Shin Kariya

E prostanoid 2 (EP2)/EP4‐mediated suppression of antigen‐specific human T‐cell responses by prostaglandin E2

Prostaglandin E2 (PGE2) is a lipid mediator that displays important immunomodulatory properties, such as polarization of cytokine production by T cells. Recent investigations have revealed that the effect of PGE2 on cytokine production is greatly influenced by external stimuli; however, it is unclear whether PGE2 plays a significant role in major histocompatibility complex‐mediated antigen‐specific T‐cell responses via binding to one of four subtypes of E prostanoid (EP) receptor alone or in combination. In the present study, we sought to determine the effect of PGE2 on antigen‐specific CD4+ T‐cell responses in humans, especially in terms of receptor specificity. We used purified protein derivative (PPD) and Cry j 1 as T helper type 1 (Th1) and Th2‐inducing antigens, respectively. We generated several different Cry j 1‐ and PPD‐specific T‐cell lines (TCLs). PGE2 significantly and dose‐dependently inhibited the proliferation and subsequent production of interleukin‐4 by Cry j 1‐specific TCLs and of interferon‐γ by PPD‐specific TCLs upon antigen stimulation. Administration of EP2 receptor agonist and EP4 receptor agonist suppressed these responses in an adenylate cyclase‐dependent manner, while EP1 and EP3 receptor agonists did not. Messenger RNA for EP2, EP3 and EP4, but not EP1, receptors were detected in Cry j 1‐ and PPD‐specific TCLs, and no differences in EP receptor expression were observed between them. Furthermore, PGE2 and EP2 receptor agonist significantly inhibited interleukin‐5 and interferon‐γ production by peripheral blood mononuclear cells in response to Cry j 1 and PPD stimulation, respectively. These results suggest that PGE2 suppresses both Th1‐ and Th2‐polarized antigen‐specific human T‐cell responses via a cAMP‐dependent EP2/EP4‐mediated pathway.

Long-term results of tonsillectomy as a treatment for IgA nephropathy

IgA nephropathy (IgAN) is the most common form of chronic glomerulonephritis with IgA deposits present mainly in the mesangial areas. We performed a 10-year retrospective case-control study of 71 patients with IgAN to evaluate the long-term effects and prognostic factors associated with tonsillectomy. Forty-one patients (19 males and 22 females) underwent tonsillectomy (Group A) and 30 patients (13 males and 17 females) did not (Group B). These patients were followed for more than 10 years after renal biopsy. The average age at initial renal biopsy was 29.78 years in Group A and 33.0 years in Group B. The average follow-up period was 13 years and 3 months in Group A, and 12 years and 7 months in Group B. Glomerular damage demonstrated on renal biopsy was more extensive in Group A than in Group B. Prognosis after 10 years of follow-up was compared between the two groups. The clinical remission rate was 24.4% in Group A and 13.3% in Group B, the stable renal function rate was 82.9% in Group A and 70.0% in Group B, and the renal survival rate was 95.1% in Group A and 73.3% in Group B. The renal survival rate in Group A was significantly higher than that in Group B (p <0.05). Although evaluation of renal pathology based on renal biopsy was useful in predicting the long-term effects of tonsillectomy in IgAN patients, the results of tonsillar provocation tests were not.

Membranous labyrinth volumes in normal ears and Meniere disease: a three-dimensional reconstruction study.

The purpose of this study was to determine the normal volume ranges of cochlear duct, saccule, and utricle, and to assess endolymphatic hydrops in Ménière disease.

Histopathologic changes of contralateral human temporal bone in unilateral Ménière's disease

Hypothesis: To disclose the histopathologic findings in the contralateral temporal bone in unilateral Ménières disease. Background: Several functional studies reported abnormal findings in the contralateral ears in patients with unilateral Ménières disease. Methods: This study involved quantitative analysis, including the number of spiral ganglion cells, the loss of cochlear hair cells, the area of stria vascularis, and the density of fibrocytes in the spiral ligament. It included 14 temporal bones from 7 subjects with bilateral Ménières disease, 30 temporal bones from 15 subjects with unilateral Ménières disease, and 17 age-matched normal control temporal bones from 12 subjects. Results: The mean number of spiral ganglion cells in the contralateral temporal bones in patients with unilateral Ménières disease was 17,376.0 and was significantly lower than that in normal controls. The mean loss of inner and outer hair cells in the contralateral temporal bones in patients with unilateral Ménières disease was significantly greater than that in normal controls in all turns. The stria vascularis was severely atrophic and degenerated in patients with Ménières disease. The mean area of stria vascularis in contralateral temporal bones in patients with unilateral Ménières disease was significantly smaller than normal controls. There was no significant difference in the density of fibrocytes in the spiral ligament between the diseased side and the contralateral side in patients with unilateral Ménières disease and between normal control and contralateral side. Conclusion: The contralateral inner ear in patients with unilateral Ménières disease has significantly more damage compared with inner ears of normal controls.

