Hironobu Nishijima

Cigarette Smoke Delays Regeneration of the Olfactory Epithelium in Mice

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.

Denervation of nasal mucosa induced by posterior nasal neurectomy suppresses nasal secretion, not hypersensitivity, in an allergic rhinitis rat model.

The posterior nasal nerve is the dominant source of the parasympathetic, sympathetic, and sensory fibers that innervate the nasal respiratory mucosa. Therefore, a posterior nasal neurectomy (PNN) is thought to induce denervation of the nasal mucosa and relieve the nasal symptoms of allergic rhinitis. However, the underlying mechanisms and therapeutic action of PNN remain unknown. To investigate the impact of PNN-induced denervation of the nasal mucosa on allergic rhinitis, we developed a rat model of PNN and examined the effects of PNN on allergic rhinitis in ovalbumin-sensitized rats. This rat model of PNN was characterized by the depletion of nerve fibers, choline acetyltransferase, and neuropeptides (eg, substance P, calcitonin gene-related peptide, vasoactive intestinal peptide, and neuropeptide Y) in the nasal respiratory mucosa. These animals exhibited nasal gland and goblet cell hypertrophy in the septal mucosa and atrophy of the submucosal gland in the lateral nasal wall, as well as reduced nasal secretion due to deficient acetylcholine synthesis. In an ovalbumin-sensitized model of allergic rhinitis, PNN also induced the depletion of nerve fibers, choline acetyltransferase, and neuropeptides in the nasal mucosa and suppressed nasal secretion. However, PNN did not affect mucosal thickening, eosinophil and mast cell infiltration, interleukin-4 and interferon-γ mRNA expression, and allergic symptoms (ie, sneezing and nasal scratching). These results suggest that the peripheral nerves and corresponding neuropeptides regulate nasal secretion, but not hypersensitivity, in allergic rhinitis, and that allergic rhinitis-related mucosal reactions occur in a highly denervated mucosa after PNN. Posterior nasal neurectomy may be a therapeutic option for the treatment of hyperrhinorrhea, but not allergic rhinitis hypersensitivity.

Ethmoidectomy combined with superior meatus enlargement increases olfactory airflow

The relationship between a particular surgical technique in endoscopic sinus surgery (ESS) and airflow changes in the post‐operative olfactory region has not been assessed. The present study aimed to compare olfactory airflow after ESS between conventional ethmoidectomy and ethmoidectomy with superior meatus enlargement, using virtual ESS and computational fluid dynamics (CFD) analysis.

Correlation of basophil infiltration in nasal polyps with the severity of chronic rhinosinusitis

Chronic rhinosinusitis (CRS) represents a heterogeneous disease group characterized by local inflammation of the sinonasal tissues.1 It has been defined as symptomatic inflammation of the sinonasal mucosa that lasts more than 12 weeks as confirmed by computed tomography (CT) and nasal endoscopy.2 Generally, CRS is divided into 2 subsets based on endoscopic findings: CRS with nasal polyps (CRSwNP) and CRS without nasal polyps (CRSsNP).3 In Europe and the United States, eosinophilia is evident in nasal polyps (NPs) from patients with CRSwNP.4 In contrast, heterogeneity of CRSwNP has been reported in East Asian countries, such as Japan, Korea, and China, where the presence and extent of eosinophilia are variable and a significant proportion of NPs do not manifest local eosinophilia.5 Although the pathogenesis of CRS remains controversial, eosinophilic inflammation is considered at least partly responsible. Eosinophilic NPs contain an environment enriched for TH2 cytokines, including interleukin (IL) 4, IL-5, and IL-13.6 TH2 cytokines are believed to contribute to the pathogenesis of eosinophilic CRSwNP, with IL-5 and IL-13 inducing eosinophil recruitment and promoting their activation and IL-4 promoting the switching of the immunoglobulin to the IgE isotype.7 Basophils are reportedly increased in the bronchial submucosa of asthmatic patients and the nasal submucosa of patients with allergic rhinitis.8,9 Research is increasingly addressing the role of basophils in inducing TH2-type responses.10 Although CRSwNP is a highly TH2-biased disease, making the involvement of basophils likely, there are few reports of the involvement of basophils in CRS.11

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

Background: The incidence of olfactory impairment increases with age; however, the detailed molecular and cellular mechanisms underlying this increase are yet to be determined. Methods: We examined the influence of aging on olfactory receptor neurons (ORNs), which are maintained by a unique stem cell system, from olfactory progenitor cells to mature ORNs, by histological comparisons of the physiological status of the olfactory epithelium between young adult and aged mice. Furthermore, we clarified the expression of genes encoding inflammatory cytokines, neurotrophins, growth factors, and extracellular matrix proteins to reveal the molecular mechanisms underlying olfactory impairment caused by aging. Results: The numbers of mature and immature ORNs, but not olfactory progenitors, decreased in the aged olfactory epithelium, with a concurrent reduction in Ki-67-positive proliferating cells. Transcriptome analyses revealed an increase in Il6, encoding a component of senescence-associated secretary phenotypes (SASP), and a decrease in Igf1, encoding a growth factor for ORNs, in the aged nasal mucosa. Interestingly, expression levels of several extracellular matrix genes, including Col1a2, decreased in the aged nasal mucosa. Consistent with the transcriptional changes, the number of Col1a2-GFP-positive cells decreased in the aged lamina propria. Conclusions: Our data suggest that reduction in ORN number and cell proliferation, reduced extracellular matrix gene expression, and increased SASP contribute to olfactory impairment during aging.

