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.

Effect of intranasal administration of neurotrophic factors on regeneration of chemically degenerated olfactory epithelium in aging mice

“…In our previous study, FGF2 was administered intranasally in PBS solution twice a day. In contrast, in the present study, the continuous effect of FGF2 was achieved owing to gelatin hydrogel placement, which led to the controlled release of growth factors, the half-life of which is very short in its free form 17 . Second, the condition of OE was significantly different in the two studies.…”

“…We examined the expression of mRNA of FGF2 and Igf1, and their receptors, Fgfr1 and Igf1r, during regeneration in the damaged OE 15 , to confirm the time of administration of FGF2 or IGF1. In an attempt to administer FGF2 or IGF1 more effectively, we included these factors in a gelatin-based hydrogel, which has the advantage of the sustained release of drugs 17 .…”

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

“…Neurogenesis was examined following previously described methods (Buckland and Cunningham, 1999 ; Ueha et al, 2014 , 2016a , b ); tissues were stained with the following anti-mouse primary antibodies: SOX2 (1:300 dilution; rabbit monoclonal, Abcam clone EPR3131; Cambridge, UK), GAP43 (1:1,000 dilution; rabbit polyclonal, NOVUS #NB300-143B; Littleton, CO, USA), Ki-67 (1:200 dilution; rabbit monoclonal, Novus #NB600-1252), OMP (olfactory marker protein; 1:8,000 dilution, goat polyclonal, Wako), and cleaved caspase-3 (1:300 dilution; rabbit polyclonal, Cell Signaling #9661; Danvers, MA, USA). SRY (sex determining region Y)-box 2 (SOX2) is a transcription factor that is widely expressed in stem cell populations and is involved in maintaining the undifferentiated state.…”

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

“…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). However, the effects of CS on each area of the allergic nasal mucosa have not been verified.…”