[Importance of aspirin challenges in patients with NSAID-exacerbated respiratory disease]. / Stellenwert von ASS-Provokationen beim Analgetika-Intoleranz-Syndrom.

BACKGROUND: Nonsteroidal anti-inflammatory drug-exacerbated respiratory disease (N-ERD) is often characterized by a severe course of chronic rhinosinusitis with nasal polyps (CRSwNP), comorbid asthma, and NSAID hypersensitivity. The gold standard for N-ERD diagnosis is challenge with acetylsalicylic acid (ASA). In expert recommendations, the diagnosis of N-ERD is established based on a plausible positive history of NSAID hypersensitivity and CRSwNP with asthma. OBJECTIVE: The following review describes the performance of ASA challenges and their sensitivity and specificity. It also examines the extent to which a positive history of NSAID hypersensitivity correlates with ASA challenge results in clinical trials and when ASA challenges should be performed. RESULTS AND CONCLUSION: ASA challenges have high sensitivity and specificity. In clinical ASA challenge studies, there is a high concordance between a positive history of NSAID hypersensitivity obtained by rhinologists and the measured data of ASA challenge in patients with CRSwNP and comorbid asthma. Therefore, ASA challenge is primarily indicated in patients with an unclear history of NSAID hypersensitivity.

Nasal hyperreactivity in allergic rhinitis and chronic rhinosinusitis with polyps: a role for neuronal pathways.

BACKGROUND: Nasal hyperreactivity (NHR) is prevalent in all chronic upper airway inflammatory phenotypes, including allergic rhinitis (AR) and chronic rhinosinusitis with nasal polyps (CRSwNP). Although NHR in patients with non-allergic rhinitis is mediated by neuronal pathways, AR and CRSwNP are mainly characterized by type 2 inflammation. METHODS: Eighteen healthy controls and 45 patients with symptomatic AR/CRSwNP underwent a cold, dry air (CDA) provocation test for objective diagnosis of NHR. Before and after, questionnaires were filled out and nasal secretions and biopsies were collected. Markers for neurogenic inflammation (substance P, calcitonin gene-related peptide, neurokinin A), epithelial activation (IL-33), and histamine were measured in secretions by ELISA; and expression of neuronal markers PGP9.5, TRPV1, and TRPM8 was studied in biopsies by RT-q-PCR. Effects of histamine on TRPV1/A1 were studied with Ca2+-imaging using murine trigeminal neurons. RESULTS: CDA-provocation reduced peak nasal inspiratory flow (PNIF) of patients with subjective NHR but not of non-NHR controls/patients CDA-provocation reduced peak nasal inspiratory flow (PNIF) of patients with subjective NHR but not of non-NHR controls/patients. Subjective (subjectively reported effect of CDA) and objective (decrease in PNIF) effects of CDA were significantly correlated. Levels of neuropeptides and histamine in nasal secretions and mRNA expression of PGP9.5, TRPV1, and TRPM8 correlated with CDA-induced PNIF-reduction. CDA-provocation induced an increase in IL-33-levels. Both TRPV1 and TRPA1 expressed on afferent neurons were sensitized by exposure to histamine. CONCLUSION: NHR is not an on/off phenomenon but spans a continuous spectrum of reactivity. A neurogenic inflammatory background and increased histamine-levels are risk factors for NHR in AR/CRSwNP.

[Evaluation of subjective scale in allergen nasal provocation test].

