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Allergic rhinitis (AR) is a multifactorial airway disease characterized by basal and goblet cell hyperplasia. Hyaluronic acid (HA) is a major component of extracellular matrix and a critical contributor to tissue repair and remodeling after injury. We previously demonstrated that the intermediate progenitor cell (IPC) surface marker CD44v3 is upregulated in the basal and suprabasal layers of well-differentiated primary human nasal epithelial (HNE) cells after stimulation with the Th2 (T-helper cell type 2) cytokine IL-4, and an antibody blocking the CD44v3-HA interaction suppressed IL-4–induced goblet cell hyperplasia. We now show that the expression of HA and two HA synthases, HAS2 and HAS3, was upregulated in both the nasal surface epithelium of subjects with AR and IL-4–stimulated HNE cells. Inhibition of HA synthesis by 4-methylumbelliferone suppressed IL-4–induced goblet cell hyperplasia. Moreover, HAS2 and HAS3 were expressed in IPCs depending on the differentiation events, as follows: the rapid, transient upregulation of HAS2 induced basal IPC proliferation and basal-to-suprabasal transition, whereas the delayed upregulation of HAS3 promoted the transition of suprabasal IPCs to a goblet cell fate. 4-methylumbelliferone treatment in a house dust mite–induced murine AR model attenuated goblet cell metaplasia. Last, HA concentrations in nasal epithelial lining fluids from patients with AR positively correlated with the concentrations of mediators causing allergic inflammation. These data suggest that HA produced after the sequential upregulation of HAS2 and HAS3 contributes to goblet cell hyperplasia in allergic airway inflammation and modulates disease progression.

Allergic rhinitis (AR) is an inflammatory disorder of the upper airway. Janus kinase 1 (JAK1), a member of JAK family, has recently been found to participate in the immune response and the development of allergic airway disease. This study was performed to evaluate the potential association of JAK1 polymorphisms with AR in a Chinese Han population. A case-control study was performed in 450 Chinese AR patients and 615 healthy controls. Three SNPs in the JAK1 gene, rs3790532, rs310241 and rs2780815, were analyzed using a polymerase chain reaction-restriction fragment length polymorphism assay (PCR-RFLP). An association was detected between SNP rs310241 in the JAK1 gene and AR in a Chinese Han population. However, no significant association was observed between the polymorphisms rs3790532 and rs2780815 and AR. For rs310241, the CC genotype and the C allele significantly increased the risk of AR. Furthermore, we found that the ACG haplotype in JAK1 gene was positively correlated with AR, while the GTG haplotype was associated with a significantly decreased risk of AR. This study indicates that the JAK1 rs310241 C-related genotype and allele are involved in AR susceptibility, making them potentially useful genetic biomarkers for AR susceptibility in the Chinese Han population.

Allergens, viral, and bacterial infections are responsible for asthma exacerbations that occur with progression of airway inflammation. cPLA2α and sPLA2X are responsible for delivery of arachidonic acid for production of eicosanoids—one of the key mediators of airway inflammation. However, cPLA2α and sPLA2X role in allergic inflammation has not been fully elucidated. The aim of this study was to analyze the influence of rDer p1 and rFel d1 and lipopolysaccharide (LPS) on cPLA2α expression and sPLA2X secretion in PBMC of asthmatics and in A549 cell line. PBMC isolated from 14 subjects, as well as A549 cells, were stimulated with rDer p1, rFel d1, and LPS. Immunoblotting technique was used to study the changes in cPLA2α protein expression and ELISA was used to analyze the release of sPLA2X. PBMC of asthmatics released more sPLA2X than those from healthy controls in the steady state. rDer p1 induced more sPLA2X secretion than cPLA2α protein expression. rFel d1 caused decrease in cPLA2α relative expression in PBMC of asthmatics and in A549 cells. Summarizing, Der p1 and Fel d1 involve phospholipase A2 enzymes in their action. sPLA2X seems to be one of important PLA2 isoform in allergic inflammation, especially caused by house dust mite allergens.

The aim of this report was to answer the question how specific immunotherapy influences the antioxidant enzyme system in patients with respiratory allergy and in longer perspective to find markers suitable to assess the efficacy of treatment. In open prospective randomised study 28 patients (18 females and 10 males, age 14–48 years) with seasonal respiratory allergy were treated with allergen immunotherapy. Subjects received subcutaneous therapy with allergens absorbed on calcium phosphate or aluminium hydroxide and were analyzed by the established protocol at the beginning, after three and 12 month of the treatment. In all treatment group red cell superoxide dismutase and glutathione peroxidase activities were in the normal range in allergic patients both before and during the treatment. Catalase activity in the allergic patients was lower as compared with controls and a significant increase of the enzyme activity occurred during and at the end of the treatment. In patients treated with calcium phosphate adsorbed allergen there was a continous increase of catalase activity from beginning up to the end of observation. In the case of the aluminium hydroxide treatment there was an increase from the baseline values up in the third month of the treatment and a decrease on the 12 th month. In summary, the present results open the question that allergen immunotherapy may cause imbalance of oxidants and antioxidants. To support our findings larger controlled field studies are needed.