Laryngeal mucus hypersecretion is exacerbated after smoking cessation and ameliorated by glucocorticoid administration.

INTRODUCTION The mechanisms underlying the effects of cigarette smoke and smoking cessation on respiratory secretion, especially in the larynx, remain unclear. OBJECTIVES The aims of this study were to determine the effects of cigarette smoke and smoking cessation on laryngeal mucus secretion and inflammation, and to investigate the effects of glucocorticoid administration. METHODS We administered cigarette smoke solution (CSS) to eight-week-old male Sprague Dawley rats for four weeks, then examined laryngeal mucus secretion and inflammatory cytokine expression on days 1, 28 and 90 after smoking cessation. We also investigated the effects of the glucocorticoid triamcinolone acetonide when administered on day 1 after smoking cessation. RESULTS Exposure to CSS resulted in an increase in laryngeal mucus secretion that was further excacerbated following smoking cessation. This change coincided with an increase in the expression of mRNA for the inflammatory cytokines tumor necrosis factor and interleukin-6, as well as mRNA for MUC5AC, which is involved in mucin production. Triamcinolone suppressed CSS-induced laryngeal mucus hypersecretion and pro-inflammatory cytokine production. CONCLUSION Cigarette smoke-associated inflammation may contribute to the exacerbated laryngeal mucus hypersecretion that occurs following smoking cessation. The inflammatory response represents a promising target for the treatment of cigarette smoke-associated mucus hypersecretion.

Intravenous olfactory test latency correlates with improvement in post-infectious olfactory dysfunction

Abstract Conclusion: This cohort study showed that onset latency in the intravenous olfactory test (IVO) may help predict when olfaction in patients with post-infectious olfactory dysfunction (PIOD) improves. Objectives: To identify factors that predict the olfactory improvement period in patients with PIOD. Methodology/Principal: All consecutive patients presenting with PIOD in 1994–2014 who were followed up for 2 years were identified retrospectively. The ability of demographic/clinical factors (age, sex, body mass index, presence/absence of allergic rhinitis, treatment/non-treatment with herbal medicines, patient dependence on herbal medicine treatment, presence/absence of diabetes mellitus, and smoking status) and olfactory test factors (response/no response and onset latency and duration in the IVO test, and detection and recognition scores on the T&T olfactory test) to predict the olfactory improvement period (defined respectively as the time from PIOD onset or olfactory testing to the first self-report of olfaction improvement) was analyzed by univariate and multivariate regression. Results: Of the 187 PIOD patients, the prognostic ability of demographic/clinical factors was analyzed in 65. None predicted the olfactory improvement period. Of the 65 patients, 20 did not respond in the IVO test. In the remaining 45 patients, onset latency (but not the other olfactory test factors) was a significant prognosticator of olfactory improvement period (R2=0.24, p = 0.003).

Longer latency of sensory response to intravenous odor injection predicts olfactory neural disorder

A near loss of smell may result from conductive and/or neural olfactory disorders. However, an olfactory test to selectively detect neural disorders has not been established. We investigated whether onset latency of sensory response to intravenous odor injection can detect neural disorders in humans and mice. We showed that longer preoperative onset latency of odor recognition to intravenous odor in patients with chronic rhinosinusitis predicted worse recovery of olfactory symptoms following sinus surgery. The onset latency of the olfactory sensory neuron (OSN) response to intravenous odor using synaptopHluorin signals from OSN axon terminals was delayed in mice with reduced numbers of OSNs (neural disorder) but not with increased mucus or blocked orthonasal pathways (conductive disorders). Moreover, the increase in onset latency correlated with the decrease in mature OSN numbers. Longer onset latency to intravenous odor injection is a useful biomarker for presence and severity of olfactory disorders with neural etiology.

Multiple fibroepithelial polyps arising from the inferior turbinate.

A 77-year-old man presented with long periods of left-sided nasal obstruction and intermittent epistaxis. Nasal fibroscopy revealed an unusual, white, cauliflower-like, well-circumscribed, firm polypoidal mass arising from the vertebral portion of the left inferior turbinate (Figure 1). The surface of the multilocular polyps was lustrous. Computed tomography showed soft-tissue opacity with no enhancement that filled the left vestibule without any bony destruction. The mass measuring 2 cm was removed by an endoscopic inferior turbinectomy. Pathological examination showed small exophytic polyps with constrictions. Figure 2 shows the fibroepithelial polyps (FEPs) consisting of a fibrous lesion covered by pseudostratified cylindrical epithelium, surrounding a hemangioma. Compared with normal nasal polyps, FEPs had less infiltration of eosinophils, lymphocytes, and inflammatory cells. There was no evidence of dysplasia or malignancy. The institutional review board of Tokyo Teishin Hospital approved this article.

Influence of the location of nasal polyps on olfactory airflow and olfaction: Nasal polyps and olfaction

Chronic rhinosinusitis with nasal polyps (CRSwNP) often results in decreased olfaction. In this study, we examined the relationship between nasal polyp location and olfactory airflow and odorant transport changes using virtual nasal polyp models at different locations and computational fluid dynamics (CFD) analysis. We also compared olfactory airflow and olfaction between patients with nasal polyps at different locations using CFD analysis and an olfactory test.