Objective:To compare the clinical value of visual analogue scale （VAS）, Lebel scale and total nasal symptom scores （TNSS） in evaluating nasal allergen provocation test （NAPT）. Methods:A total of 151 patients suspected of allergic rhinitis admitted to the Department of Otolaryngology-Head and Neck Surgery of our hospital from April 2020 to September 2020 were included, of which 76 were positive for house dust mites and 75 were negative for allergens. Nasal airway resistance（NAR） was measured by active anterior nasal manometry. Nasal symptoms were evaluated by VAS, Lebel and TNSS. House dust mite allergen was used for NAPT by spray method. An increase≥40% in NAR was used as the gold standard for objective evaluation of NAPT. ROC curves of VAS, Lebel and TNSS were drawn to compare the evaluation effectiveness of different subjective evaluation methods, and the optimal critical point of each ROC curve was obtained. Results:With NAR increased by ≥40% as the gold standard, the area under ROC curve of VAS was 0.884, and the sensitivity and specificity were 97.75% and 80.65%, respectively. The area under ROC curve of Lebel was 0.773, and the sensitivity and specificity were 68.54% and 75.81%, respectively. The area under ROC curve of TNSS was 0.792, and the sensitivity and specificity were 68.54% and 79.03%, respectively. There was no significant difference between Lebel and TNSS（P>0.05）. The VAS differed significantly from Lebel and TNSS（P<0.05）. The Kappa values of VAS, Lebel, TNSS and NAR were 0.803, 0.432 and 0.459, respectively. Conclusion:The VAS, Lebel, TNSS subjective scale and NAR are consistent in evaluating the efficacy of NAPT, with the VAS assessment showing highest consistency with NAR. As objective assessment instruments are not widely used in China, subjective assessment method could be adopted to evaluate the efficacy of NAPT in clinical practice, and VAS scale is recommended as a priority.

[Value of allergen nasal provocation test in assessment of the efficacy of house dust mites specific immunotherapy].

Objective:To investigate the value of nasal provocation test（NPT） in evaluating the efficacy of allergen immunotherapy（AIT） in patients with dust mite induced allergic rhinitis（AR）. Methods:A total of 83 patients with dust mite induced AR with/without asthma were included. Symptom score（SS）, daily medication score（DMS）, combined symptom and medication score（CSMS）, rhinoconjunctivitis quality of life questionnaire（RQLQ）, NPT and skin prick test（SPT） were assessed before and after 1 year AIT. Results:There were statistical differences in SS（P<0.000 1）, DMS（P<0.000 1）, CSMS（P<0.000 1）, and RQLQ（P<0.000 1） after 1 year of AIT compared with pre-treatment. The effective rate of CSMS was 73.49%, and the effective rate of NPT was 42.17%. CSMS was consistent with NPT in efficacy assessment（Kappa=0.437, P<0.001）; while in 54 patients with pre-treatment NPT concentrations other than the original concentration, CMSM and NPT showed better consistence（Kappa=0.895, P<0.001）. Among the 48 patients with ineffective NPT assessment in the first year, 25 patients completed the second-year follow-up, and 12 patients（48.00%） showed effective in NPT. However, 10 out of 12 patients（83.33%） with NPT concentration other than original solution pre-treatment showed effective NPT at the second year. Conclusion:NPT can be used as one of the indicators for efficacy evaluation for dust mite induced AR patients, especially for patients with positive NPT induced at lower concentrations before treatment.

[Research progress and clinical application of allergen nasal provocation test].

The allergen nasal provocation testing（NPT）, in which allergens are applied directly to the nasal mucosa under standard and controlled conditions to provoke the main symptoms of allergic rhinitis（AR）, reproduces the response of the upper respiratory tract to natural exposure to allergens under controlled conditions and is the only test currently available to confirm nasal reactivity to allergens. It is invaluable in studying the mechanisms of AR and in assessing the response to novel anti-allergic treatments. The test may play an increasingly important role in clinical practice, especially in the identification of local AR, the diagnosis of occupational AR, the clarification of the composition of allergens, the assessment of the efficacy of AR treatment and the selection of candidates undergoing allergen immunotherapy. This article reviewed the application of NPT in the diagnosis of allergic and non-allergic rhinitis, and also introduces the indications, contraindications, advantages and limitations of NPT in evaluating nasal response.