Age-related histopathologic changes in the human cochlea: A temporal bone study

OBJECTIVES: Previous reports on aging of human cochlea included subjects with ear diseases or ototoxic drugs. We studied spiral ganglion cells, hair cells, and lateral wall of cochlea from subjects without ear disease or ototoxic drugs. STUDY DESIGN: This study included 39 temporal bones from 24 subjects aged 1 day to 86 years. We assessed standard cytocochleograms, mean loss of fibrocytes in spiral ligament, and areas of stria vascularis. RESULTS: Losses of outer hair cells and fibrocytes were significantly greater in childern, adults, and the elderly compared with infants. Spiral ganglion cell loss was significantly greater in adults and elderly compared with infants and children. Areas of stria vascularis of infants were significantly larger than the elderly. CONCLUSIONS: Degenerative changes of outer hair cells occur in children but spiral ganglion cells remain the same until around 20 years. Degeneration of stria vascularis due to aging appears to be slower than spiral ligament. EBM rating: C.

Prostaglandin E2 suppresses staphylococcal enterotoxin-induced eosinophilia-associated cellular responses dominantly through an E-prostanoid 2-mediated pathway in nasal polyps

BACKGROUND Recent investigations have revealed that staphylococcal enterotoxins (SEs), COX metabolism, or both might participate in the pathogenesis of eosinophilic airway diseases, such as chronic rhinosinusitis with nasal polyposis. OBJECTIVE We sought to determine whether COX metabolism, especially prostaglandin (PG) E(2), plays a significant role in SE-induced cellular responses in nasal polyps. METHODS Dispersed nasal polyp cells (DNPCs) were prepared from nasal polyps by means of enzymatic digestion. DNPCs were cultured with SEB in the presence or absence of COX inhibitors (diclofenac and indomethacin) for 72 hours; then the levels of IL-5, IL-13, RANTES, and eotaxin in the supernatants were measured. The effect of PGE(2) on SEB-induced responses by diclofenac-treated DNPCs was examined, especially in terms of receptor specificity. RESULTS DNPCs produced significant amounts of IL-5, IL-13, and RANTES in response to SEB. COX inhibitors significantly increased the production of these cytokines. The degree of local eosinophilia was significantly and positively correlated with the changes in IL-5 production induced by diclofenac treatment. PGE(2) significantly and dose-dependently inhibited SEB-induced IL-5, IL-13, and RANTES production by diclofenac-treated DNPCs. E-prostanoid (EP) 2 receptor-selective agonist strongly inhibited the production of all 3 cytokines. EP3 and EP4 receptor-selective agonists partially suppressed these responses, whereas EP1 receptor-selective agonist did not. Interestingly, all of the combined treatments with 2 of the 4 EP receptor-selective agonists significantly inhibited the SEB-induced responses by diclofenac-treated DNPCs. CONCLUSIONS These results suggest that PGE(2) inhibits the pathogenesis of SEB-induced eosinophilic inflammation primarily through the EP2-mediated pathway in patients with chronic rhinosinusitis with nasal polyposis.

Ménière's disease in childhood

We report 3 rare cases of Ménières disease in children. In Case 1 and 3, vertigo, hearing loss and tinnitus recovered soon after medical therapy. In Case 2, however, vertigo recurred and the hearing level on the right side markedly deteriorated. The equal-loudness contours on three-dimensional audiogram showed that right-sided aggravated hearing loss fluctuated for 4 years at middle-and low-frequencies despite medication. Finally intratympanic injection of gentamicin sulfate was performed. The patient has had no definitive spell of vertigo after gentamicin therapy. At our department, the incidence of Ménières disease in pediatric patients with vertigo was 2.9%.

Time Courses of Changes in Phospho- and Total- MAP Kinases in the Cochlea after Intense Noise Exposure

