A shift in the IL-6/STAT3 signalling pathway imbalance towards the SHP2 pathway in severe asthma results in reduced proliferation process

BackgroundBronchial fibroblasts are the main structural cells responsible for extracellular matrix production and turnover in lung tissue. They play a key role in airway remodelling in asthma through different cytokines including interleukin (IL-6).ObjectiveTo decipher IL-6 signalling in bronchial fibroblasts obtained from severe eosinophilic asthmatics compared to mild asthmatics and healthy controls.MethodsHuman bronchial fibroblasts were isolated from bronchial biopsies of mild and severe eosinophilic asthmatics and non-atopic healthy controls. IL-6 was assessed by qRT-PCR and ELISA. Phosphorylated STAT3, SHP2 and p38/MAPK were evaluated by Western blot. Chemical inhibitors for SHP2 and p38 were used. Fibroblast proliferation was evaluated by BrdU incorporation test.ResultsIL-6 release was significantly increased in fibroblasts from mild and severe asthmatics compared to healthy controls. Fibroblasts from severe asthmatics showed a reduced STAT3 activation compared to mild asthmatics and healthy controls. Constitutive activation of phosphatase SHP2 was found to negatively regulate IL-6 induced STAT3 phosphorylation in fibroblasts from severe asthmatics. This effect was accompanied by a decrease in fibroblast proliferation rate due to the activated p38/mitogen-activated protein kinase. SHP2 and p38/MAPK specific inhibitors (PHPS1 and SB212190) significantly induce a restoration of STAT3 phosphorylation, IL-6 target gene expression and cell proliferation.ConclusionThese data show dysregulated IL-6 signalling in bronchial fibroblasts derived from severe eosinophilic asthmatic subjects involving the protein tyrosine phosphatase SHP2 and p38MAPK. Collectively, our data provides new insights into the mechanisms by which bronchial fibroblasts regulate airway remodelling in severe asthma.     

Modulation of interleukin expression by medicinal plants and their secondary metabolites: A systematic review on anti-asthmatic and immunopharmacological mechanisms

BackgroundAsthma is one of the most common chronic inflammatory conditions of the lungs in modern society. Asthma is associated with airway hyperresponsiveness and remodeling of the airways, with typical symptoms of cough, wheezing, shortness of breath and chest tightness. Interleukins (IL) play an integral role in its inflammatory pathogenesis. Medicinal herbs and secondary metabolites are gaining considerable attention due to their potential therapeutic role and pharmacological mechanisms as adjunct tools to synthetic bronchodilator drugs.PurposeTo systematically review the literature on the use of single or mixed plants extracts therapy in vivo experimental systems for asthma, emphasizing their regulations on IL production to improve lung.MethodsLiterature searches were performed on PubMed, EMBASE, Scopus and Web of Science databases. All articles in English were extracted from 1999 up to September 2019, assessed critically for data extraction. Studies investigating the effectiveness and safety of plant extracts administered; inflammatory cell count, immunoglobulin E (IgE) production and regulation of pro-inflammatory cytokine and T helper (Th) 1 and Th2-driven cytokine expression in bronchoalveolar lavage fluid (BALF) and lung of asthmatic animals were included.ResultsFour hundred and eighteen publications were identified and 51 met the inclusion criteria. Twenty-six studies described bioactive compounds from plant extracts. The most frequent immunopharmacological mechanisms described included reduction in IgE and eosinophilic recruitment, decreased mucus hypersecretion and airway hyperreactivity, enhancement of the balance of Th1/Th2 cytokine ratio, suppression of matrix metallopeptidase 9 (MMP-9) and reversal of structural alterations.ConclusionPlant extract therapies have potential control activities on asthma symptoms by modulating the secretion of pro-inflammatory (IL-1β, IL-8), Th17 (IL-17), anti-inflammatory (IL-10, IL-23, IL-31, IL-33), Th1 (IL-2, IL-12) and Th2 (IL-4, IL-5, IL-6, IL-13) cytokines, reducing the level of biomarkers of airway inflammation.     

