Kengo Kanai

Early interventional treatment with intranasal mometasone furoate in Japanese cedar/cypress pollinosis: a randomized placebo-controlled trial.

BACKGROUND Little is known about the safety and effectiveness of early interventional treatment (EIT) with intranasal corticosteroids for seasonal allergic rhinitis. We designed a double-blinded, randomized, placebo-controlled 12-week trial of EIT with mometasone furoate nasal spray (MFNS) for Japanese cedar/cypress pollinosis (JCCP). METHODS A total of 50 JCCP patients received MFNS (200μg once daily: n = 25) or placebo (n = 25) starting on February 1, 2010. Treatments continued until the end of April. The primary endpoint was the comparison of the total nasal symptom score (TNSS) between the MFNS and placebo groups. The secondary endpoints included comparisons of QOL, daytime sleepiness, nasal ECP levels, and safety. RESULTS Continuous dispersion of Japanese cedar pollen began on February 22. Although the placebo group showed a significant worsening of symptoms after the start of the continuous dispersion, no worsening occurred in the MFNS group. A significant difference in the TNSS between the two groups was seen starting at 4 weeks after the treatment. Similar results were seen for QOL and sleepiness. Nasal ECP levels in March were significantly lower in the MFNS group. A total of 56% of the MFNS group progressed to a persistent allergic rhinitis state in accordance with the ARIA classification, as opposed to 84% of the placebo group. MFNS was well tolerated, and the plasma cortisol concentrations were similar between the two groups. CONCLUSIONS EIT with MFNS for JCCP is both safe and effective. This treatment can potentially lessen symptoms and help pollinosis patients remain in the intermittent state.

Cellular Responses to Staphylococcus aureus Alpha-Toxin in Chronic Rhinosinusitis with Nasal Polyps

BACKGROUND In contrast to Staphylococcus aureus-derived superantigenic exotoxins, the role of non-superantigenic exotoxins in the pathogenesis of eosinophilic airway diseases remains obscure. We sought to characterize S. aureus alpha-toxin-induced cellular responses in chronic rhinosinusitis with nasal polyps (CRSwNP). METHODS Dispersed nasal polyp cells and uncinate tissue cells were prepared from patients with CRS with and without nasal polyps, respectively. Cells were incubated with various concentrations of alpha-toxin or staphylococcal enterotoxin B and then the levels of IL-5, IL-13, IFN-γ, IL-17A, and IL-10 in the cell supernatants were determined. The pathophysiological significance of alpha-toxin-induced cytokine production was also determined including radiological severity of rhinosinusitis, tissue and blood eosinophilia, serum total IgE level, and 1-s forced expiratory volume/forced vital capacity ratio (FEV1/FVC). RESULTS Nasal polyp cells produced substantial amounts of IL-5, IL-13, IFN-γ, IL-17A, and IL-10 in response to alpha-toxin. Cytokine production was higher in nasal polyp cells than in uncinate tissue cells. The potency of alpha-toxin in stimulating IL-5, IL-13, and IL-10 production was comparable to that of enterotoxin. Alpha-toxin-induced IFN-γ, IL-17A, and IL-10 production significantly and negatively correlated with the degree of eosinophil infiltration into nasal polyps. Conversely, alpha-toxin-induced IFN-γ and IL-10 production significantly and positively correlated with FEV1/FVC. IL-10 production was significantly lower in asthmatic patients compared to non-asthmatics CONCLUSIONS S. aureus-derived alpha-toxin can provoke cellular responses in nasal polyps. These responses, especially failure to synthesize IL-10, may play a role in the pathophysiology of CRSwNP.

Local expression of interleukin-17a is correlated with nasal eosinophilia and clinical severity in allergic rhinitis.

