IL-12和支气管哮喘

支气管哮喘是一种气道慢性炎症性疾病。越来越多的事实表明,哮喘的发生与内源性IL-12生成不足有关。IL-12无论单独应用还是作为免疫佐剂,均可逆转哮喘动物模型体内Th1/Th2失衡和抑制气道变态反应性炎症。该文综述了IL-12的生物学效应、IL-12与哮喘的关系、IL-12在哮喘治疗中的作用及其应用。     

真菌过敏性哮喘的治疗研究进展

真菌过敏性哮喘是由环境中真菌致敏原暴露诱导的一种呼吸道慢性炎症性疾病。真菌过敏哮喘患者肺部炎症细胞、结构细胞及细胞组分间有复杂的相互作用,使得患者气道壁重塑并伴渐进性肺功能障碍,表现为喘息、胸闷、呼吸困难等症状,对患者的工作和生活造成严重影响,而目前糖皮质激素及抗菌药物等传统疗法对其治疗效果欠佳。近年来,很多研究开始致力于对真菌过敏性哮喘新的治疗方法进行积极探索,使得真菌过敏性哮喘的治疗除应用糖皮质激素等传统方法外,在抗真菌感染及其免疫学治疗控制真菌过敏性哮喘方面取得一定新进展。     

Effects of catalpol on bronchial asthma and its relationship with cytokines

An animal (BALB/c mice) model of catalpol associated with bronchial asthma in vivo was established, and the effects of catalpol and its relationship with cytokines were investigated. A total of 30 adult BALB/c mice were randomly divided into a positive control group, a model group, and a catalpol group, with 10 mice in each group. The lung function of mice, the cell count, and the cytokine concentrations in bronchoalveolar lavage fluid (BALF) were detected. The levels of cytokines [interleukin 4 (IL-4), interleukin 5 (IL5), and interferon gamma (IFN-γ)] in BALF were measured with enzyme-linked immunosorbent assay methods. The total number of cells in the BALF of the group treated with catalpol was significantly lower than the model group. After treatment with catalpol, the eosinophils and neutrophils of the mice were remarkably reduced compared with the model group. The malondialdehyde content in the lung tissue homogenate of the mice was also decreased in the catalpol group. The cytokines IL-5 and IL-4 exhibited a similar tendency: the concentrations of IL-4 and IL-5 for the catalpol group were dramatically decreased compared with the model group. However, the IFN-γ concentration for the catalpol group was higher than the model group. The results indicated that IL-5 may involve in the pathologic process of asthma-like IL-4, and an inflammatory reaction may still exist in the airway during the remission stage of asthma. The imbalances of the cytokine network might be an important molecular basis in the asthma pathogenesis. It is suggested that catalpol may be a potential drug for the clinical treatment of asthma.     

Assessment of some oxidative stress parameters in patients with bronchial asthma after selenium supplementation

The goal of this study was to investigate the effect of selenium deficit replenishment in patients with bronchial asthma (BA) on manifestations of oxidative stress and conditions of the antioxidant system (AOS). The need of correction of selenium deficit in BA-patients is determined by increased requirements in antioxidants due to chronic inflammatory process responsible for pathogenesis of BA. Latvia as well as Eastern Finland, Byelorussia, some regions of Ukraine, North-Western Russia, and New Zealand belong to the endemic areas with marked selenium deficit in soils and foodstuff. Twenty patients (7 men and 13 women) with selenium deficit and verified diagnosis of BA have been examined. In addition to basic therapy all patients received organic selenium as SelenoPRECISE (PharmaNord) 200 μg daily for 16 weeks. This caused statistically significant increase of plasma selenium from 50.94 ± 7.58 to 63.59 ± 10.87 μg/l (p < 0.001), the increase of selenium-dependent glutathione peroxidase (from 38.64 ± 10.72 U/g Hb to 58.57 ± 14.64 U/g Hb, p = 0.01). Treatment of patients with selenium also normalized the parameters characterizing oxidative stress (chemiluminescence), significantly exceeded normal values before this treatment. The use of selenium in addition to basic therapy allows to abolish or reduce oxidative stress by correcting the antioxidant system.     