Rinite alérgica persistente com elevada sensibilização a pólen de gramíneas: a medicina personalizada pode identificar os verdadeiros alérgicos a polens na imunoterapia / Persistent allergic rhinitis with high sensitization to grass pollen: personalized medicine can identify immunotherapy patients who are truly allergic to pollen

Este trabalho teve como objetivo avaliar pacientes com rinite alérgica persistente, sensibilizados a ácaros domésticos, associado à elevada sensibilização por pólen de gramíneas, sem sintomatologia estacional. Usou-se como método o diagnóstico molecular por componentes para selecionar os verdadeiramente alérgicos ao pólen de gramíneas. Foi realizado um estudo retrospectivo com análise de prontuários de pacientes em áreas de Caxias do Sul e municípios próximos no estado do RS, nos anos de 2016 e 2017, com as mesmas características climáticas. Foram selecionados 50 pacientes com alergia a ácaros, através de teste de punctura (pápula > 5 mm) associado ao pólen de gramíneas (pápula de > 7 mm) sem sintomatologia na primavera. Um total de 52% era do sexo feminino, a idade variou entre 4 e 56 anos, com uma média de 26,6 anos. Pesquisou-se a dosagem de IgE específica no soro para antígenos moleculares de pólen de gramíneas como estes: Phl p1, Phl p5, Cyn d1, em todos os pacientes. Houve 13 pacientes (26%) com diagnóstico, pelo menos, a um dos antígenos moleculares estudados. A amostra restringida apresentou 5 (10%) deles que possuíam Phl p5 > Phl p1, ou seja, eram verdadeiramente alérgicos à subfamília Poideae, enquanto 2 (4%) apresentaram Cyn d1 (subfamília Chloridoideae) > Phl p1. O estudo mostra que, em pacientes com rinite alérgica persistente, polissensibilizados a ácaros associados a pólen de gramíneas, sem sintomas estacionais característicos, os testes moleculares podem diagnosticar os verdadeiros alérgicos ao pólen.

This study aimed to evaluate patients with persistent allergic rhinitis who are sensitized to house mites and have high sensitization to grass pollen without seasonal symptoms. Molecular diagnosis was used to determine patients truly allergic to grass pollen. This retrospective study analyzed the medical records of patients from areas of Caxias do Sul and nearby municipalities (all with the same climatic characteristics) in the state of Rio Grande do Sul, Brazil between 2016 and 2017. Fifty patients allergic to dust mites were selected through a prick test (papule > 5 mm) and grass pollen (papule > 7 mm), but were asymptomatic in the spring. A total of 52% were female, and their ages ranged from 4 to 56 (mean 26.6) years. Specific serum IgE levels for grass pollen antigens, such as Phl p1, Phl p5, and Cyn d1, were investigated in all patients. Thirteen patients (26%) were diagnosed with at least one studied molecular antigen. The restricted sample included 5 (10%) patients with Phl p5 > Phl p1, ie, truly allergic to the Pooideae subfamily, while 2 (4%) had Cyn d1 (Chloridoideae subfamily) > Phl p1. The results indicate that among patients with persistent allergic rhinitis polysensitized to mites and grass pollen but without characteristic seasonal symptoms, molecular tests can diagnose those who are truly allergic to pollen.

Development of nasal allergen challenge with cockroach in children with asthma.

BACKGROUND: Nasal allergen challenge (NAC) could be a means to assess indication and/or an outcome of allergen-specific therapies, particularly for perennial allergens. NACs are not commonly conducted in children with asthma, and cockroach NACs are not well established. This study's objective was to identify a range of German cockroach extract doses that induce nasal symptoms and to assess the safety of cockroach NAC in children with asthma. METHODS: Ten adults (18-37 years) followed by 25 children (8-14 years) with well-controlled, persistent asthma and cockroach sensitization underwent NAC with diluent followed by up to 8 escalating doses of cockroach extract (0.00381-11.9 µg/mL Bla g 1). NAC outcome was determined by Total Nasal Symptom Score (TNSS) and/or sneeze score. Cockroach allergen-induced T-cell activation and IL-5 production were measured in peripheral blood mononuclear cells. RESULTS: 67% (6/9) of adults and 68% (17/25) of children had a positive NAC at a median response dose of 0.120 µg/mL [IQR 0.0380-0.379 µg/mL] of Bla g 1. Additionally, three children responded to diluent alone and did not receive any cockroach extract. Overall, 32% (11/34) were positive with sneezes alone, 15% (5/34) with TNSS alone, and 21% (7/34) with both criteria. At baseline, NAC responders had higher cockroach-specific IgE (P = .03), lower cockroach-specific IgG/IgE ratios (children, P = .002), and increased cockroach-specific IL-5-producing T lymphocytes (P = .045). The NAC was well tolerated. CONCLUSION: We report the methodology of NAC development for children with persistent asthma and cockroach sensitization. This NAC could be considered a tool to confirm clinically relevant sensitization and to assess responses in therapeutic studies.