Herbal decoction Divya-Swasari-Kwath attenuates airway inflammation and remodeling through Nrf-2 mediated antioxidant lung defence in mouse model of allergic asthma

Background and purposeAsthma is a chronic respiratory disease orchestrated by immune and structural cells. Identification of novel therapeutic strategies are needed for asthma due to the limitations of existing therapies. We have validated the anti-inflammatory, anti-asthmatic and immunomodulatory therapeutic properties of herbal decoction, Divya-Swasari-Kwath (DSK) using mouse model of ovalbumin (OVA) induced allergic asthma.Methods and resultsHPLC analysis identified the presence of Rutin, Glycyrrchzin, Gallic acid, Cinnamic acid, Chlorogenic acid, Caffeic acid and Piperine as bioactive herbal metabolites in DSK. Therapeutic treatment with herbal decoction DSK significantly alleviated the pathological features of allergic asthma including inflammatory cell accumulation in Broncho-Alveolar Lavage (BAL) fluids, specifically lymphocytes and eosinophils, lung inflammation, oxidative stress, airway remodelling, and pro-inflammatory cytokine levels. H&E analysis of lung tissue sections identified attenuated inflammatory cell infiltration and thickening of bronchial epithelium by DSK. PAS staining and MT staining identified decrease in OVA-induced mucus hyper secretion and peri-bronchial collagen deposition respectively, upon DSK treatment. Treatment with DSK increased the mRNA expression of antioxidative defence gene Nrf-2 and its downstream target genes HO-1 and NQO-1. In the same line, biochemical analysis for the markers of oxidative/antioxidant system confirmed the restoration of activity of Catalase, GPx, SOD and EPO and the levels of GSH, GSSG, MDA and Nitrite in whole lungs. In line with PAS staining, DSK treatment decreased the OVA-induced expression of Muc5AC and Muc5B genes. DSK treatment reduced the steady state mRNA expression levels of IL-6, IL-1β, TNF-α, IL-4, -5, -33, IFN-γ in whole lung; and IL-6, TNF-α and IL-1β protein levels in BALF.ConclusionCollectively, our results suggest that herbal decoction DSK is effective in protecting against allergic airway inflammation and remodelling by regulating anti-oxidant mechanisms. We postulate that DSK could be the potential therapeutic option for allergic asthma management.     

Efficacy of Anti-Interleukin-5 Therapy with Mepolizumab in Patients with Asthma: A Meta-Analysis of Randomized Placebo-Controlled Trials

Background

Interleukin (IL)-5 is believed to be a key cytokine in eosinophil inflammatory infiltration in asthma. Previous clinical trials have evaluated the efficacy and safety of mepolizumab, a monoclonal antibody against IL-5, in patients with asthma. However, most of these studies were small, the conclusions were inconsistent, and the precise effects are therefore debatable.

Methods

A meta-analysis of randomized placebo-controlled trials was conducted to evaluate the effect of intravenous infusion of mepolizumab on clinical outcomes in patients with asthma. Trials were searched in PubMed, Embase, Web of Science, Cochrane CENTRAL, Scopus, reviews, and reference lists of relevant articles. The outcome variables analyzed included eosinophil counts in blood and sputum, airways outcome measures, exacerbations, asthma control, and quality of life scores.

Results

Seven studies met final inclusion criteria (total n = 1131). From the pooled analyses, mepolizumab significantly reduced eosinophils in blood (MD −0.29×10⁹/L, 95% CI −0.44 to −0.14×10⁹/L, P = 0.0001) and sputum (MD −6.05%, 95% CI −9.34 to −2.77%, P = 0.0003). Mepolizumab was also associated with significantly decreased exacerbation risk than placebo (OR 0.30, 95%CI 0.13 to 0.67, P = 0.004), and with a significant improvement in the scores on the Asthma Quality of Life Questionnaire (AQLQ) (MD 0.26, 95% CI 0.03 to 0.49, P = 0.03) in patients with eosinophilic asthma. There were no statistical differences between the groups with respect to FEV₁, PEF, or histamine PC₂₀ (all P>0.05)_, and a non-significant trend for improvement in scores on the Juniper Asthma Control Questionnaire (JACQ) (MD −0.21, 95% CI −0.43 to 0.01, P = 0.06) in the mepolizumab group was observed.