Correlation of exhaled breath temperature with bronchial blood flow in asthma

In asthma elevated rates of exhaled breath temperature changes (Δe°T) and bronchial blood flow (Q_aw) may be due to increased vascularity of the airway mucosa as a result of inflammation.We investigated the relationship of Δe°T with Q_aw and airway inflammation as assessed by exhaled nitric oxide (NO). We also studied the anti-inflammatory and vasoactive effects of inhaled corticosteroid and β₂-agonist.Δe°T was confirmed to be elevated (7.27 ± 0.6 Δ°C/s) in 19 asthmatic subjects (mean age ± SEM, 40 ± 6 yr; 6 male, FEV₁ 74 ± 6 % predicted) compared to 16 normal volunteers (4.23 ± 0.41 Δ°C/s, p < 0.01) (30 ± 2 yr) and was significantly increased after salbutamol inhalation in normal subjects (7.8 ± 0.6 Δ°C/ s, p < 0.05) but not in asthmatic patients. Q_aw, measured using an acetylene dilution method was also elevated in patients with asthma compared to normal subjects (49.47 ± 2.06 and 31.56 ± 1.6 μl/ml/min p < 0.01) and correlated with exhaled NO (r = 0.57, p < 0.05) and Δe°T (r = 0.525, p < 0.05). In asthma patients, Q_aw was reduced 30 minutes after the inhalation of budesonide 400 μg (21.0 ± 2.3 μl/ml/min, p < 0.05) but was not affected by salbutamol.Δe°T correlates with Q_aw and exhaled NO in asthmatic patients and therefore may reflect airway inflammation, as confirmed by the rapid response to steroids.     

支气管扩张合并支气管哮喘患者的病原菌检测及危险因素分析

目的分析支气管扩张合并支气管哮喘患者的病原菌及危险因素。方法选取湖州市中心医院115例支气管扩张合并支气管哮喘患者作为观察组,另选取同期110例健康体检者作为对照组。分析患者病原菌的组成、耐药性及发病危险因素。结果观察组患者送检痰样本经痰培养,阳性检出者68例,阳性率为59.13%(68/115)。全部样本共分离出104株病原菌,其中革兰阴性菌92株(以铜绿假单胞菌最多,占54.81%),革兰阳性菌8株,真菌4株。药敏试验结果表明革兰阴性菌对复方新诺明、头孢曲松、左旋左氧氟沙星和阿莫西林/克拉维酸等药物的耐药性均较高,对妥布霉素、亚胺培南、头孢哌酮/舒巴坦和哌拉西林的耐药性较低。Logistic回归分析显示,吸烟史、药物过敏史、食物过敏史、过敏性鼻炎、哮喘、过敏性肺炎、慢性支气管炎及慢性阻塞性肺疾病均是支气管扩张伴支气管哮喘发生的危险因素。结论支气管扩张合并支气管哮喘患者其病原菌以革兰阴性菌为主,吸烟史、药物过敏史、食物过敏史、过敏性鼻炎等是支气管扩张伴支气管哮喘发生的危险因素。     

Influence of degree of specific allergic sensitivity on severity of rhinitis and asthma in Chinese allergic patients

Background

The clinical manifestations of severe asthma are heterogeneous. Some individuals with severe asthma develop irreversible fixed airway obstruction, which is associated with poor outcomes. We therefore investigated the factors associated with fixed airway obstruction in Korean patients with severe asthma.

Methods

Severe asthma patients from a Korean adult asthma cohort were divided into two groups according to the results of serial pulmonary function tests. One group had fixed airway obstruction (FAO) [forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) ratio < 0.7, n = 119] and the other had reversible airway obstruction (RAO) [FEV1/FVC ratio ≥ 0.7, n = 116]. Clinical and demographic parameters were compared between the two groups.

Results

Multivariate analysis showed that longer duration of disease, greater amount of cigarette smoking and absence of rhinosinusitis were significantly related to the development of FAO in severe asthmatics. Other parameters, including atopic status, pattern of airway inflammatory cells in induced sputum, and frequency of asthma exacerbations did not differ between the FAO and RAO groups.

Conclusion

Severe asthma patients with longer disease duration and the absence of rhinosinusitis are more likely to develop FAO. This study also demonstrates the importance of quitting smoking in order to prevent irreversible airway obstruction. Further investigation is required to determine the mechanism by which these factors can modify the disease course in Korean patients with severe asthma.     

The effect of house design and environment on fungal movement in homes of bronchial asthma patients

The effect of house building design and environment on the fungal movement in the houses of 41 bronchial asthma (BA) patients has been investigated by examining house dust. The presence and composition of fungi were determined and compared in relation to building structure, house age, size of living room, main flooring material, presence of a living-room rug or air purifier, and frequency of vacuum cleaning. Among these elements, fungal CFU apparently varied only between building structure: wooden-board houses had significantly higher numbers of fungi than reinforced concrete houses (p < 0.01), and wooden mortar or iron-framed prefabricated houses had significantly higher numbers of fungi than reinforced concrete houses (p < 0.05). Classification of the types of fungi present in the house dust of BA patients showed that, regardless of the building designs, there were high levels of osmophilic fungi (group A) and fungi that survive at relatively dry conditions (group B), whereas fungi that survive in very wet conditions (group D) were present at low frequency. This revised version was published online in August 2006 with corrections to the Cover Date.     