Effect of LTRA in L-ASA Challenge for Aspirin-Exacerbated Respiratory Disease Diagnosis.

BACKGROUND: Aspirin-exacerbated respiratory disease (AERD) consists of asthma, chronic rhinosinusitis with polyps, and hypersensitivity to aspirin and/or nonsteroidal anti-inflammatory drugs (NSAIDs). Nasal Lysine Aspirin Challenge is an effective tool for the diagnosis of hypersensitivity to aspirin and/or NSAIDs in patients with AERD. However, there is no unified international consensus version to perform nasal provocation tests (NPTs). OBJECTIVE: To investigate the effect of a leukotriene receptor antagonist (LTRA), montelukast, on the lysine-acetylsalicylate (L-ASA) nasal challenge. METHODS: We included 86 patients divided into 3 samples: group A (AERD without LTRA), group B (AERD with LTRA), and the control group (NSAID-tolerant asthmatics). NPT with L-ASA was performed with 25 mg of L-ASA every 30 minutes 4 times followed by rhinomanometry and spirometric measurements and evaluation of symptoms using a novel clinical scale. RESULTS: In group A, 94.5% of patients (35 of 37) developed a positive response to NPT (drop >40% in total nasal flow), whereas only 46% of group B subjects (13 of 28) showed a positive response to the nasal challenge (P < .001). Control subjects did not show any response to the L-ASA challenge. A novel clinical score demonstrated accuracy in classifying the hypersensitivity to aspirin and/or NSAIDs when patients avoid LTRA (33 of 37). CONCLUSION: Patients with AERD without LTRA showed a greater positive response to the L-ASA challenge than those taking this drug; therefore, LTRA treatment should be discontinued before the challenge for optimal diagnostic accuracy.

[Study on the diagnosis of idiopathic rhinitis by cold dry air provocation].

Objective:This study aimed to compare the nasal response of cold dry air（CDA） provocation in patients with idiopathic rhinitis（IR） and healthy individuals, and further assess its ability in diagnosing IR. Method:CDA provocation was performed among 15 healthy volunteers and 17 IR patients from Beijing Tongren Hospital Outpatient Department. Nasal symptom scores, total nasal volume（TNV）, total nasal resistance（TNR） and minimal cross-sectional area（MCA） were checked before and after the provocation. Logistic regression analysis and Receiver Operating Characteristic（ROC） curves were used in data evaluation. Result:Subjects in the IR group showed significantly larger changes after CDA provocation in total nasal symptom score（TNSS）, total nasal resistance（TNR）, minimal cross-sectional area（MCA） and total nasal volume（TNV）, compared with healthy volunteers. We built a predictive model for IR, Y=0.394×ΔTNSS-0.061 ×ΔTNV（%）+0.014×ΔTNV（%） -2.318, whose area under curve was 0.919 based on multi-factor logistic regression and ROC curve. According to the Youden index, the cut-off criteria was set to be Y >0.49, when its sensitivity and specificity were 82.4% and 84.6%, respectively. Conclusion:Aggravated nasal symptoms and decreased nasal ventilation could be seen after CDA provocation in the IR population. The CDA provocation provides a possible method for assisting the diagnosis of IR, and we'll expand the sample size in future research to verify its clinical application value.