Interleukin (IL)-17A is a major cytokine produced by Th17 cells, which are associated with chronic inflammations. The local expression of IL-17A in allergic rhinitis (AR) remains to be characterized. We sought to determine the role of IL-17A expression in human inferior turbinate mucosa in the pathophysiology of AR. Inferior turbinate mucosa was sampled from medical treatment-resistant, surgery-required patients with perennial AR (PAR, n = 21), nonallergic rhinitis with eosinophilia syndrome (NARES, n = 7), and nonallergic hypertrophic rhinitis (HR, n = 13). IL-17A expression was determined with immunohistochemical staining. The mean number of IL-17A+ cells and eosinophils per field were counted. Total serum immunoglobulin E (IgE) levels, blood eosinophil count, and forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) ratio were also examined in each patient. IL-17A was primarily expressed in infiltrating inflammatory cells. The number of IL-17A+ cells in nasal mucosa was significantly higher in the PAR group compared with HR (p = 0.002) and NARES (p = 0.021) groups. There was a significant and positive correlation between the number of IL-17A+ cells and total nasal symptom score (rho = 0.403; p = 0.011), especially sneezing score (rho = 0.471; p = 0.003). The number of IL-17A+ cells was significantly and positively correlated with the degree of eosinophil infiltration (rho = 0.623; p < 0.001), but not with total serum IgE levels (rho = 0.284; p = 0.098), blood eosinophil counts (rho = 0.302; p = 0.056), or FEV1/FVC ratio (rho = 0.092; p = 0.569). The present study provides evidence that IL-17A expression in the nasal mucosa is associated with the pathophysiology of AR, including disease severity and nasal eosinophilia.

IL-22/IL-22R1 signaling regulates the pathophysiology of chronic rhinosinusitis with nasal polyps via alteration of MUC1 expression

BACKGROUND IL-22 is an IL-10-family cytokine that regulates chronic inflammation. We investigated the role of IL-22 and its receptor, IL-22R1, in the pathophysiology of chronic rhinosinusitis with nasal polyps (CRSwNP). METHODS IL-22 and IL-22R1 protein and mRNA expression in NP and in uncinate tissues (UT) from CRS and non-CRS patients was examined using immunohistochemistry and real-time PCR, respectively. Dispersed NP and UT cells were cultured with the Staphylococcus aureus exotoxins, staphylococcal enterotoxin B and alpha-toxin, following which exotoxin-induced IL-22 levels and their association with clinicopathological factors were analyzed. Effects of IL-22 on MUC1 expression and cytokine release in NP cells were also determined. RESULTS IL-22 and IL-22R1 in NP were mainly expressed in infiltrating inflammatory cells and in epithelial cells, respectively. IL-22 mRNA levels in NP were significantly higher than those in UTs from non-CRS patients whereas IL-22R1 levels were conversely lower in NPs. NP cells produced substantial amounts of IL-22 in response to exotoxins. Exotoxin-induced IL-22 production by NP cells significantly and negatively correlated with the degree of local eosinophilia and postoperative computed tomography (CT) score, whereas conversely it positively correlated with the forced expiratory volume in 1s (FEV1)/forced vital capacity (FVC) ratio. IL-22 significantly enhanced MUC1 mRNA expression in NP cells. IL-22-induced MUC1 mRNA levels were significantly and positively correlated with IL-22R1 mRNA levels in NPs. CONCLUSIONS These data suggest that imbalance of IL-22/IL-22R1 signaling regulates the pathogenesis of CRSwNP, including local eosinophilia, via alteration of MUC1 expression.

Regulatory effect of TLR3 signaling on staphylococcal enterotoxin-induced IL-5, IL-13, IL-17A and IFN-γ production in chronic rhinosinusitis with nasal polyps

BACKGROUND Toll-like receptor 3 (TLR3) is expressed in upper airways, however, little is known regarding whether Toll-like receptor 3 (TLR3) signals exert a regulatory effect on the pathogenesis of chronic rhinosinusitis with nasal polyps (CRSwNP), especially on eosinophilic inflammation. We sought to investigate the effect of Poly(IC), the ligand for TLR3, on cytokine production by dispersed nasal polyp cells (DNPCs). METHODS DNPCs were pretreated with or without Poly(IC), and were then cultured in the presence or absence of staphylococcal enterotoxin B (SEB), following which the levels of IL-5, IL-10, IL-13, IL-17A and interferon (IFN)-γ in the supernatant were measured. To determine the involvement of IL-10 and cyclooxygenase in Poly(IC)-mediated signaling, DNPCs were treated with anti-IL-10 monoclonal antibody and diclofenac, the cyclooxygenase inhibitor, respectively. Poly(IC)-induced prostaglandin E2 (PGE2) production was also determined. RESULTS Exposure to Poly(IC) induced a significant production of IL-10, but not of IL-5, IL-13, IL-17A or IFN-γ by DNPCs. Pretreatment with Poly(IC) dose-dependently inhibited SEB-induced IL-5, IL-13 and IL-17A, but not IFN-γ production. Neutralization of IL-10 significantly abrogated the inhibitory effect of Poly(IC). Treatment with diclofenac also abrogated the inhibitory effect of Poly(IC) on SEB-induced IL-5 and IL-13 production. However, unlike exposure of diclofenac-treated DNPCs to lipopolysaccharide, the ligand for TLR4, exposure of these cells to Poly(IC) did not enhance IL-5 or IL-13 production. Poly(IC) did not significantly increase PGE2 production by DNPCs. CONCLUSIONS These results suggest that TLR3 signaling regulates eosinophilia-associated cytokine production in CRSwNP, at least in part, via IL-10 production.

