Reduction of Proliferating Olfactory Cells and Low Expression of Extracellular Matrix Genes Are Hallmarks of the Aged Olfactory Mucosa

et al. 2018

Front. Aging Neurosci.

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Introduction: Exposure to cigarette smoke is a cause of olfactory dysfunction. We previously reported that in young mice, cigarette smoke damaged olfactory progenitors and decreased mature olfactory receptor neurons (ORNs), then, mature ORNs gradually recovered after smoking cessation. However, in aged populations, the target cells in ORNs by cigarette smoke, the underlying molecular mechanisms by which cigarette smoke impairs the regenerative ORNs, and the degree of ORN regeneration after smoking cessation remain unclear.Objectives: To explore the effects of cigarette smoke on the ORN cell system using an aged mouse model of smoking, and to investigate the extent to which smoke-induced damage to ORNs recovers following cessation of exposure to cigarette smoke in aged mice.Methods: We intranasally administered a cigarette smoke solution (CSS) to 16-month-old male mice over 24 days, then examined ORN existence, cell survival, changes of inflammatory cytokines in the olfactory epithelium (OE), and olfaction using histological analyses, gene analyses and olfactory habituation/dishabituation tests.Results: CSS administration reduced the number of mature ORNs in the OE and induced olfactory dysfunction. These changes coincided with an increase in the number of apoptotic cells and Tumor necrosis factor (TNF) expression and a decrease in Il6 expression. Notably, the reduction in mature ORNs did not recover even on day 28 after cessation of treatment with CSS, resulting in persistent olfactory dysfunction.Conclusion: In aged mice, by increasing ORN death, CSS exposure could eventually overwhelm the regenerative capacity of the OE, resulting in continued reduction in the number of mature ORNs and olfactory dysfunction.

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Cigarette Smoke-Induced Cell Death Causes Persistent Olfactory Dysfunction in Aged Mice

et al. 2018

Front. Aging Neurosci.

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“…Although IGF-1 is mainly produced in the liver and skeletal muscles, it is also generated in the central nervous system, where it plays an important role in the differentiation and maturation of neurons ( Nishida et al, 2011 ; Nieto-Estevez et al, 2016 ; Pardo et al, 2016 ). As our previous study showed, reduction in ORN number and cell proliferation in the aged OE reduced gene expression of IGF-1, which may contribute to olfactory impairment during aging ( Ueha et al, 2018a ). Considering the previous studies, the balance of IGF-1 might be of importance in the regulation of OE homeostasis in the aging population.…”

Section: Introductionmentioning

confidence: 87%

“…Olfaction is known to be impaired by aging. Aging negatively affects the ORN cell system in the olfactory neuroepithelium (OE) ( Ueha et al, 2018a ). The OE has a unique regenerative stem-cell system, which is maintained by the life-long replenishment of mature ORNs in the luminal layer from the progenitor cells in the basal layer ( Costanzo, 1991 ; Schwob, 2002 ; Supplementary Figure S1 ).…”

Section: Introductionmentioning

confidence: 99%

Dose-Dependent Effects of Insulin-Like Growth Factor 1 in the Aged Olfactory Epithelium

et al. 2018

Front. Aging Neurosci.

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Background: Olfaction is known to be impaired by aging. We hypothesized that insulin-like growth factor-1 (IGF-1) administered at an appropriate dose could prevent age-induced negative effects on olfactory receptor neurons (ORNs). We explored the effects of low- and high-dose administration of IGF-1 on the ORN cell system in aged mice and investigated the involvement of the cellular mechanisms of IGF-1 in the regeneration of ORNs in aged mice.Methods: We subcutaneously administered recombinant human IGF-1 (rhIGF-1) to 16-month-old male mice over 56 days, and then examined the histological effects of rhGF-1 on cellular composition, cell proliferation, and cell death in the aged olfactory epithelium (OE), by comparing among saline-treated and low- and high-dose rhIGF-1-treated mice.Results: Low-dose rhIGF-1 administration increased the numbers of olfactory progenitors, immature ORNs, and mature ORNs in the OE, despite an increase in Cas3+ apoptotic cells. Notably, high-dose rhIGF-1 administration increased the numbers of only immature ORNs, not olfactory progenitors and mature ORNs, with a concurrent increase in apoptotic cells.Conclusion: Our data suggest that in aged mice, IGF-1 administered at an appropriate dose could increase the number of mature ORNs and further human studies may contribute to the development of treatments for aging-related olfactory impairment.

“…The olfactory mucosa serves olfaction and consists of the olfactory epithelium (OE) and the sub-epithelium tissue. The number of mature olfactory receptor neurons (ORNs) in the OE is closely related to the degree of olfaction (Ueha et al, 2018a), and the ORNs are classified into four groups according to their zonal expression patterns (Mori et al, 2000). Regarding the impact of smoking on the OE, we previously reported that CS impaired the OE and olfaction by reducing the olfactory progenitor cells and mature ORNs (Ueha et al, 2016a) and that CS delayed regeneration of the OE (Ueha et al, 2016b).…”

Section: Introductionmentioning

confidence: 99%

Effects of Cigarette Smoke on the Nasal Respiratory and Olfactory Mucosa in Allergic Rhinitis Mice

et al. 2020

Front. Neurosci.

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Objective: Cigarette smoke (CS) exposure reportedly enhances allergic airway inflammation. However, some studies have shown an association between current cigarette smoke exposure and a low risk for allergic rhinitis. Thus, the impact of CS exposure on allergic rhinitis remains poorly understood. The purpose of this study was to investigate the effects of CS on the respiratory mucosa (RM) and the olfactory epithelium (OE) of mice with allergic rhinitis, as the effects may differ depending on the nasal histological compartments.Methods: Eight-week-old male BALB/c mice were used for this study. We developed a mouse model of smoking by intranasally administering 10 doses of a CS solution (CSS), and a mouse model of allergic rhinitis by sensitization with intraperitoneal ovalbumin (OVA) injection and intranasal challenge with OVA. We examined the effects of CS on the nasal RM and OE in mice with or without allergic rhinitis using histological, serum, and genetic analyses. First, we examine whether CSS exposure induces allergic responses and then, examined allergic responses in the OVA-sensitized allergic rhinitis mice with or without CSS exposure.Results: Short-term CSS administration intensified allergic responses including increased infiltration of eosinophils and inflammatory cells and upregulation of interleukin-5 expression in the nasal RM of OVA-immunized mice, although only CSS induced neither allergic responses nor impairment of the RM and OE. Notably, repetitive OVA-immunization partially impaired the OE in the upper-lateral area, but CSS administration did not reinforce this impairment in OVA-induced allergic mice.Conclusion: Short-term CSS exposure strengthened allergic responses in the nasal RM and did not change the structure of the OE. These results suggest that patients with allergic rhinitis could experience exacerbation of allergic symptoms after CS exposure.