Gene Expression Analysis to Investigate Biological Networks Underlying Nasal Inflammatory Dysfunctions Induced by Diesel Exhaust Particles Using an In Vivo System.

OBJECTIVES: Diesel exhaust particles (DEP)s are notorious ambient pollutants composed of a complex mixture of a carbon core and diverse chemical irritants. Several studies have demonstrated significant relationships between DEP exposure and serious nasal inflammatory response in vitro, but available information regarding underlying networks in terms of gene expression changes has not sufficiently explained potential mechanisms of DEP-induced nasal damage, especially in vivo. METHODS: In the present study, we identified DEP-induced gene expression profiles under short-term and long-term exposure, and identified signaling pathways based on microarray data for understanding effects of DEP exposure in the mouse nasal cavity. RESULTS: Alteration in gene expression due to DEP exposure provokes an imbalance of the immune system via dysregulated inflammatory markers, predicted to disrupt protective responses against harmful exogenous substances in the body. Several candidate markers were identified after validation using qRT-PCR, including S100A9, CAMP, IL20, and S100A8. CONCLUSIONS: Although further mechanistic studies are required for verifying the utility of the potential biomarkers suggested by the present study, our in vivo results may provide meaningful suggestions for understanding the complex cellular signaling pathways involved in DEP-induced nasal damages.

Diagnostic approach to occupational rhinitis: the role of nasal provocation tests.

PURPOSE OF REVIEW: The diagnosis of occupational rhinitis is a challenge. Underdiagnosis is substantial as the clinical presentation is nonspecific and often no occupational history is taken. Detection of occupational rhinitis can be improved by including screening questions on occupational exposure in the assessment of every patient with adult-onset rhinitis. RECENT FINDINGS: Case reports, case series and epidemiological studies continuously demonstrate new sensitizers and irritants capable of inducing allergic or nonallergic (irritant-induced) occupational rhinitis. Recent reviews have focused on the value of immunological tests with specific IgE, skin prick tests or basophil activation tests in demonstrating sensitization to occupational agents. Nasal provocation tests (NPT) can establish a definite diagnosis of allergic occupational rhinitis. Several NPT guidelines have been published, however, focusing exclusively on standardized high-molecular weight allergens. When performing NPT with nonstandardized agents -- like most occupational sensitizers -- adapted protocols are needed. SUMMARY: We provide pragmatic guidance to clinicians taking care of rhinitis patients on how to diagnose occupational rhinitis, based on recent insights from the literature. We focus on the challenges in the diagnostic work-up, on how to identify suspected causes, and on the role of NPT.

Monocytes accumulate in the airways of children with fatal asthma.

BACKGROUND: Activated T helper type 2 (Th2) cells are believed to play a pivotal role in allergic airway inflammation, but which cells attract and activate Th2 cells locally have not been fully determined. Recently, it was shown in an experimental human model of allergic rhinitis (AR) that activated monocytes rapidly accumulate in the nasal mucosa after local allergen challenge, where they promote recruitment of Th2 cells and eosinophils. OBJECTIVE: To investigate whether monocytes are recruited to the lungs in paediatric asthma. METHODS: Tissue samples obtained from children and adolescents with fatal asthma attack (n = 12), age-matched non-atopic controls (n = 9) and allergen-challenged AR patients (n = 8) were subjected to in situ immunostaining. RESULTS: Monocytes, identified as CD68+S100A8/A9+ cells, were significantly increased in the lower airway mucosa and in the alveoli of fatal asthma patients compared with control individuals. Interestingly, cellular aggregates containing CD68+S100A8/A9+ monocytes obstructing the lumen of bronchioles were found in asthmatics (8 out of 12) but not in controls. Analysing tissue specimens from challenged AR patients, we confirmed that co-staining with CD68 and S100A8/A9 was a valid method to identify recently recruited monocytes. We also showed that the vast majority of accumulating monocytes both in the lungs and in the nasal mucosa expressed matrix metalloproteinase 10, suggesting that this protein may be involved in their migration within the tissue. CONCLUSIONS AND CLINICAL RELEVANCE: Monocytes accumulated in the lungs of children and adolescents with fatal asthma attack. This finding strongly suggests that monocytes are directly involved in the immunopathology of asthma and that these pro-inflammatory cells are potential targets for therapy.

