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Background Hyaluronan is one of the major extracellular matrixes in chronic rhinosinusitis (CRS) associated with tissue remodeling. Prostaglandin D2(PGD2) is also associated with the pathogenesis of CRS. However, little is known about whether PGD2regulates hyaluronan production by human airway fibroblasts.Objective We sought to determine the effect of PGD2on the mRNA expression of three isoforms of membrane-bound hyaluronic acid synthase (HAS1, HAS2 and HAS3) in fibroblasts, the major source of hyaluronan production, derived from CRS patients.Methods Nasal polyp-derived fibroblasts (NPDF) and uncinate tissue-derived fibroblasts (UTDF) were established from CRS patients with nasal polyps and those without, respectively. These fibroblasts were stimulated with PGD2or PGD2receptor (DP/CRTH2)-selective agonists in the presence or absence of receptor-selective antagonists. mRNA levels for HAS1, HAS2 and HAS3 were determined by real-time quantitative PCR.Results PGD2(1 µM) significantly enhanced HAS1 but not HAS2 or HAS3 mRNA expression by NPDF. Enhanced HAS1 mRNA expression was also obtained by stimulation with a DP receptor-selective agonist, but not with a CRTH2 receptor-selective agonist. In addition, PGD2-induced HAS1 mRNA expression was significantly inhibited by pre-treatment with DP receptor-selective antagonists. Similar induction of PGD2-induced HAS1 mRNA expression was seen in UTDF.Conclusion PGD2selectively stimulates HAS1 mRNA expression in local fibroblasts in CRS via DP, but not CRTH2, receptors.

Background Signal transducer and activator of transcription (STAT) 1 signaling pathway mediates biological functions of interferon (IFN) γ, which is a key cytokine-regulating T helper 1 (Th1) differentiation. Although constitutive activation of STAT1 has been reported in the airway epithelium of patients with chronic asthma, its in vivo role in the pathogenesis of allergic rhinitis is not clear. We determined the role of STAT1 in the pathogenesis of allergic rhinitis in vivo using STAT1 gene-deficient (STAT1–/–) mice and a murine model of Schistosoma mansoni egg antigen (SEA)–induced allergic rhinitis.Methods STAT1 –/– BALB/c and wild-type (WT) mice were sensitized by intranasal administration of SEA, and their immunologic responses were examined.Results STAT1 –/– mice showed impaired nasal eosinophilia and markedly reduced histamine-induced nasal hyperresponsiveness after SEA sensitization. Moreover, levels of Th2-associated SEA-specific IgG1 and IgE antibodies were lower in STAT1 –/– mice. Anti-CD3–stimulated nasal lymphocytes from STAT1–/–mice also produced less amounts of Th2-associated cytokines IL-4, IL-5, IL-10, and IL-13 compared with WT mice, but both produced comparable levels of IFN-γ.Conclusion These results show that STAT1 is involved in the pathogenesis of SEA-induced allergic rhinitis in BALB/c mice. Furthermore, they reveal a surprising role of STAT1 in induction of nasal eosinophilia, and Th2-type cytokine production from nasal lymphocytes during allergic rhinitis.

Background Prostaglandin D2 (PGD2) is the major prostanoid produced in the acute phase of allergic reactions. However, its pathophysiological role in addition to the pathway of production in allergic rhinitis remains unclear. We sought to determine the expression of synthases and receptors for PGD2 in human nasal mucosa. These expressions were compared between allergic and nonallergic patients.Methods The expression and localization of hematopoietic-type (h)-PGD2 synthase (PGDS) and lipocalin-type (l)-PGDS were detected by immunohistochemistry. The expression of D prostanoid (DP) receptor and chemoattractant receptor–homologous molecule expressed on Th2 cells (CRTH2) was determined by quantitative real-time PCR.Results The h-PGDS but not l-PGDS was clearly expressed in nasal mucosa. The expression of h-PGDS in allergic patients was significantly higher than in control patients without mucosal hypertrophy. A variety of infiltrating cells including mast cells, eosinophils, macrophages, and lymphocytes as well as constitutive cells such as epithelial cells and fibroblasts expressed h-PGDS. The expression of both DP and CRTH2 was confirmed also. Although either the amount of DP or the amount of CRTH2 was not correlated with serum levels of IgE, the amount of CRTH2 but not DP was highly and significantly correlated with the number of eosinophils infiltrating into nasal musosa.Conclusion These results suggest that PGD2 is released via the action of h-PGDS from various cells, and the expression of h-PGDS may be associated with the hypertrophic inflammation in the nose. In addition, ligation of PGD2 to CRTH2 appears to be selectively involved in eosinophil recruitment into the nose regardless of atopic status.