Mitogen-activated protein kinases (MAP kinases) are intracellular signaling kinases activated by phosphorylation in response to a variety of extracellular stimuli. Mammalian MAP kinase pathways are composed of three major pathways: MEK1 (mitogen-activated protein kinase kinase 1)/ERK 1/2 (extracellular signal-regulated kinases 1/2)/p90 RSK (p90 ribosomal S6 kinase), JNK (c-Jun amino (N)-terminal kinase)/c-Jun, and p38 MAPK pathways. These pathways coordinately mediate physiological processes such as cell survival, protein synthesis, cell proliferation, growth, migration, and apoptosis. The involvement of MAP kinase in noise-induced hearing loss (NIHL) has been implicated in the cochlea; however, it is unknown how expression levels of MAP kinase change after the onset of NIHL and whether they are regulated by transient phosphorylation or protein synthesis. CBA/J mice were exposed to 120-dB octave band noise for 2 h. Auditory brainstem response confirmed a component of temporary threshold shift within 0–24 h and significant permanent threshold shift at 14 days after noise exposure. Levels and localizations of phospho- and total- MEK1/ERK1/2/p90 RSK, JNK/c-Jun, and p38 MAPK were comprehensively analyzed by the Bio-Plex® Suspension Array System and immunohistochemistry at 0, 3, 6, 12, 24 and 48 h after noise exposure. The phospho-MEK1/ERK1/2/p90 RSK signaling pathway was activated in the spiral ligament and the sensory and supporting cells of the organ of Corti, with peaks at 3–6 h and independently of regulations of total-MEK1/ERK1/2/p90 RSK. The expression of phospho-JNK and p38 MAPK showed late upregulation in spiral neurons at 48 h, in addition to early upregulations with peaks at 3 h after noise trauma. Phospho-p38 MAPK activation was dependent on upregulation of total-p38 MAPK. At present, comprehensive data on MAP kinase expression provide significant insight into understanding the molecular mechanism of NIHL, and for developing therapeutic models for acute sensorineural hearing loss.

Role of Macrophage Migration Inhibitory Factor in Otitis Media with Effusion in Adults

ABSTRACT Otitis media with effusion (OME) is one of the most common ear diseases. Bacterial endotoxins and several inflammatory cytokines appear to be involved in the pathogenesis of OME in children; however, little is known of the immunological aspects of the onset of OME in adults. We sought to determine the presence of macrophage migration inhibitory factor (MIF) as well as interleukin 1β (IL-1β), tumor necrosis factor alpha (TNF-α), RANTES (regulated upon activation, normal T-cell expressed and presumably secreted), and endotoxin in middle ear effusions (MEEs) from adult patients with OME. In addition, the levels of MIF in MEEs from adults and children were compared. MEE was obtained from 95 adults and 11 children. The levels of MIF, IL-1β, TNF-α, and RANTES were determined by enzyme-linked immunosorbent assay, and the concentrations of endotoxin and total protein were determined by the Endospec assay and bicinchoninic acid assay, respectively. MIF was detected in 97.9% of the MEEs from adults, while endotoxin, IL-1β, TNF-α, and RANTES were detected in 96.8, 12.6, 5.3, and 43.9%, respectively. In addition, the level of MIF was significantly higher than those of endotoxin, IL-1β, and TNF-α. A positive correlation between the levels of MIF and endotoxin was observed. MIF and endotoxin were detected in 81.8 and 72.7%, respectively, of the MEEs from the children. The level of MIF was significantly higher in the children, and conversely that of endotoxin was significantly higher in the adults. These results suggest that the interaction between MIF and endotoxin may promote fluid collection in the middle ear, particularly in adults.

Expression and Characterization of PGD2 Receptors in Chronic Rhinosinusitis: Modulation of DP and CRTH2 by PGD2

Background: Prostaglandin D2 (PGD2) participates in airway inflammation. We reported that levels of hematopoietic-type PGD2 synthase (h-PGDS) in sinonasal tissues may play an important role in the pathophysiology of chronic rhinosinusitis (CRS). Two PGD2 receptors have been isolated, DP and CRTH2, but whether they participate in CRS remains unclear. We sought to determine the expression and characterization of DP and CRTH2 in CRS. Methods: Expression of DP and CRTH2 in nasal polyps (NP) and uncinate process mucosae (UPM) was examined by in situ hybridization and immunohistochemistry and evaluated by real-time quantitative PCR. h-PGDS, IL-5, eotaxin and RANTES expression was also determined. In addition, the effect of PGD2 on the expression of both receptors in UPM was assessed. Results: DP was widely expressed, not only in infiltrating inflammatory cells but also in constitutive cells such as vascular endothelial cells and ciliated columnar epithelia. CRTH2 was selectively expressed in inflammatory cells and some glands. Significantly greater levels of DP mRNA and conversely decreased levels of CRTH2 mRNA were observed in NP compared with UPM. DP and CRTH2 mRNA levels were not only positively and inversely correlated with levels of h-PGDS but also with eotaxin, respectively. Furthermore, addition of PGD2 significantly increased DP expression and conversely reduced CRTH2 expression in UPM. Conclusions: These results suggest that distinct expression of DP and CRTH2 is associated with the pathophysiology of CRS, including NP formation, and the expression of these receptors may be regulated by h-PGDS and PGD2.