Association between impaired IL-10 production following exposure to Staphylococcus aureus enterotoxin B and disease severity in eosinophilic chronic rhinosinusitis

BACKGROUND IL-10 is a major anti-inflammatory cytokine that prevents inflammation-mediated tissue damage. We characterized the production of IL-10 by sinonasal tissue cells following exposure to Staphylococcus aureus enterotoxin B (SEB), which elicits cellular responses and is associated with the pathogenesis of eosinophilic chronic rhinosinusitis (ECRS). METHODS Dispersed nasal polyp (NP) cells and uncinate tissue (UT) cells were prepared from patients with CRS with and without NP, respectively. Cells were incubated with SEB, and then the levels of IL-10 in the cell supernatants were determined. The effect of neutralizing IL-10 on SEB-induced IL-5, IL-13, IFN-γ, and IL-17A production was examined. Expression of IL-10 in NPs was also determined. RESULTS IL-10 was expressed in infiltrating inflammatory cells in NPs. NP cells, especially non-adherent NP cells, produced substantial amounts of IL-10 in response to SEB. Although baseline production of IL-10 was significantly higher in NP cells than UT cells, the degree of IL-10 response to SEB was not significantly different between the cell types. The degree of IL-10 production was negatively correlated with the degree of eosinophilia both in tissues and peripheral blood whereas positively correlated with the 1-s forced expiratory volume/forced vital capacity ratio. Patients with severe ECRS displayed a significant decrease in IL-10 production compared with those with non-ECRS. IL-10 neutralization significantly augmented SEB-induced IL-13 and IFN-γ production by NP cells. CONCLUSIONS Impaired IL-10 production in response to SEB in NP may exacerbate the pathophysiology of ECRS including eosinophilia and lower airway obstruction.

Evaluation of a New and Simple Classification for Endoscopic Sinus Surgery

Objective In 2013, the Japanese Rhinologic Society proposed a simple classification for endoscopic sinus surgery (ESS). This classification consists of five procedures (type I, fenestration of the ostiomeatal complex, with uncinectomy and widening of the natural ostium; type II, single-sinus procedure, with manipulating the inside of the sinus; type III, polysinus procedure; type IV, pansinus procedure; type V, extended procedure beyond the sinus wall). The clinical relevance of this classification in chronic rhinosinusitis (CRS) and paranasal sinus cyst was evaluated. Study Design A retrospective validation study. Methods A total of 122 patients (195 sinuses) who underwent ESS in Okayama University Hospital in 2012 were enrolled. The relationships between the ESS classification and the clinical course, including the operation time, bleeding amounts during surgery and postoperative changes of olfaction, the computed tomography (CT) score, and nasal airway resistance were analyzed. Results A total of 195 ESS procedures were classified into type I (n = 3), type II (n = 17), type III (n = 91), type IV (n = 82), and type V (n = 2). The major phenotypes of type II, III, and IV ESS were paranasal sinus cyst (68%), CRS without nasal polyps (77%), and CRS with nasal polyps (55%), respectively, and the difference was significant. The degree of ESS based on this classification was positively and significantly correlated with the operation time and bleeding amounts. As a whole, olfaction, CT score, and nasal airway resistance were significantly improved after surgery. The degree of improvement was similar between type III and type IV ESS. Conclusion This simple classification for ESS reflected the perioperative burden of the disease.