Possible role of HE4 level elevation in the pathogenesis of TH2-high asthma.

OBJECTIVES: As a heterogeneous disease, asthma is characterized by airway hyperresponsiveness, airway inflammation, and airway mucus hypersecretion. According to the pathological changes, symptoms, preventive and treatment methods, asthma can be divided into TH2-high and TH2-low asthma. We show that the expression of the tumor biomarker human epididymis protein 4 (HE4) was significantly increased in TH2-high asthma group, while there was no marked difference in its expression between TH2-low asthma and healthy control groups. HE4 levels were significantly increased in plasma, induced sputum, and alveolar lavage fluid (BALF) samples and airway epithelial cells from TH2-high asthma group, showing that HE4 has a possible role in the pathogenesis of TH2-high asthma. METHODS: Using RT-qPCR, ELISA, Western blot (WB), and immunohistochemistry, we assessed differences in HE4 expression in plasma, induced sputum, BALF, and airway epithelial cells among patients with the TH2-related asthma subtypes and healthy controls. To explore the role of HE4 in TH2-high asthma, we conducted a correlation analysis between HE4 levels in plasma, induced sputum, BALF, and airway epithelial cells and multiple indicators of airway eosinophilic inflammation, airway mucus secretion, and airway remodeling. CONCLUSION: We found for the first time that HE4 was differentially expressed in the TH2-related asthma subtypes. In TH2-high asthma, HE4 levels were markedly elevated in airway epithelial cells, plasma, induced sputum, and BALF. HE4 may play an important role in various pathogenic mechanisms of asthma, such as airway eosinophilic inflammation, airway mucus secretion, and airway remodeling. HE4 in plasma may be a clinically biomarker for differentiating TH2-related asthma subtypes.

Effect of Neurokinin-1 Receptor Knockdown on the Expression of RANTES in Allergic Rhinitis.

BACKGROUND: Neurokinin-1 receptor (NK-1R) and normal T cell expressed and secreted (RANTES) have been shown to play important roles in allergic rhinitis (AR). However, whether the regulating effect of NK-1R in AR is achieved via RANTES remains unknown. METHODS: In the present study, Sprague-Dawley rats were sensitized and challenged with ovalbumin to make AR models. During the challenge period, the rats were treated intranasally with NK-1R-specific small interfering RNA (siRNA) for NKR group, negative siRNA for NCS group, rats in NSAR group and NS group were given saline. The amount of nasal secretion and the numbers of nose rubs and sneezes were measured in each rat. The levels of NK-1R and RANTES in the nasal mucosal tissues were determined through real-time fluorescence quantitative RT-PCR and immunohistochemical staining. The numbers of eosinophils in the collected nasal lavage fluid (NLF) were counted, and the concentration of RANTES in NLF was determined by enzyme-linked immunosorbent assay. RESULTS: Compared with that in the NS group, the expression of NK-1R and RANTES was significantly higher in the nasal mucosa of NSAR and NCS group rats. The sneezing and nose rubbing counts and the amount of nasal secretions were increased significantly in the NSAR and NCS groups. Rats in the NKR group experienced greater relief from AR symptoms than rats in the NSAR and NCS groups. Furthermore, knockdown of NK-1R expression also significantly eliminated RANTES expression and eosinophil infiltration in the nasal mucosa of NKR group rats. CONCULSION: For the first time, we show that intranasal treatment with NK-1R-specific siRNA can significantly decrease RANTES expression, AR-related symptoms, and eosinophil inflammation, suggesting that the regulating effect of NK-1R in the development of AR occurs via alteration of RANTES expression.

Adult eosinophilic esophagitis and advances in its treatment.

Eosinophilic esophagitis (EoE) is a chronic eosinophil inflammation that seems to be T helper type 2 antigen-driven. The disease is one of several eosinophilic gastrointestinal disorders in which there appears to be inflammation of the gastrointestinal tract without any apparent underlying causes. Differential diagnosis needs to be made with gastroesophageal reflux, which is characterized by chronic inflammation due to gastric refluxate from disorders related to motility. EoE, however, is considered a chronic allergic inflammatory disorder related to destructive tissue remodeling. There seems to be a higher prevalence of EoE in Western countries. It is typically found in atopic male individuals. Physiopathological risk factors include atopy, environmental factors, esophageal epithelial barrier dysfunctions, etc. EoE can cause several symptoms that include retrosternal burning sensation, dysphagia, food impaction, chronic reflux symptoms, nausea, and vomiting. Early diagnosis, which requires a biopsy to assess for esophageal inflammation, is essential for proper treatment. The aim of our brief overview is to summarize the current literature regarding the characteristics, diagnosis, complications, mechanisms of pathology, clinical features, influence of comorbidities, and treatment in patients with EoE.

