Katsuhiro Hirakawa

Novel scoring system and algorithm for classifying chronic rhinosinusitis: the JESREC Study.

Chronic rhinosinusitis (CRS) can be classified into CRS with nasal polyps (CRSwNP) and CRS without nasal polyps (CRSsNP). CRSwNP displays more intense eosinophilic infiltration and the presence of Th2 cytokines. Mucosal eosinophilia is associated with more severe symptoms and often requires multiple surgeries because of recurrence; however, even in eosinophilic CRS (ECRS), clinical course is variable. In this study, we wanted to set objective clinical criteria for the diagnosis of refractory CRS.

Pathological Mechanisms and Clinical Features of Eosinophilic Chronic Rhinosinusitis in the Japanese Population

The overall pathological view of paranasal sinus inflammation in the Japanese population has profoundly changed in recent years. Eosinophilic chronic rhinosinusitis (ECRS) is a clinical entity of intractable chronic sinus inflammation accompanied by numerous infiltrations of activated eosinophils in the paranasal sinus mucosa and/or nasal polyps. Several pathologic processes are considered to act in concert to promote the accumulation of eosinophils in ECRS. They include infiltration of progenitor cells, increase in local IL-3, IL-5, IL-13, GM-CSF and eotaxin production, and upregulation of adhesion molecules. The role of nasal allergen sensitization and innate immunity responses in the sinus mucosa has also been proposed in the development of ECRS. Various pathogens including TLRs ligands may trigger an abnormal immune response at the mucosal surface. The objectives of ECRS management should focus directly on inhibition of local eosinophil infiltration. Surgical procedures include widely opening the bony wall septum of every affected sinus and mechanical removal of diseased mucosal lesion. The use of local and/or systemic steroids, leukotriene receptor antagonists, and Th2 cytokine antagonists is recommended. Local administration of steroids is a potent treatment strategy for preventing relapse of nasal polyposis and is considered to be the first-line treatment for ECRS patients.

Localization of transient receptor potential vanilloid (TRPV) in the human larynx

Conclusion. Transient receptor potential vanilloid (TRPV) 1, 2, 3, and 4 were expressed in the human larynx, which may act as laryngeal nociceptors perceiving luminal noxious stimuli, play an important role in thermal sensation and osmotic sensation, and are also related to some pathological conditions and prevention of aspiration. Objective. Expression of TRPV1, 2, 3, and 4 in the human larynx was analyzed. Materials and methods. Specimens of human epiglottic epithelium obtained from six patients were used in this study. The localization of TRPV1, 2, 3, and 4 in the laryngeal epithelium was investigated by immunohistochemistry. Results. Immunohistochemical study revealed the presence of TRPV1, 2, 3, and 4 in the laryngeal epithelial cells. Chemoradiotherapy may reduce the expression of TRPV1, 2, 3, and 4, which might be a result of the mucositis and neuropathy in laryngeal epithelium.

Nuclear Factor-Kappa B Activation in the Nasal Polyp Epithelium: Relationship to Local Cytokine Gene Expression†

Objectives A panel of cytokines has been found to be important for eosinophil accumulation and activation in nasal polyps. The aims of this study were to ascertain whether the activation of nuclear factor‐kappa B (NF‐κB) occurred in the polyp epithelium, and to examine the relationship between the degree of activation and local cytokine gene expression.

Age-dependent changes in the expression of klotho protein, TRPV5 and TRPV6 in mouse inner ear