Background: Eosinophils generate large amounts of oxidant species. The eosinophil-dominant type of chronic rhinosinusitis (CRS) with nasal polyps is related to more extensive disease and a decreased likelihood of surgical success. Superoxide dismutase (SOD) is the first-line and only antioxidant enzyme that converts superoxide to hydrogen peroxide. Methods: The patients with CRS with nasal polyps were divided into eosinophilic and noneosinophilic groups. The expression of three isoforms of SOD, intracellular copper-zinc SOD (CuZnSOD), mitochondrial manganese SOD (MnSOD) and extracellular SOD (ECSOD), were examined by enzyme activity assay, immunohistochemistry and quantitative real-time RT-PCR sampled by laser capture microdissection. Results: SOD activity in the eosinophilic and noneosinophilic groups was significantly reduced compared to that of the control groups. Immunostaining of both CuZnSOD and MnSOD in the eosinophilic group was significantly decreased compared with that in the noneosinophilic and control groups. CuZnSOD mRNA of the eosinophilic group was significantly decreased compared with that of the control group, whereas MnSOD mRNA in the eosinophilic group was significantly decreased compared with that in the noneosinophilic and control groups. Neither immunoreactivity nor mRNA of ECSOD was different among the three groups. The degree of epithelial damage and disease severity were inversely correlated with CuZnSOD and MnSOD immunoreactivity. Conclusions: The reduction in SOD activity and the downregulation of the SOD message are suggested to be related to eosinophil recruitment and epithelial damage of CRS with nasal polyps.

The localization of neuronal nitric oxide synthase (nNOS) in the mucosa of the inferior and middle turbinates of 30 patients with and without allergic rhinitis was examined by immunohistochemical methods. Staining of paraffin sections from allergic and nonallergic patients revealed nNOS immunoreactivity (nNOS-IR) in the muscular layer of vessels, in the basal portion of submucosal glands and in the periost and the osteocytes of the turbinate bones. In contrast to earlier investigations, nNOS-IR was also seen in the nasal respiratory epithelium of allergic and nonallergic patients. The immunostaining of sections of submucosal glands from allergic patients was stronger than that of sections from patients with idiopathic rhinitis or patients with no nasal obstruction. The present result – nNOS-IR around glands is elevated in patients with allergic rhinitis – could indicate that this enzyme is involved in the pathogenesis and symptomatology of allergic rhinitis.

Matrix metalloproteinase 9 (MMP9) gene has been shown to be involved in the pathogenesis of allergic rhinitis (AR) and asthma. Previous studies suggested that single-nucleotide polymorphisms (SNPs) of the MMP9 gene conferred a risk for childhood asthma. However, whether the SNPs confer a risk for AR has not been previously investigated. The objective of this study was to investigate whether SNPs of the MMP9 gene are associated with risk of seasonal AR (pollinosis), perennial AR and allergen sensitization. A total of 670 school children were recruited in Japan and genotyped for functional polymorphism in the promoter (-1590C/T: rs3918242) and three amino-acid substitutions (R297Q: rs17576; P574R: rs2250889; R668Q: rs17577). Serum levels of total and specific IgE were determined. Disease status and other clinical characteristics of the subjects were investigated using a questionnaire. Associations between the MMP9 SNPs and both AR and serum IgE levels were evaluated. -1590C/T showed significant association with cedar pollinosis (corrected P (Pcor)=0.039). R668Q was in strong linkage disequilibrium (LD) with -1590C/T and showed significant association with cedar pollinosis (Pcor=0.023) and serum cedar pollen-specific IgE level (Pcor=0.022). A haplotype associated with -1590T and 668Q showed a significant association with cedar pollinosis, orchard grass pollinosis and cedar pollen-specific IgE (Pcor=0.0012, Pcor=0.0059 and Pcor=0.0041, respectively). R297Q and P574R were in weak LD with the rest of the SNPs and did not show significant association with disease. Compared with wild-type MMP9 protein (279R-574P-668R), a variant enzyme (279R-574P-668Q) that showed association with pollinosis had lower activity. However, lower enzyme activity was not associated with disease risk because another variant (279Q-574R-668R) showed lower enzyme activity but was not associated with pollinosis. The -1590T allele and its corresponding haplotype was associated with higher promoter activity and with pollen-specific IgE levels and pollinosis, suggesting that -1590C/T may have more impact on sensitization and disease development than R668Q. Our results suggest that the MMP9 gene confers susceptibility to cedar pollinosis in Japanese children. The MMP9 gene may be associated with pollinosis through sensitization processes.