银杏叶提取物对豚鼠哮喘模型血红素氧合酶-1表达的影响

目的探讨银杏叶提取物(Egb761)对豚鼠哮喘模型血红素氧合酶-1(HO-1)表达的影响.方法 将30只豚鼠随机分为3组(n=10)(1)正常组;(2)哮喘组;(3)治疗组.测定全血一氧化碳血红蛋白(COHb)的百分比含量、气道阻力并观察气道壁嗜酸性粒细胞(EOS)浸润情况, 用免疫组织化学染色方法观察HO-1在豚鼠肺组织中的表达变化.结果各组气道上皮细胞HO-1阳性表达的平均吸光度分别为 0.170±0.020、0.707±0.058、0.397±0.034.哮喘组HO-1的表达水平显著高于正常组(P<0.01).治疗组HO-1的表达水平显著低于哮喘组(P<0.01). 结论银杏叶提取物能显著抑制哮喘豚鼠气道壁内上皮细胞HO-1的表达,提示银杏叶提取物抑制HO-1的表达可能是银杏叶提取物治疗哮喘的作用机制之一.     

Exhaled breath profiling by electronic nose enabled discrimination of allergic rhinitis and extrinsic asthma

Aim: To assess whether an e-nose could discriminate between subjects affected by allergic rhinitis with and without concomitant extrinsic asthma, as well as from healthy controls, in terms of exhaled VOC-profile.

Methods: Fourteen patients with Extrinsic Asthma and Allergic Rhinitis (AAR), 14 patients with Allergic Rhinitis without asthma (AR) and 14 healthy controls (HC) participated in a cross-sectional study. Exhaled breath was collected by a standardized method and sampled by an e-nose (Cyranose 320). Raw data were reduced by Principal component analysis and analyzed by canonical discriminant analysis. Cross-validation accuracy (CVA) and Receiver Operating Characteristic(ROC)-curves were calculated. External validation in newly recruited patients (7 AAR, 7?AR and 7 HC) was tested using the previous training model.

Results: Breathprints of patients with AR clustered from those with AAR (CVA?=?85.7%), as well as HC (CVA?=?82.1%). Breathprints from AAR were also separated from those of HC (CVA?=?75.0%). External validation confirmed the above findings.

Conclusions: An e-nose can discriminate exhaled breath from subjects with allergic rhinitis with and without extrinsic asthma, which represent two different diseases with partly overlapping features. This supports the view of using breath profiling to diagnose asthma also in patients with allergic rhinitis.     

染料木黄酮对哮喘豚鼠肺部炎症和气道重塑的预防作用

目的：研究蛋白酪氨酸激酶（PTK）抑制剂染料木黄酮对哮喘豚鼠肺部炎症和气道重塑的作用。方法：成年雄性豚鼠30只,随机分成3组（n=10）：对照组（C组）、哮喘组（A组）和染料木黄酮干预组（B组）,以腹腔内注射联合雾化吸入卵蛋白复制哮喘模型。测支气管肺泡灌洗液（BALF）中细胞总数及其分类数,测细支气管炎症细胞浸润及支气管重塑指标,免疫纽化方法测磷酸化酪氨（p-tyrosine）在肺组织中的表达。结果：A组BALF中细胞总数、嗜酸性粒细胞分类与C组比较明显增加,B组与A组比较明显降低,差异有统计学意义（P〈0．01）;A组细支气管嗜酸性粒细胞（E）数和淋巴细胞（L）数较C组明显增多,B组与A组比较明显降低,差异有统计学意义（P〈0．01）;B组细支气管重塑较A组明显减轻（P〈0．01）,与C组比较,差异无统计学意义（P〈0．05）;免疫组化显示p-tyrosine在支气管平滑肌、支气管上皮、血管滑平滑肌及炎性细胞均有表达,尤其以支气管和血管平滑肌及炎性细胞明显,A组比C组表达明显增高,差异有统计学意义（P〈0．01）,而B组与C组比较,无明显差别（P〉0．05）。结论：PTK对哮喘豚鼠肺部炎症和支气管重塑具有促进作用：PTK抑制剂染料木黄酮对哮喘豚鼠肺炎症和支气管重塑具有预防和抑制作用。     

Aldose reductase deficiency in mice protects from ragweed pollen extract (RWE)-induced allergic asthma

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.     