Conclusions. klotho protein content decreases with increasing age, which weakens resistance to oxidative stress, resulting in induced cell death as well as modulating endolymph fluid homeostasis. Down-regulation of klotho also leads to down-regulation of TRPV5 and TRPV6, resulting in modified Ca2 + homeostasis in the inner ear, dysfunction of sensory cell transduction and causing hearing loss and/or vestibular disorders. Objective. Expression of klotho, TRPV5 and TRPV6 in the mouse inner ear and age-related changes were analysed. Materials and methods. CBA/J mice aged 8 weeks and 24 months were used in this study. The localization of klotho, TRPV5 and TRPV6 in the inner ear of young and old mice was investigated by immunohistochemistry. Results. Immunostaining for klotho was observed in stria vascularis, outer and inner hair cells (OHCs and IHCs), and in vestibular sensory cells and dark cells, and less intensely in the spiral and vestibular ganglion cells. Expression of TRPV5 was found in stria vascularis, organ of Corti, vestibular sensory cells and dark cells, and less intensely in the spiral and vestibular ganglion cells. Expression of TRPV6 was found in supporting cells of the organ of Corti, with weak labelling in OHCs and IHCs. Weak fluorescence was also noted in stria vascularis, and faint fluorescence in the spiral ligament. Vestibular sensory and dark cells as well as vestibular ganglion cells showed weak fluorescence. In the old animals, the expression patterns of klotho, TRPV5 and TRPV6 were identical with those in young animals, although fluorescence intensity was significantly weaker.

Leukotriene Receptor Antagonist Pranlukast Suppresses Eosinophil Infiltration and Cytokine Production in Human Nasal Mucosa of Perennial Allergic Rhinitis

The purpose of this study was to investigate the influence of pranlukast on eosinophilic inflammation and cytokine production in human nasal mucosa. Twelve patients were treated with pranlukast, and samples were obtained from the nasal mucosa of the inferior turbinate. With respect to cell infiltration, a significant decrease was observed in the percentage of inflammatory cells (secreted eosinophil cationic protein [EG2] and neutrophil elastase) after treatment. The levels of cytokines and chemical mediators (interleukin [IL]–4, IL-5, RANTES [regulated on activation, normal T cell expressed and secreted], cysteinyl leukotrienes, IL-1β, tumor necrosis factor–α, and IL-8) assessed by enzyme-linked immunosorbent assay and enzyme immunoassay were significantly decreased. These results indicate that pranlukast decreased the levels of a majority of the cytokines in nasal mucosa, leading to improvement in subjective nasal symptoms. Furthermore, these results support the hypothesis that pranlukast exerts its therapeutic action primarily by blocking the leukotriene receptors on eosinophils.

Localization of transient receptor potential channel vanilloid subfamilies in the mouse larynx

Conclusion. Laryngeal epithelium contains TRPV1, 2, 3 and 4, which may act as laryngeal nociceptors perceiving luminal noxious stimuli, play an important role in thermal sensation, osmotic sensation, and are also related to pathological conditions, such as inflammatory response, genesis of cough, asthma. Objective. Expression of TRPV1, 2, 3 and 4 in the normal CBA/J mouse larynx was analysed. Materials and methods. CBA/J mice were used in this study. The localizations of TRPV1, 2, 3 and 4 in the laryngeal epithelium were investigated by immunohistochemistry. Results. Immunohistochemical study revealed the presence of TRPV1, 2, 3 and 4 in the laryngeal epithelial cells. TRPV1 and TRPV2 were often co-localized with substance P, while the co-localization of substance P and TRPV3 was rare and TRPV4 was not co-localized with substance P.

Suppression of the Th2 pathway by suplatast tosilate in patients with perennial nasal allergies.

Background Suplatast tosilate (IPD-1151T), a selective Th2 cytokine inhibitor that suppresses the production of interleukin (IL)-4 and IL-5 in vitro or in animal models has been proved clinically effective for allergic rhinitis (AR). The aim of this study was to investigate changes in the Th2 pathway in human nasal mucosa after medication with IPD-1151T. Twelve patients were treated with IPD-1151T. Methods Twelve healthy volunteers served as normal controls. The following parameters were evaluated: (i) subjective nasal clinical symptoms, (ii) percentages of inflammatory cells (EG2, CD4, and CD8) by immunocytological staining, and (iii) levels of cytokines (IL-4, IL-5, IL-13, regulated on activation, normal T-cell expressed, and secreted [RANTES], and interferon [IFN] γ) by enzyme-linked immunosorbent assay. Results Nasal symptom scores significantly decreased after treatment. With respect to cell infiltration, a significant decrease was observed in the percentage of inflammatory cells (EG2 and CD4) and CD4/CD8 ratio. The levels of cytokines (IL-4, IL-5, IL-13, and IFN-γ) and the IL-5/IFN-γ ratio were significantly decreased, and the IL-4/IFN-γ ratio became not significantly different from that in normal subjects. In contrast, RANTES did not change significantly. The percentage of reduction in IL-5 correlated with that in eosinophil infiltration, whereas that in RANTES did not. Conclusion These results suggest that IPD-1151T can reduce the Th2 pathway.