Background MCAD-deficiency is the most common inborn error of fatty acid oxidation now included in many newborn screening programms using MS/MS. During prolonged catabolic episodes, patients may suffer from metabolic decompensation with dysfunction of liver, skeletal- and heart muscle as well as brain. In anabolism, neither clinical symptoms nor biochemical signs of organ dysfunction occur. Case presentation We report a female patient with MCAD-deficiency in whom at the age of 11 years isolated AST-elevation was found without any clinical or biochemical signs of organ dysfunction. We showed by polyethylene glycol precipitation that macro-AST formation was responsible for this biochemical finding. AST was probably complexed with immunoglobulins possibly related to an allergic disposition. Macro-AST formation is not a special feature of MCAD-deficiency but rather a non-specific, coincidental finding which also occurs in healthy individuals. The general practitioner consulted by the patient before coming to our outpatient clinic for inborn errors of metabolism was worried that isolated AST-elevation indicated cell damage in MCAD-deficiency. He ordered further diagnostic tests like ultrasound, ECG and echocardiography without any pathology. Conclusion In isolated AST-elevation, macro-AST has to be considered in order to avoid unnecessary, costly and invasive evaluation. This is not only true for healthy persons but for patients with chronic diseases like MCAD as well.

Background Childhood hospitalization related to asthma remains at historically high levels, and its incidence is on the rise world-wide. Previously, we have demonstrated that aldose reductase (AR), a regulatory enzyme of polyol pathway, is a major mediator of allergen-induced asthma pathogenesis in mouse models. Here, using AR null (AR -/- ) mice we have investigated the effect of AR deficiency on the pathogenesis of ragweed pollen extract (RWE)-induced allergic asthma in mice and also examined the efficacy of enteral administration of highly specific AR inhibitor, fidarestat. Methods The wild type (WT) and AR -/- mice were sensitized and challenged with RWE to induce allergic asthma. AR inhibitor, fidarestat was administered orally. Airway hyper-responsiveness was measured in unrestrained animals using whole body plethysmography. Mucin levels and Th2 cytokine in broncho-alveolar lavage (BAL) were determined using mouse anti-Muc5A/C ELISA kit and multiplex cytokine array, respectively. Eosinophils infiltration and goblet cells were assessed by H&E and periodic acid Schiff (PAS)-staining of formalin-fixed, paraffin-embedded lung sections. T regulatory cells were assessed in spleen derived CD4 + CD25 + T cells population. Results Deficiency of AR in mice led to significantly decreased PENH, a marker of airway hyper-responsiveness, metaplasia of airway epithelial cells and mucus hyper-secretion following RWE-challenge. This was accompanied by a dramatic decrease in infiltration of eosinophils into sub-epithelium of lung as well as in BAL and release of Th2 cytokines in response to RWE-challenge of AR -/- mice. Further, enteral administration of fidarestat significantly prevented eosinophils infiltration, airway hyper-responsiveness and also markedly increased population of T regulatory (CD4 + CD25 + FoxP3 + ) cells as compared to RWE-sensitized and challenged mice not treated with fidarestat. Conclusion Our results using AR -/- mice strongly suggest the role of AR in allergic asthma pathogenesis and effectiveness of oral administration of AR inhibitor in RWE-induced asthma in mice supports the use of AR inhibitors in the treatment of allergic asthma.

The purpose of this study was to investigate the expression and distribution of superoxide anion, NADPH oxidase (NOX)1, and NOX4 in healthy, allergic nasal mucosa and nasal polyps to evaluate the possible influence of oxidative stress on the development of allergic rhinitis and nasal polyps. The expression and distribution of superoxide anion, NOX1 and NOX4 were evaluated in healthy and allergic nasal mucosa and nasal polyps, using dihydroethidium fluorescence, semiquantitative reverse transcriptase-polymerase chain reaction, immunohistochemistry, and Western blot. NOX1 and NOX4 were localized mainly in the epithelial layer, submucosal glands, vascular endothelium, and inflammatory cells in healthy and allergic nasal mucosa and nasal polyps. The cellular source that generated superoxide anion is also localized in the epithelial cells, submucosal glands, vascular endothelium, and inflammatory cells, demonstrating the similar sites of expression of NOX1 and NOX4 in healthy and allergic nasal mucosa and nasal polyps. NOX1 and NOX4 mRNA and proteins and superoxide anions had increased levels of expression in allergic nasal mucosa and nasal polyps compared with healthy nasal mucosa. These results indicate that NOX1 and NOX4 may play an important role in reactive oxygen species production, contributing to the oxidative stress in allergic rhinitis and nasal polyp tissues.