Background Interaction between CD40 and CD40L is thought to regulate immune responses in several allergic diseases. However, little is known about its in vivo role in the pathophysiology of allergic rhinitis. We sought to determine whether the lack of signals through CD40 affects the pathophysiology of allergic rhinitis using a murine model.Methods Wild type (WT) and CD40-deficient BALB/c (CD40-/-) mice were sensitized intranasally to Schistosoma mansoni egg antigen (SEA). After repeated sensitization, histamine responsiveness, serum antibody titer including immunoglobulin E (IgE), nasal eosinophilia, and cytokine production by nasal mononuclear cells were determined in each group.Results Intranasal sensitization with SEA in WT mice elicited a strong Th2 response including SEA-specific IgE production, nasal eosinophilia, and interleukin (IL)-4, and IL-5 production by nasal mononuclear cells after antigen challenge. Production of SEA-specific IgE and IgG1 was abolished in SEA-sensitized CD40-/-mice. These mice showed impaired nasal eosinophilia and displayed markedly reduced histamine-induced nasal hyperresponsiveness as compared with WT mice. Furthermore, reduced production of IL-4 and IL-5 by nasal mononuclear cells was seen in CD40-/-mice.Conclusion These results show that signals through CD40 play a critical role in not only IgE production but also pathophysiology of allergic rhinitis such as nasal hyperresponsiveness and nasal eosinophilia.

Background Little is known about the immunologic aspects and the pathogenesis of the paranasal sinus mucocele.Methods The fluids of paranasal sinus mucoceles were obtained from 12 subjects. The concentration of macrophage migration inhibitory factor (MIF), interleukin 1β, tumor necrosis factor a, and regulated on activation normal T cell expressed and secreted (RANTES) were determined by enzyme-linked immunosorbent assay, and the levels of endotoxin were detected with kinetic Turbidimetric Assay.Results MIF and endotoxin were detected in the fluid of all samples, whereas interleukin-1β and RANTES were detected in 1 and 3 subjects out of 12 samples. Tumor necrosis factor a was not detected in any of the samples. A significant positive correlation between the levels of MIF and the period with symptoms such as pain, swelling of face, and visual disturbance was observed.Conclusion These findings suggest that MIF and endotoxin may play an important role in the pathogenesis of paranasal sinus mucocele. MIF may be an important factor causing the development and exacerbation of the disease.

Exotoxins derived from Staphylococcus aureus appear to be involved in the pathogenesis of allergic diseases, especially atopic dermatitis (AD). However, little is known about sensitization to enterotoxins in cases of respiratory allergies. Because the nasal cavity is a primary site of colonization by S. aureus, we sought to determine the prevalence and role of serum immunoglobulin E (IgE) antibodies against staphylococcal enterotoxin A (SEA) and SEB in patients with allergic rhinitis (AR). The presence of SEA- and SEB-specific IgE was determined in 40 patients with AR and 16 healthy control subjects. In the rhinitis group, nasal symptom score, total serum IgE, sensitization to other inhaled allergens and the presence of sinusitis were determined. Twenty-five percent of patients with AR were sensitized to SEA/SEB whereas 6.3% of controls were sensitized to the toxins. Sensitization to SEB was predominant relative to SEA. There were no significant differences in the severity of nasal symptoms and complications of other allergic diseases including AD and bronchial asthma, between patients with or without sensitization to SEA/SEB. However, patients sensitized to these toxins were likely to show increased total serum IgE and polyvalent sensitization, suggesting that exposure and subsequent sensitization to SEA/SEB may be involved in polyvalent sensitization.