Expression of transient receptor potential channel vanilloid (TRPV) 1–4, melastin (TRPM) 5 and 8, and ankyrin (TRPA1) in the normal and methimazole-treated mouse olfactory epithelium

Abstract Conclusion: It is suggested that TRPV1, 2, 3, and 4, TRPM5 and 8, and TRPA1 may play several roles in the olfactory epithelium (OE), contributing to olfactory chemosensation, olfactory adaptation, olfactory–trigeminal interaction, and OE fluid homeostasis. In patients with olfactory disturbance, TRPV1 and TRPM8 may be closely related to a high rate of recognition of curry and menthol odors, while TRPV2 may also play a crucial role in the regeneration of olfactory receptor neurons. Objective: Expression of TRPV1–4, TRPM5 and 8, and TRPA1 in the normal and methimazole-treated mouse OE was analyzed. Methods: The localization of TRPV1–4, TRPM5 and 8, and TRPA1 in the OE of normal and methimazole-treated CBA/J mice was investigated by immunohistochemistry. Results: Normal OE showed a positive immunofluorescent reaction to TRPV1–4, TRPM5 and 8, and TRPA1. In lamina propria, the nerve fibers displayed TRPV 1, 2, and 3, TRPM8 and TRPA1. In the pathological condition, the expression of TRPV3, TRPV4, TRPM5, and TRPA1 was markedly reduced and took a long time to recover. In contrast, expression of TRPM8 was scarcely affected, even in the pathological condition, while TRPV1 and TRPV2 showed early recovery following methimazole treatment.

Efficacy of combined treatment with S-carboxymethylcysteine (carbocisteine) and clarithromycin in chronic rhinosinusitis patients without nasal polyp or with small nasal polyp

OBJECTIVE In Japan, fourteen-membered ring macrolides, antibacterial agents, and S-carboxymethylcysteine (SCMC; carbocisteine), a mucolytic, are commonly used to treat chronic rhinosinusitis (CRS), and they are also used in combination. However, no large-scale randomized study has examined the effects of these pharmacotherapies. The aim of this study is to evaluate the effect of combined administration of clarithromycin (CAM), a fourteen-membered ring macrolide, and SCMC, compared with CAM single therapy. METHODS Patients with CRS were centrally registered and randomly assigned to treatment with CAM (200mg/day) alone (monotherapy group) or CAM (200mg/day) in combination with SCMC (1500mg/day; combination group) for 12 weeks. We assessed the clinical efficacy of the treatments using measures of subjective symptoms and objective findings, health-related quality of life (HRQOL) determined by the 20-Item Sino-Nasal Outcome Test (SNOT-20) score and computed tomography (CT) score. RESULTS Four hundred twenty-five subjects were enrolled (combination group, 213; monotherapy group, 212). At week 12 of treatment, the rate of effectiveness was significantly higher in the combination group (64.2%) compared with the monotherapy group (45.6%; P=0.001). In addition, objective findings, including characteristics of nasal discharge (P=0.008) and post-nasal discharge (P=0.002) were significantly improved in the combination group. In both groups, SNOT-20 and CT scores were significantly improved from week 0 (P<0.001), and were not significantly different between groups. CONCLUSION The results indicated that long-term combination therapy with SCMC at a dose of 1500mg/day and CAM at a dose of 200mg/day is effective for improving subjective symptoms and objective findings in adult patients with CRS.