Conclusions

Mepolizumab reduces the risk of exacerbations and improves quality of life in patients with eosinophilic asthma, but no significant improvement in lung function outcomes was observed. Further research is required to establish the possible role of anti–IL-5 as a therapy for asthma.     

Anti-inflammatory deficiencies in neutrophilic asthma: reduced galectin-3 and IL-1RA/IL-1β

Background

Galectin-3 (gal-3), a member of the β-galactoside-binding animal lectins, is involved in the recruitment, activation and removal of neutrophils. Neutrophilic asthma is characterized by a persistent elevation of airway neutrophils and impaired efferocytosis. We hypothesized that sputum gal-3 would be reduced in neutrophilic asthma and the expression of gal-3 would be associated with other markers of neutrophilic inflammation.

Methods

Adults with asthma (n = 80) underwent a sputum induction following clinical assessment and blood collection. Sputum was dispersed for a differential cell count and ELISA assessment of gal-3, gal-3 binding protein (BP), interleukin (IL)-1β, IL-1 receptor antagonist (RA), IL-8 and IL-6. Gal-3 and gal-3BP immunoreactivity were assessed in mixed sputum cells.

Results

Sputum gal-3 (median, (q1,q3)) was significantly reduced in neutrophilic asthma (183 ng/mL (91,287)) compared with eosinophilic (293 ng/mL (188,471), p = 0.021) and paucigranulocytic asthma (399 ng/mL (213,514), p = 0.004). The gal-3/gal-3BP ratio and IL-1RA/IL-1β ratio were significantly reduced, while gal-3BP and IL-1β were significantly elevated in neutrophilic asthma compared with eosinophilic and paucigranulocytic asthma.

Conclusion

Patients with neutrophilic asthma have impairment in anti-inflammatory ratio of gal-3/gal-3BP and IL-1RA/IL-1β which provides a further framework for exploration into pathologic mechanisms of asthma phenotypes.

Electronic supplementary material

The online version of this article (doi:10.1186/s12931-014-0163-5) contains supplementary material, which is available to authorized users.     

Non-Eosinophilic Nasal Polyps Shows Increased Epithelial Proliferation and Localized Disease Pattern in the Early Stage

BackgroundNon-eosinophilic nasal polyps (NPs) show less inflammatory changes and are less commonly associated with lower airway inflammatory disorders such as asthma, compared with eosinophilic NPs. However, the development of non-eosinophilic NPs which is a predominant subtype in Asian population still remains unclear.MethodsA total of 81 patients (45 with non-eosinophilic NPs and 36 with eosinophilic NPs) were enrolled. Clinical information and computed tomography (CT), endoscopic, and histological findings were investigated. Tissue samples were analyzed for total IgE levels and for mRNA expression levels of interleukin (IL)-4, IL–5, IL–13, interferon (IFN)-γ, tumor necrosis factor (TNF)-α, IL-17A, IL–22, IL-23p19, transforming growth factor (TGF)-β1, TGF-β2, TGF-β3, and periostin. Immunostaining assessment of Ki–67 as a proliferation marker was performed.ResultsWe found that epithelial in-growing patterns such as pseudocysts were more frequently observed in histological and endoscopic evaluations of non-eosinophilic NPs, which was linked to increase epithelial staining of Ki–67, a proliferating marker. Eosinophilic NPs were characterized by high infiltration of inflammatory cells, compared with non-eosinophilic NPs. To investigate the developmental course of each subtype, CT was analyzed according to CT scores and subtypes. Non-eosinophilic NPs showed more localized pattern and maxillary sinus involvement, but lesser olfactory involvement in early stage whereas eosinophilic NPs were characterized by diffuse ethmoidal and olfactory involvement. In addition, high ethmoidal/maxillary (E/M) CT scores, indicating ethmoidal dominant involvement, were one of surrogate markers for eosinophilic NP. E/M CT scores was positively correlated with levels of T_H2 inflammatory markers, including IL–4, IL–5, periostin mRNA expression and total IgE levels in NPs, whereas levels of the T_H1 cytokine, IFN- γ were inversely correlated. Moreover, if the combinatorial algorithm meet the three of the four markers, including IL–5 (<2.379), periostin (<3.889), IFN-γ (>0.316), and E/M ratio (<2.167), non-eosinophilic CRSwNP are diagnosed with a sensitivity of 84.4% and a specificity of 84.8%.ConclusionHistologic, immunologic and clinical data suggest that non-eosinophilic NPs showed enhanced epithelial alteration and more localized maxillary involvement. Combination of cutoff value on IL–5, periostin, IFN-γ, and E/M scores may be one of surrogate markers for non-eosinophil NP subtype.     

