009831:Olfactory Mucosa / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D018034:Olfactory Receptor Neurons / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D020127:Recovery of Function / Q000187:drug effects / Q000502:physiology; D012903:Smell / Q000502:physiology; D012906:Smoke; D012907:Smoking / Q000009:adverse effects* / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology*; D014026:Nicotiana
chemical_list: C583557:IGF1 protein, human; D018696:Neuroprotective Agents; D012333:RNA, Messenger; D011994:Recombinant Proteins; D012906:Smoke; C519530:insulin-like growth factor-1, mouse; D008713:Methimazole; D007334:Insulin-Like Growth Factor I
keywords: Cigarette smoke solution; Insulin-like growth factor-1; Olfactory epithelium; Olfactory receptor neuron; Regeneration