Increased expression of CSF1 in patients with eosinophilic asthma.

BACKGROUND: The link between colony-stimulating factor 1 (CSF1) and asthma was reported recently. However, the role and mechanism of CSF1 in asthma remain poorly understood. In this study, we aimed to explore the expression and its potential mechanism of CSF1 in asthma. METHODS: CSF1 expression in the airway samples from asthmatics and healthy controls were examined, then the correlations between CSF1 and eosinophilic indicators were analyzed. Subsequently, bronchial epithelial cells (BEAS-2B) with CSF1 overexpression and knockdown were constructed to investigate the potential molecular mechanism of CSF1. Finally, the effect of CSF1R inhibitor on STAT1 was investigated. RESULTS: The expression of CSF1 was significantly increased in patients with asthma compared to healthy controls, especially in patients with severe and eosinophilic asthma. Upregulated CSF1 positively correlated with airway-increased eosinophil inflammation. In vitro, cytokines interleukin 13 (IL-13) and IL-33 can stimulate the upregulation of CSF1 expression. CSF1 overexpression enhanced p-CSF1R/CSF1R and p-STAT1/STAT1 expression, while knockdown CSF1 using anti-CSF1 siRNAs decreased p-CSF1R/CSF1R and p-STAT1/STAT1 expression. Furthermore, the inhibitor of CSF1R significantly decreased p-STAT1/STAT1 expression. CONCLUSIONS: Sputum CSF1 may be involved in asthmatic airway eosinophil inflammation by interacting with CSF1R and further activating the STAT1 signaling. Interfering this potential pathway could serve as an anti-inflammatory therapy for asthma.

CD109 on Dendritic Cells Regulates Airway Hyperreactivity and Eosinophilic Airway Inflammation.

Asthma is a chronic airway inflammatory disease characterized by airway hyperreactivity (AHR) and eosinophilic airway inflammation. Dendritic cells (DCs) are essential for the development of asthma via presenting allergens, causing T-helper cell type 2 (Th2) skewing and eosinophil inflammation. Recent studies have revealed that CD109, a glycosylphosphatidylinositol-anchored glycoprotein, is involved in the pathogenesis of inflammatory diseases such as rheumatoid arthritis and psoriasis. However, no study has addressed the role of CD109 in asthma. This study sought to address the role of CD109 on DCs in the development of AHR and allergic inflammation. CD109-deficient mice (CD109-/-) were sensitized with house dust mite or ovalbumin and compared with wild-type mice for induction of AHR and allergic inflammation. CD109-deficient mice had reduced AHR and eosinophilic inflammation together with lower Th2 cytokine expression compared with wild-type mice. Interestingly, CD109 expression was induced in lung conventional DC2s (cDC2s), but not lung cDC1s, upon allergic challenge. Lung cDC2s from CD109-/- mice had a poor ability to induce cytokine production in ex vivo DC-T cell cocultures with high expression of RUNX3 (runt-related transcription factor 3), resulting in suppression of Th2 differentiation. Adoptive transfer of bone marrow-derived CD109-/- DCs loaded with house dust mite failed to develop AHR and eosinophilic inflammation. Finally, administration of monoclonal anti-CD109 antibody reduced airway eosinophils and significantly decreased AHR. Our results suggest the involvement of CD109 in asthma pathogenesis. CD109 is a novel therapeutic target for asthma.

Involvement of autophagy in exacerbation of eosinophilic airway inflammation in a murine model of obese asthma.