Aspergillus antigen induces robust Th2 cytokine production,inflammation, airway hyperreactivity and fibrosis in the absence of MCP-1 or CCR2

BackgroundAsthma is characterized by type 2 T-helper cell (Th2) inflammation, goblet cell hyperplasia, airway hyperreactivity, and airway fibrosis. Monocyte chemoattractant protein-1 (MCP-1 or CCL2) and its receptor, CCR2, have been shown to play important roles in the development of Th2 inflammation. CCR2-deficient mice have been found to have altered inflammatory and physiologic responses in some models of experimental allergic asthma, but the role of CCR2 in contributing to inflammation and airway hyperreactivity appears to vary considerably between models. Furthermore, MCP-1-deficient mice have not previously been studied in models of experimental allergic asthma.MethodsTo test whether MCP-1 and CCR2 are each required for the development of experimental allergic asthma, we applied an Aspergillus antigen-induced model of Th2 cytokine-driven allergic asthma associated with airway fibrosis to mice deficient in either MCP-1 or CCR2. Previous studies with live Aspergillus conidia instilled into the lung revealed that MCP-1 and CCR2 play a role in anti-fungal responses; in contrast, we used a non-viable Aspergillus antigen preparation known to induce a robust eosinophilic inflammatory response.ResultsWe found that wild-type C57BL/6 mice developed eosinophilic airway inflammation, goblet cell hyperplasia, airway hyperreactivity, elevations in serum IgE, and airway fibrosis in response to airway challenge with Aspergillus antigen. Surprisingly, mice deficient in either MCP-1 or CCR2 had responses to Aspergillus antigen similar to those seen in wild-type mice, including production of Th2 cytokines.ConclusionWe conclude that robust Th2-mediated lung pathology can occur even in the complete absence of MCP-1 or CCR2.     

Airway Microbiota in Severe Asthma and Relationship to Asthma Severity and Phenotypes

BackgroundThe lower airways harbor a community of bacterial species which is altered in asthma.ObjectivesWe examined whether the lower airway microbiota were related to measures of asthma severity.MethodsWe prospectively recruited 26 severe asthma, 18 non-severe asthma and 12 healthy subjects. DNA was extracted from induced sputum and PCR amplification of the V3-V5 region of bacterial 16S rRNA gene was performed.ResultsWe obtained 138,218 high quality sequences which were rarefied at 133 sequences/sample. Twenty OTUs had sequences ≥1% of total. There were marked differences in the distribution of Phyla between groups (P = 2.8x10^-118). Bacteroidetes and Fusobacteria were reduced in non-severe and severe asthmatic groups. Proteobacteria were more common in non-severe asthmatics compared to controls (OR = 2.26; 95% CI = 1.94–2.64) and Firmicutes were increased in severe asthmatics compared to controls (OR = 2.15; 95%CI = 1.89–2.45). Streptococcal OTUs amongst the Firmicutes were associated with recent onset asthma, rhinosinusitis and sputum eosinophilia.ConclusionsSputum microbiota in severe asthma differs from healthy controls and non-severe asthmatics, and is characterized by the presence of Streptococcus spp with eosinophilia. Whether these organisms are causative for the pathophysiology of asthma remains to be determined.     

Sputum IgE and Cytokines in Asthma: Relationship with Sputum Cellular Profile

Background

Local IgE production may play a role in asthma pathogenesis. The aim of the study was to assess sputum total IgE and cytokines in asthmatics according to sputum cellular phenotype.