Provocation test with 5% glycerol has fast and fleeting effects on the nasal mucosa / Teste de provocação com glicerol 5%: efeito rápido e fugaz na mucosa nasal

The effects observed with nasal provocation testing using 5% glycerol were associated only with irritation/burning sensation within the first few minutes, reducing spontaneously and disappearing quickly. The use of 5% glycerol was found to have no influence on the prevalence of nasal obstruction, rhinorrhea, sneezing and nasal/ocular itching obtained through summing symptoms, as evaluated in different nasal provocation tests, after 15-20 minutes. Overall, dilution with 5% glycerol did not change the final score for symptoms during nasal provocation testing.

Os efeitos observados com glicerol a 5% na provocação nasal foram associados unicamente a irritação e sensação de prurido nos primeiros minutos, cedendo espontaneamente e desaparecendo rapidamente. O uso de glicerol a 5% não influenciou a prevalência de obstrução nasal, rinorreia, espirros e prurido nasal e ocular obtidos na soma dos sintomas, quando avaliado em diferentes testes de provocação nasal específica, após 15-20 minutos. Tomada em conjunto, essa diluição com glicerol a 5% não altera a pontuação final dos sintomas durante a provocação nasal.

Differences in cytokine levels between the nasal polyps of adolescents with local allergic and adolescents with allergic or nonallergic rhinitis.

BACKGROUND: Local allergic rhinitis (LAR) is rhinitis with a localized nasal allergic response in the absence of systemic allergy. This study aimed to evaluate the pathogenesis specific to LAR compared with allergic rhinitis (AR) and nonallergic rhinitis (NAR) by using cytokines from polypous tissues. METHODS: We recruited 43 patients with AR (n = 15; mean age, 17.4 years), LAR (n = 12; mean age, 15.9 years), and NAR (n = 16; mean age, 15.6 years) who underwent polypectomy. Atopic status was defined as presenting a sufficiently high total immunoglobulin E (IgE) serum concentration and skin-prick test or serum allergen test. Immunoassays were performed by using polyp tissue homogenates to quantify the levels of regulated on activation of normal T cell expressed and secreted (RANTES), tumor necrosis factor (TNF) alpha, interleukin (IL) 5, and sera to assess total IgE and eosinophil cationic protein. RESULTS: RANTES levels were higher in patients with LAR than in patients with AR and NAR. There was a significant correlation in the concentration of RANTES between polyp tissue homogenates and serum (R2 = 0.51, p < 0.05). The levels of IL-5, TNF alpha, and interferon gamma also demonstrated positive correlations between polyp tissue homogenates and serum; however, they were not significantly different. CONCLUSION: Results of our study indicated that RANTES may play an important role and contribute to allergic reaction in LAR, and RANTES may be related to the pathogenesis of LAR.

Females have stronger neurogenic response than males after non-specific nasal challenge in patients with seasonal allergic rhinitis.

