Cell-Type-Specific Expression of Hyaluronan Synthases HAS2 and HAS3 Promotes Goblet Cell Hyperplasia in Allergic Airway Inflammation.

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.

Xinqin exhibits the anti-allergic effect through the JAK2/STAT5 signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Xinqin, a polyherbal medicine, is an important traditional Chinese herbal formula used in traditional oriental medicine for treatment of allergic rhinitis (AR). The formula is based on the Chinese Pharmacopoeia AIM OF THE STUDY: Previously, Xinqin exhibited potent anti-allergic effect in a guinea pig model of AR. In this study, we explored the molecular mechanism of the anti-allergic effect mediated by Xinqin. MATERIALS AND METHODS: AR was induced in guinea pigs (Hartley) with toluene-2, 4-diisocyanate (TDI) in vivo and in HMC-1 mast cells with A23187/phorbol 12-myristate-13-acetate (PMA) in vitro. The releases of allergic inflammatory mediators such as histamine, leukotriene (LT) D4, immunoglobulin (Ig) E, TNF-α, and IL-6 were analyzed for allergy. The mast cell degranulation was displayed in HMC-1 mast cells. The activities of janus protein kinase 2 (JAK2), signal transduction and activator of transcription 5 (STAT5) and suppressor of cytokine signaling 3 (SOCS3) were evaluated by Western blot. RESULTS: Treatment with Xinqin resulted in AR symptoms and decreases in levels of histamine, LTD4, IgE, TNF-α, and IL-6 in serum of guinea pig model of AR and in A23187/PMA-stimulated HMC-1 mast cells. Treatment with Xinqin also inhibited cell degranulation in A23187/PMA-stimulated HMC-1 mast cells. The JAK2/STAT5 signaling pathway could play an important role in the anti-allergic activity mediated by Xinqin. CONCLUSIONS: Xinqin exerts the anti-allergic effect by modulating mast cell-mediated allergic responses by down-regulating JAK2/STAT5 signaling pathway. Results from this study provide a mechanistic basis for the application of Xinqin in the treatment of AR.

Association between JAK1 gene polymorphisms and susceptibility to allergic rhinitis.

OBJECTIVES: 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. METHODS: 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). RESULTS: 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. CONCLUSION: 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.

Angiotensin-converting enzyme insertion/deletion polymorphism and susceptibility to allergic rhinitis in Chinese populations: a systematic review and meta-analysis.

In view of the controversies surrounding the angiotensin-converting enzyme (ACE)-allergic rhinitis (AR) association, a systematic review and meta-analysis of the ACE genetic association studies of AR was performed in Chinese populations. PubMed, Springer Link, OvidSP, Chinese biomedical database, Chinese national knowledge infrastructure, Chinese VIP and Wanfang databases were searched for related studies. A total of 4 studies including 415 AR patients and 309 controls were involved in this meta-analysis. Overall, significant association was found between ACE I/D polymorphism and AR risk when all studies in Chinese populations pooled into the meta-analysis (allele, OR 1.50, 95 % CI 1.19-1.90; homozygous, OR 2.59, 95 % CI 1.52-4.41, recessive, OR 2.05, 95 % CI 1.27-3.32). In the subgroup analysis by ethnicity, ACE I/D polymorphism was associated with significant elevated risks of AR in Chinese Han under homozygous and recessive models (homozygous, OR 4.36, 95 % CI 1.76-10.82, recessive, OR 2.51, 95 % CI 1.18-5.34). In conclusion, this meta-analysis provides the evidence that ACE I/D polymorphism may contribute to the AR development in Chinese populations and studies with large sample size and wider spectrum of population are warranted to verify this finding.

Serum indolamine 2,3 dioxygenase as a marker in the evaluation of allergic rhinitis.

BACKGROUND: Allergic rhinitis occurs on exposure to a known allergen and is correlated with a positive skin test and physical examination results. Tryptophan is a substrate of many important proteins, e.g., indolamine 2,3 dioxygenase (IDO). IDO, an immunomodulator, is a metabolic enzyme induced by immune activation. It has a significant role in allergic reactions. T-helper 2 cell is proposed to affect the expression of IDO. AIM: To evaluate IDO levels in patients with allergic rhinitis compared with controls and its relationship to the severity of allergic rhinitis. METHODS: This case-control study included 20 patients who were atopic and with allergic rhinitis who attended the allergy clinic of Ain Shams University Hospitals. Twenty age- and sex-matched patients who were not atopic were included as controls. An allergic rhinitis diagnosis was made according to the Allergic Rhinitis and its Impact on Asthma document. Complete history taking, physical examination, skin-prick test, complete blood cell count, erythrocyte sedimentation rate, total serum immunoglobulin E (IgE), IDO concentration, and nasal smear for eosinophils were done for the patients. RESULTS: There was a significant increase in IDO levels in allergic rhinitis in comparison with subjects without allergy (p < 0.001). IDO was positively correlated with total IgE levels (p < 0.037). There was an insignificant relationship among IDO levels and age, sex, duration of the disease, severity score, nasal and blood eosinophilia, and number of positive allergens. CONCLUSION: IDO plays an important role in patients with atopic symptomatic allergic rhinitis, especially with increased levels of IgE. There is no relationship between IDO levels and severity of disease.

[Expression of AMCase mRNA in nasal mucosa of allergic rhinitis in SD rats].