Methods

We studied 122 subjects including 22 non atopic healthy subjects, 41 eosinophilic (sputum eosinophils ≥3%), 16 neutrophilic (sputum neutrophils >76%) and 43 pauci-granulocytic asthmatics (sputum eosinophils <3% and sputum neutrophils ≤76%) recruited from the asthma clinic at CHU Liege.Sputum supernatant total IgE (tIgE) was measured by ImmunoCAP and sputum supernatant cytokines (IL-4, IL-5, IL-6, IL-10, IL-13, IL-17, IFN-γ and TNF-α) were measured with the Luminex xMAP Technology by using commercially available Fluorokine MAP kits.

Results

After concentrating sputum samples, total IgE was detectable in the majority of subjects. Sputum IgE was raised in asthmatics when compared to healthy subjects. Overall, asthmatics did not significantly differ from healthy subjects with respect to cytokine levels. The eosinophilic asthma phenotype, however, was characterised by raised sputum tIgE, IL-5 and IL-13 compared to healthy subjects (p<0.001, p<0.001 and p<0.05 respectively) and pauci-granulocytic asthma (p<0.01, p<0.001 and p<0.05 respectively) and raised IL-5 compared to neutrophilic asthma (p<0.01). When patients were classified according to sputum IgE levels, it appeared that IL-5, IL-6, IL-17 and TNF-α sputum supernatant levels were raised in the “IgE high” asthmatics (IgE ≥0.1 kU/l) when compared to “IgE low” asthmatics (IgE<0.1 kU/l).

Conclusion

The eosinophilic asthma phenotype was associated with raised sputum IgE and a Th2 cytokine profile. Raised sputum IgE was associated with a heterogeneous cytokine overproduction.     

嗜酸乳杆菌La28和植物乳杆菌LP45对过敏小鼠的干预作用

[目的]研究嗜酸乳杆菌La28和植物乳杆菌LP45对特应性皮炎和过敏性哮喘小鼠的干预作用,解析其在相关免疫调节上的菌株特异性差异.[方法]对特应性皮炎研究中将40只小鼠随机分为对照组、模型组、La28组和LP45组,除对照组外的其他三组采用2,4-二硝基氟苯诱导耳肿胀和皮炎模型,La28组和LP45组每天灌胃5×108...     

Mesenchymal Stem Cells Suppress Severe Asthma by Directly Regulating Th2 Cells and Type 2 Innate Lymphoid Cells

Patients with severe asthma have unmet clinical needs for effective and safe therapies. One possibility may be mesenchymal stem cell (MSC) therapy, which can improve asthma in murine models. However, it remains unclear how MSCs exert their beneficial effects in asthma. Here, we examined the effect of human umbilical cord blood-derived MSCs (hUC-MSC) on two mouse models of severe asthma, namely, Alternaria alternata-induced and house dust mite (HDM)/diesel exhaust particle (DEP)-induced asthma. hUC-MSC treatment attenuated lung type 2 (Th2 and type 2 innate lymphoid cell) inflammation in both models. However, these effects were only observed with particular treatment routes and timings. In vitro co-culture showed that hUC-MSC directly downregulated the interleukin (IL)-5 and IL-13 production of differentiated mouse Th2 cells and peripheral blood mononuclear cells from asthma patients. Thus, these results showed that hUC-MSC treatment can ameliorate asthma by suppressing the asthmogenic cytokine production of effector cells. However, the successful clinical application of MSCs in the future is likely to require careful optimization of the route, dosage, and timing.     

Increased serum IL-17A and Th2 cytokine levels in patients with severe uncontrolled asthma

Abstract

Asthma is a syndrome of chronic bronchial inflammation and airway remodelling. Initially, asthma has been categorized into atopic and nonatopic types, based on antigen-specific IgE levels. Moreover, recently, asthma has been classified into different endotypes based on its pathophysiology, leading to the selection of the most optimal and effective therapies. Although T helper cell type 2 (Th2) cytokines were proven to play critical roles in atopic asthma, IL-17A has been reported to be involved in severe refractory asthma.

Patients and methods

In this study, we measured the levels of 24 cytokines/chemokines in the sera of healthy controls (HCs) (n = 34) and patients with asthma (n = 77), that were compared among patient groups with different disease activities and characteristics.