Obesity is a common comorbidity in patients with asthma, and obese asthma patients present the most refractory phenotype among patients with severe asthma. Similar to the observations in non-obese asthma patients, clinical studies have revealed heterogeneity in obese asthma patients, including the occurrences of T helper (Th)2-high and Th2-low phenotypes. However, the mechanisms underlying obesity-related asthma are not completely understood. Though macroautophagy/autophagy is involved in asthma and obesity, its role in obesity-associated asthma is unknown. We hypothesized that autophagy is involved in the pathogenesis of obese asthma. For our investigations, we used high-fat diet-induced Atg5 (autophagy related 5)-deficient mice and epithelial cell-specific atg5-/- (Scgb1a1/CCSP-atg5-/-) obesity-induced mice. House dust mite (HDM)-sensitized atg5-/- obese mice exhibited marked eosinophilic inflammation and airway hyper-reactivity (AHR), compared to wild-type (WT) obese mice. Analyses of atg5-/- obese mice showed increased levels of Th2 cells but not ILC2s together with elevated expression of Th2 cytokines in the lung. In response to the HDM challenge, activated epithelial autophagy was observed in lean but not obese WT mice. Epithelium-specific deletion of Atg5 induced eosinophilic inflammation in Scgb1a1/CCSP-atg5-/- obese mice, and genetic analyses of epithelial cells from HDM-immunized atg5-/- obesity-induced mice showed an elevated expression of thymic stromal lymphopoietin (TSLP) and IL33. Notably, HDM-sensitized atg5-/- mice developed TSLP- and IL33-dependent eosinophilic inflammation and AHR. Our results suggest that autophagy contributes to the exacerbation of eosinophilic inflammation in obese asthma. Modulations of autophagy may be a therapeutic target in obesity-associated asthma.Abbreviations: AHR: airway hyper-reactivity; BAL: bronchoalveolar lavage; Cdyn: dynamic compliance; BM: bone marrow; HDM: house dust mite; HFD: high-fat diet; ILC2s: type 2 innate lymphocyte cells; ROS: reactive oxygen species; RL: lung resistance; TSLP: thymic stromal lymphopoietin; TCC: total cell count; WT: wild type.

Eosinophil Inflammation and Hyperresponsiveness in the Airways as Phenotypes of COPD, and Usefulness of Inhaled Glucocorticosteroids.

Background: The differential diagnosis in persistent airway limitation is sometimes not so clear in older adults. Airway eosinophilia and airway hyperresponsiveness may develop in some cases with chronic obstructive lung disease (COPD), independent of asthma. However, little is known about clinical significance of these phenotypes of COPD in detail. Aims and objectives: This clinical study was designed to examine prevalence of airway eosinophilia and airway hyperresponsiveness in COPD who have no symptom and no past history of asthma, and to examine involvement of these pathophysiological features of asthma in the management and therapy for COPD. Methods: Sputum examination via qualitative and quantitative procedures was performed in stable COPD (GOLD 1-3). When sputum eosinophils were qualitatively (≥+) or quantitatively assessed (≥3%), ciclesonide (inhaled glucocorticosteroids) was added on bronchodilators. In cases with FEV1 ≥ 70% of predicted values, acetylcholine provocation test was examined for assessment of airway hyperresponsiveness. Therapeutic effect was evaluated using spirometry and COPD assessment test (CAT). Results: Sputum eosinophils were observed in 65 (50.4%) of 129 subjects using qualitative analysis; in contrast, lower grade (>0%) and higher grade (≥3%) were observed in 15 (20.3%) and 25 (33.8%) of 74 subjects using quantitative analysis. Airway hyperresponsiveness developed in 46.9% of these subjects with sputum eosinophils. Exacerbations occurred much more frequently in lower-grade airway eosinophilia without ciclesonide than in higher-grade airway eosinophilia with ciclesonide. Airway hyperresponsiveness significantly increased frequency of exacerbations in COPD with both lower and higher grade in airway eosinophilia. Addition of ciclesonide to indacaterol markedly improved lung function (FEV1, IC), CAT score, and reliever use in these subjects with airway eosinophilia determined by qualitative analysis. However, ciclesonide was less effective in improving these values in subjects with airway hyperresponsiveness than in those without airway hyperresponsiveness. Conclusions: Airway eosinophilia and airway hyperresponsiveness are complicated with 25-50% of COPD that have no symptom and history for asthma. These phenotypes of COPD are closely related to symptom stability and reactivity to glucocorticosteroids. These phenotypes may play key roles for advancement of the management and therapy of this disease.