OBJECTIVE: To examine AMCase mRNA expression levels in nasal mucosa of allergic rhinitis SD rats. METHOD: Thirty SD rats were chosen and randomly divided into the experimental group and the control group. 20 in experimental group and 10 in the control group. AR model rats were established through repeated intraperitoneal shot of ovalbumin (OVA) for 2 weeks and consequently confirmed by local challenge with OVA for 1 week. The control group was treated by the same method with Physiological saline water instead of OVA. After the last excitation allergic rhinitis was diagnosed according to the accumulation score about nasal symptom. The septal mucosa of all rats were used to diagnose pathologically by HE dyeing. AMCase mRNA in nasal mucosa, obtained from the bilateral nasal mucosa in two groups, were used to do reverse transcriptive polymerase chain reaction. Real-time polymerase chain reaction was used to examine AMCase mRNA expression levels. RESULT: (1) The results showed definitely that there were positive expression of AMCase mRNA in normal nasal mucosa. This expression increase significantly during nasal allergy (P < 0.05). (2) The increased expression of AMCase mRNA in allergic rhinitis are related with the nasal symptoms score (r = 0.411, P < 0.05). CONCLUSION: Increased expression of AMCase mRNA in nasal mucosa in allergic rhinitis model might play roles in the pathogenesis of AR, and Restrain the enzyme activity could become new treatment targets of allergic rhinitis.

[The promoting research of phospholipase C epsilon-1 on nasal Th2 cell polarization].

Phospholipase C epsilon-1 (PLCE1) is a phospholipase C isoenzyme encoded by PLCE1 gene, and has more complicated molecular structure and function than other subtypes. Phospholipase C epsilon-1 is accepted the dual regulation by the upstream G proteins and GTP enzymes of Ras family. The downstream signal of PLCE1 is not only cause the Ca2+ flow and protein kinase C(PKC) activation, but also can be used as the GTP enzyme guanylic acid conversion factor of Ras superfamily, so as to regulate the expression of certain genes, adjusting cell growth and differentiation processes. PLCE1 plays a very important role in the signal transduction in the regulation of cell growth, differentiation, proliferation and apoptosis. Previous studies showed that phospholipase C epsilon-1 played an important role in the development of malignant tumors (especially the digestive tumors), heart disease, nephrotic syndrome and other diseases, but there are some questions about the mechanisms of PLCE1 involved in allergic rhinitis, this article will make an overview about PLCE1 promotes allergic rhinitis CD4+ T cells differentiate to Th2 cells by PKC-NF-κB pathway and Ras-MAPK pathway.

The step further to understand the role of cytosolic phospholipase A2 alpha and group X secretory phospholipase A2 in allergic inflammation: pilot study.

Allergens, viral, and bacterial infections are responsible for asthma exacerbations that occur with progression of airway inflammation. cPLA2 α and sPLA2X are responsible for delivery of arachidonic acid for production of eicosanoids-one of the key mediators of airway inflammation. However, cPLA2 α 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 cPLA2 α 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 cPLA2 α 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 cPLA2 α protein expression. rFel d1 caused decrease in cPLA2 α 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.

Nasal polyp chitinolytic activity associated with smoking or allergy.

BACKGROUND: Cells of the innate immune system that are implicated in allergy and immunity bind to chitin during tissue infiltration in a process negatively regulated by vertebrate chitinases. Both acidic mammalian chitinase (AMCase) and chitotriosidase (ChT) exert chitinolytic activity. The levels of activities of these enzymes in nasal polyps (NPs) of subjects who smoke or who suffer from allergies are unknown. In the present work, we measured the activities of AMCase and ChT in NPs of smokers and allergic subjects. METHODS: We report a prospective cohort study in a tertiary care facility. AMCase and ChT activities of NPs were measured in buffers of several pH values using the fluorogenic substrate 4-methylumbelliferyl-ß-d-N,N',N″-triacetyl-chitotriose. RESULTS: The activities of AMCase and ChT in NPs did not differ significantly among smokers, nonsmokers, and ex-smokers. AMCase and ChT activities were significantly higher in NPs of allergic subjects than in NPs of those who did not suffer from allergy. CONCLUSION: Increased levels of chitinolytic activities in NPs were associated with the allergic rhinitis. We suggest that control of such rhinitis may help to prevent the development and growth of NPs.

Angiotensin-converting enzyme insertion/deletion polymorphism associated with allergic rhinitis susceptibility: evidence from 1410 subjects.

BACKGROUND AND OBJECTIVE: Whether the insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene increases susceptibility to allergic rhinitis (AR) is still undetermined. Therefore, this meta-analysis was performed to systematically assess the possible association between them. METHODS: The OVID, Medline, Embase, Web of Science, CNKI and Wangfang databases were searched to identify the eligible studies focusing on the association between ACE I/D polymorphism and susceptibility to AR. RESULTS: A total of 1410 subjects from six studies were subjected to meta-analysis. In the overall analysis, ACE I/D polymorphism had a statistically significant association with increased AR risk under all genetic models (p<0.05). In the subgroup analysis by ethnicity, significant elevated AR risks were associated with ACE I/D polymorphism in Asians under all genetic models (p<0.05) and in Caucasians under under allele contrast, homozygous comparison and recessive models (p<0.05). In the subgroup analysis by age, ACE I/D polymorphism was associated with significant elevated risks of AR in adults (p<0.05) but not in children (p>0.05) under all genetic models. CONCLUSIONS: The ACE I/D polymorphism may be a risk factor for AR and studies with large sample size and representative population are warranted to verify this finding.