Results

The serum levels of nine cytokines were significantly higher in patients with asthma than in HCs, and the levels of IL-17A and SCF were significantly different between uncontrolled and well-controlled patient groups (p = 0.003). The IL-17A levels were significantly correlated with those of IL-4, IL-25, IL-10, and IFN-γ in patients with uncontrolled asthma, and the patients with the highest levels of all the above cytokines were refractory to high-dose of inhaled corticosteroid therapy and have a history of acute exacerbation within 1 year, requiring systemic steroid therapy.

Discussion

This study examines the profiles of upregulation and downregulation of various cytokines and chemokines in relation to asthmatic control status. IL-17A was significantly upregulated in patients with the uncontrolled and refractory status. Therefore, IL-17A may play important roles in asthmatic exacerbation, and its high level, in combination with upregulated Th2 and other cytokines, may indicate the refractory endotype of asthma.

     

Suppression of Th2-driven, allergen-induced airway inflammation by sauchinone

Sauchinone, a lignan compound isolated from the root of Saururus chinensis, has been recently demonstrated to exhibit anti-inflammatory activity via the suppression of NF-kB p65 activity in vitro. In an effort to evaluate the in vivo anti-inflammatory function of sauchinone, we have evaluated the effects of sauchinone on allergen-induced airway inflammation using a murine model of allergic asthma. We observed that marked eosinophilic and lymphocyte infiltration in the BAL fluid were suppressed to a significant degree by sauchinone, and that mucus-secreting goblet cell hyperplasia and collagen deposition in the airways were also ameliorated by administration of sauchinone treatment. Moreover, gene expression of the inflammatory cytokines, IL-13, and IL-5 and eotaxin in the lung, and IL-5 in the draining lymph node were significantly decreased in sauchinone-treated mice. We demonstrated that sauchinone repressed Th2 cell development in vitro and IL-4 production by Th2 cells, and also inhibited GATA-3-mediated IL-5 promoter activity in a dose-dependent manner. Collectively, sauchinone ameliorated allergen-induced airway inflammation, in part, by repressing GATA-3 activity for Th2 cell development, indicating the possible therapeutic potential of sauchinone in airway inflammatory diseases including allergic asthma and rhinitis.     

Spatial and temporal expression of CCR3 and the common beta chain of the IL-3, IL-5 and GM-CSF receptor in the nasal epithelium and lymphoid tissues in a rat model of allergic rhinitis

BackgroundAllergic rhinitis (AR) and asthma are closely related conditions that often co-exist, and are characterized by a Th2 inflammatory response where eosinophils occupy a predominant role. Strategies aimed at blocking signaling through the CC chemokine receptor 3 (CCR3) and/or the common beta chain of the IL-3, IL-5 and GM-CSF receptor (βc) efficiently reduced eosinophilic inflammation in both animal models and in asthmatic patients. This study was therefore aimed at characterizing the spatio-temporal expression pattern of βc and CCR3 using a rat model of AR.MethodsSensitized rats were challenged with ovalbumin and sacrificed at 2 h, 8 h, 16 h or 24 h post-challenge. Nasal tissues were microdissected and used for mRNA quantification by QPCR, while histological evaluation determined the presence of eosinophils and mucosubstances.ResultsAllergen-induced recruitment of eosinophils in the distal septum and turbinates was maximal at 8 h post-challenge, and was correlated with 2–4-fold increase in CCR3 and βc mRNA. Recruitment of eosinophils was also accompanied by upregulated IL-5, IL-4Rα, TNF-α and IFN-γ mRNA at early time-points. In contrast, IL-13 and MUC5AC mRNA, as well as production of mucosubstances were maximal at 24 h.Conclusionsβc and CCR3 could play important roles in the modulation of the allergic response, and their inhibition may represent a promising therapeutic approach for AR.     