Epidemiological studies show female predominance in the prevalence of non- allergic rhinitis (NAR) and local allergic rhinitis (LAR). Experimental studies show female patients with allergic rhinitis (AR) demonstrate higher levels of sensitivity to irritants and airway hyperresponsiveness than males. Bronchial asthma shows female predominance in post-puberty patients, and gender interaction with severe asthma endotypes. Fibromyalgia, chronic fatigue syndrome, migraine and chronic cough, syndromes, which are commonly related to neurokinin substance P (SP) in the literature, also show strong female predominance. Studies have demonstrated that sex hormones, primarily oestrogens, affect mast cell activation. Mast cell proteases can amplify neurogenic inflammatory responses including the release of SP. Based on human epidemiological data and animal experimental data we hypothesized that female patients have different interaction between mast cell activation and neurogenic inflammation, i.e. substance P release, resulting in a different nasal symptom profile. To test the hypothesis we performed allergen and non-specific nasal challenges in patients with seasonal allergic rhinitis (SAR) out of season and looked for gender differences in subjective and objective responses. The interaction between subjective and objective reactivity was evaluated through the comparison of subjective symptom scores, concentrations of neurokinin substance P (SP) and cellular markers in nasal lavages after low doses of nasal allergen challenges. Female allergic subjects tended to have higher substance P (SP) concentrations both before and after non-specific challenges. The difference between post-allergen and post - hypertonic saline (HTS) challenge was highly significant in female patients (p = 0.001), while insignificant in male subjects (p = 0.14). Female patients had significantly stronger burning sensation after HTS challenge than male. These data indicate difference in the interaction between inflammatory cells and the neurogenic response, which is gender- related, and which may affect symptom profiles after challenges. Different regulation of neurogenic inflammation in females may have impact on symptoms and endotyping in respiratory disorders, not only in allergic rhinitis, but also asthma, chronic rhinosinusitis and irritant -induced cough.

[The influence of cold dry air on nasal mucosa].

Nonspecific nasal hyperreactivity (NHR) has been widespread observed in patients with allergic rhinitis (AR) and nonallergic rhinitis (NAR). As a clinical hallmark, NHR is more common in patients with NAR. The cold dry air (CDA) can stimulate nasal symptoms such as rhinorrhea and nasal obstruction, and the CDA provocation test can be used as a reliable objective method to evaluate NHR. The mechanism of CDA-induced nasal symptoms is very complicated and thus it has not yet been fully illuminated. The innervation of the nasal nerves includes sensory nerve (trigeminal ganglion), sympathetic nerve (superior cervical ganglion) and parasympathetic nerve (sphenopalatine ganglion). CDA innervation may also be associated with these nerves and associated signal pathway. Recently, general attention has been focused on the transient receptor potential (TRP) channel, including TRP vanilloid-1 (TRPV1) and TRP ankyrin-1 (TRPA1). More relevant researches are needed to further clarify the mechanism.

Activin-A Is a Pro-Inflammatory Regulator in Type-2-Driven Upper Airway Disease.

BACKGROUND: Allergic upper airway disease involves pro-inflammatory type-2 cytokines such as IL-5 and regulatory tissue repair mediators, in particular transforming growth factor (TGF)-ß1. The TGF-ß-superfamily member activin-A displays multiple biological functions and shares certain signalling pathways with TGF-ß1. We aimed to examine the coregulation of mucosal activin-A and TGF-ß1 in acute allergic and chronic Th2-driven upper airway disease. METHODS: We investigated mucosal cytokine expression profiles and kinetics using RT-PCR after nasal allergen challenges in patients with seasonal allergic rhinitis. Furthermore, we analysed mucosal specimens from patients with chronic upper airway disease with nasal polyps using ELISPOTs and confocal microscopy. In addition, we stimulated nasal mucosa ex vivo from patients with nasal polyps as well as primary nasal cell cultures from healthy donors. RESULTS: Mucosal activin-A expression revealed increasing correlation with IL-5 and TGF-ß1 at 0.25, 6, and 24 h, respectively, and was significantly upregulated at 6 h after allergen challenge. The correlated expression was found to be more pronounced in chronic disease with nasal polyps, showing substantially (48-fold) increased activin-A-producing cells in nasal polyps by ELISPOT, while submucosal downstream signalling as determined by confocal microscopy was decreased. Ex vivo stimulations of nasal tissue suggested that activin-A and TGF-ß1 mutually regulate each other's expression at the mRNA level and, when combined, enhance IL-5 expression. CONCLUSION: Activin-A in allergic upper airway disease acts as a pro-inflammatory mediator and TGF-ß1 modifier. Our data in the upper airways oppose the view of potentially anti-inflammatory properties in contrast to lymphatic compartments.