Th2 cells and cytokine networks in allergic inflammation of the lung

The cytokines released from Th2 and Th2-like cells are likely to be central to the pathophysiolgy of asthma and allergy, contributing to aberrant IgE production, eosinophilia and, perhaps, mucosal susceptibility to viral infection. IL-4 has emerged as a central target, not only for B cell IgE production, but also in the commitment of both CD4+ and CD8+ T cells to cells with Th2 effector function capable of secreting IL-5 resultlng in eosinophilic inflammation. In view of the central role of this cytokine and the evidence that glucocorticoids are unable to modify many IL-4 dependent effects, Th2 inhibitors may prove to be novel therapies for the treatment of bronchial asthma.     

Hyperglycaemia,oxidative stress and inflammatory markers

Introduction: The increasing prevalence of hyperglycaemia implicates a state of oxidative stress and inflammation. Traditional and emerging biomarkers associated with increasing hyperglycaemia were assessed to clarify their role they play in hyperglycaemia.

Results: 309 participants attending a rural diabetic screening program were categorised into control and quintile groups based upon glucose levels: 1st quintile - <4.5?mmol/L and 4th, 5th quintile - >6.1?mmol/L. Significant results were obtained for anthropometric data and biochemical markers - glucose, HbA1c and total cholesterol (P?P?P?P?Conclusion: This study provided further evidence that inflammatory and oxidative stress biomarkers may contribute to diagnostic information associated with preclinical increases in BGL. Further we have provided a unique study in the analysis of ratios of inflammatory biomarkers and correlations with increasing BGL.     

Let-7a在哮喘T淋巴细胞失衡中的作用研究

目的:探讨let-7a在哮喘中的表达水平及调节T淋巴细胞亚群失衡的功能作用。方法:收集39例哮喘患者及19例非哮喘对照,Real-time PCR检测let-7a的表达。从哮喘患者外周血单核细胞(Peripheral blood mononuclear cell,PBMC)中分选Th1,Th2和Th17细胞,检测let-7a在T淋巴细胞亚群中的表达。磁珠分选naive T细胞,分别诱导分化成Th1、Th2和Th17细胞,分析let-7a在T淋巴细胞亚群中的表达。Let-7a mimic分别转染Th2和Th17细胞,ELISA检测IL-13和IL-17的表达。结果:与对照组比较,let-7a在哮喘患者肺组织和血清中低表达,并随着哮喘病程进展,let-7a的表达水平也越低。哮喘患者来源的CD4~+T细胞中,let-7a表达明显低于非哮喘对照组。Let-7a在哮喘来源和体外刺激分化的哮喘炎性Th2和Th17细胞中的表达明显下调,而在Th1细胞中的表达没有变化。Let-7a mimic改变了Th2和Th17相关细胞因子IL-13和IL-17的表达。结论:Let-7a在哮喘中低表达,调节哮喘T淋巴细胞亚群失衡,改变了Th2和Th17细胞的功能,是哮喘理想的诊断和治疗靶点。     

槐杞黄颗粒联合吸入糖皮质激素对支气管哮喘患儿肺功能、细胞免疫因子及CCL3、CCL5水平的影响

摘要 目的：探讨槐杞黄颗粒联合吸入糖皮质激素对支气管哮喘患儿肺功能、细胞免疫因子及趋化因子3（CCL3）、趋化因子5（CCL5）水平的影响。方法：按照随机数字表法,将我院收治的轻度持续性支气管哮喘患儿（n=90）,分为对照组（吸入糖皮质激素,45例）和研究组（槐杞黄颗粒联合吸入糖皮质激素,45例）,两组均治疗3个月。对比两组患儿治疗前、治疗后1、3、6个月的常规肺功能、细胞免疫因子及CCL3、CCL5水平。观察两组临床疗效、指标和不良反应。结果：研究组的临床总有效率71.11%（32/45）高于对照组91%（41/45）,差异有统计学意义（P<0.05）。治疗后1个月（T2）、治疗后3个月（T3）、治疗后6个月（T4）时间点,两组第1秒用力呼气量占预测值百分比（FEV₁%）、呼气峰流速占预测值百分比（PEF%）、最大呼气中期流速占预计值的百分比（MMEF75/25）升高,总呼吸阻抗（Z5）、肺弹性阻力（X5）及共振频率（Fres）下降,且研究组的改变程度大于对照组（P<0.05）。T2、T3、T4时间点,两组免疫球蛋白（IgE）、白细胞介素-4（IL-4）、白细胞介素-5（IL-5）、白细胞介素-13（IL-13）、白细胞介素-17（IL-17）下降,且研究组的改变程度大于对照组（P<0.05）。T2、T3、T4时间点,两组CCL3、CCL5下降,且研究组的改变程度大于对照组（P<0.05）。两组不良反应发生率组间对比无差异（P>0.05）。研究组C-ACT评分高于对照组,呼吸道感染次数、哮喘发作次数少于对照组（P<0.05）。两组因哮喘住院次数组间对比未见统计学差异（P>0.05）。结论：槐杞黄颗粒联合吸入糖皮质激素治疗支气管哮喘,可促进患儿肺功能恢复,改善细胞免疫因子及CCL3、CCL5水平。     

miR-1165-3p、miR-145水平在支气管哮喘患者中的表达及其临床意义

摘要 目的：探讨微小RNA（MicroRNA,miR）-1165-3p、miR-145水平在支气管哮喘患者中的表达及其临床意义。方法：收集2021年1月-2022年3月中国人民解放军总医院第六医学中心62例支气管哮喘患者作为研究组,其中轻度急性发作27例,中度急性发作22例,重度急性发作13例。另收集同时期、同年龄段30例健康体检者作为对照组。采用实时荧光定量PCR（RT-PCR）检测各组血清miR-1165-3p、miR-145表达水平。采用Spearman相关分析不同程度支气管哮喘患者与血清miR-1165-3p、miR-145之间的相关性。通过受试者工作特征（ROC）分析血清miR-1165-3p、miR-145表达水平对不同程度支气管哮喘的诊断效能。结果：与对照组相比,研究组中白细胞介素-6（IL-6）、嗜酸性粒细胞、总免疫球蛋白E（IgE）水平显著升高,第1秒用力呼气容积（FEV₁）占预测值百分比（FEV₁%）则显著降低,差异均有统计学意义（P＜0.05）。不同严重程度支气管哮喘患者（轻度、中度、重度）血清miR-1165-3p、miR-145表达水平均高于健康对照组,支气管哮喘越严重,其表达水平越高,且组间、组内比较差异均有统计学意义（P＜0.05）。Spearman相关分析显示,miR-1165-3p、miR-145、IL-6表达水平与哮喘严重程度呈正相关（P＜0.05）,FEV₁%与哮喘严重程度呈负相关（P＜0.05）,嗜酸性粒细胞、总IgE与哮喘严重程度无相关性（P＞0.05）。对轻度、中度、重度急性支气管哮喘发作的诊断效能显示：血清miR-1165-3p的曲线下面积（AUC）（0.95CI）分别为3.085（0.326～29.221）、0.712（0.611～0.829）、0.755（0.602～0.948）。血清miR-145的AUC（0.95CI）分别为0.833（0.708～0.979）、0.754（0.590～0.964）、0.816（0.671～0.993）。结论：血清miR-1165-3p、miR-145表达水平具有较高的诊断效能,支气管哮喘越严重,诊断的特异性越高,可作为支气管哮喘严重程度的无创诊断指标。     

Ras activation in T cells determines the development of antigen-induced airway hyperresponsiveness and eosinophilic inflammation

The central role for Th2 cells in the development of Ag-induced airway hyperresponsiveness and eosinophilic inflammation is well documented. We have reported a crucial role for TCR-induced activation of the Ras/extracellular signal-regulated kinase mitogen-activated protein kinase cascade in Th2 cell differentiation. Here, we show that the development of both OVA-induced airway hyperresponsiveness and eosinophilic airway inflammation in a mouse asthma model are attenuated in transgenic mice by the overexpression of enzymatically inactive Ras molecules in T cells. In addition, reduced levels of IL-5 production and eosinophilic inflammation induced by nematode infection (Nippostrongylus brasiliensis or Heligmosomoides polygyrus) were detected. Thus, the level of Ras activation in T cells appears to determine Th2-dependent eosinophilic inflammation and Ag-induced airway hyperresponsiveness.