Schistosoma japonicum peptide SJMHE1 suppresses airway inflammation of allergic asthma in mice

Helminths and their products can shape immune responses by modulating immune cells, which are dysfunctional in inflammatory diseases such as asthma. We previously identified SJMHE1, a small molecule peptide from the HSP60 protein of Schistosoma japonicum. SJMHE1 can inhibit delayed‐type hypersensitivity and collagen‐induced arthritis in mice. In the present study, we evaluated this peptide's potential intervention effect and mechanism on ovalbumin‐induced asthma in mice. SJMHE1 treatment suppressed airway inflammation in allergic mice, decreased the infiltrating inflammatory cells in the lungs and bronchoalveolar lavage fluid, modulated the production of pro‐inflammatory and anti‐inflammatory cytokines in the splenocytes and lungs of allergic mice, reduced the percentage of Th2 cells and increased the proportion of Th1 and regulatory T cells (Tregs). At the same time, Foxp3 and T‐bet expression increased, and GATA3 and RORγt decreased in the lungs of allergic mice. We proved that SJMHE1 can interrupt the development of asthma by diminishing airway inflammation in mice. The down‐regulation of Th2 response and the up‐regulation of Th1 and Tregs response may contribute to the protection induced by SJMHE1 in allergic mice. SJMHE1 can serve as a novel therapy for asthma and other allergic or inflammatory diseases.     

Antioxidant enzymes and melatonin levels in patients with bronchial asthma and chronic obstructive pulmonary disease during stable and exacerbation periods

An imbalance between oxidative stress and antioxidative capacity may play an important role in the development and progression of bronchial asthma (BA) and chronic obstructive pulmonary disease (COPD). We carried out a study to assess the systemic oxidant–antioxidant status during the exacerbation and the stable period in patients with BA and COPD. A total of 33 patients, 16 with BA and 17 with COPD were included in the study. During the exacerbation and the stable periods, levels of malondialdehyde (MDA), activities of superoxide dismutase (SOD), glutathione peroxidase (GSH‐Px), glutathione reductase (GRd), and catalase (CAT) in erythrocytes and serum melatonin concentrations were investigated. Blood counts, respiratory functions, and blood gases of the patients were also performed. During an exacerbation period of BA, despite the decreases in GSH‐Px, GRd and melatonin levels, MDA and CAT levels, and the white blood cell count, the percentage of eosinophils were significantly higher than in the stable period. Also, it was found that FEV₁/L (where FEV₁ is the forced expiratory volume in 1 s), FVC/L (where FVC is forced vital capacity), PEF/L/s (where PEF is peak expiratory flow), pO₂ (where pO₂ is oxygen pressure) levels increased during the stable period in patients with BA. MDA and SOD values were higher in the exacerbation period than in the stable period although GSH‐Px, GRd, melatonin, pH, and pO₂ values were lower in the exacerbation period than in the stable period. The blood counts and the respiratory function tests did not change between the exacerbation and the stable period of patients with COPD significantly. In conclusion, we observed that oxidative stress in the exacerbation period of patients with BA and COPD increased whereas the antioxidant enzymes and melatonin values reduced. The episodes of BA or COPD might be associated with elevated levels of oxidative stress. Copyright © 2009 John Wiley & Sons, Ltd.     

肠道菌群与过敏性哮喘

近年来随着过敏性哮喘发病率的持续升高,人们开始注意到环境、生活方式的改变可能会影响过敏性哮喘的发生。流行病学调查显示,过敏性哮喘的发生和发展与生命早期肠道菌群的紊乱密切相关。本研究主要综述近年来肠道菌群对过敏性哮喘发生的影响及机制,探讨影响肠道菌群定植的主要因素,以及微生态调节剂在过敏性哮喘等变应性疾病中的预防和治疗作用。     

香栓菌的平喘及抗氧化活性研究

本文对香栓菌子实体提取物的平喘作用和抗氧化活性进行研究。平喘药理实验采用鸡卵清蛋白（OVA）致敏法建立小鼠过敏性哮喘模型,灌胃给药香栓菌水提物（高240mg/kg、中120mg/kg、低60mg/kg剂量）和石油醚提取物（高24mg/kg、中12mg/kg、低6mg/kg剂量）。比较各组小鼠行为变化,检测IgE、TNF-α、IL-1β、IL-6、IL-4和IFN-γ等指标,分类计数血液及支气管肺泡灌洗液（BALF）中的嗜酸性粒细胞数量,分析肺组织病理变化;抗氧化实验采用香栓菌水提取物、乙酸乙酯提取物、氯仿提取物、石油醚提取物比较清除DPPH和ABTS自由基能力。平喘试验结果表明,香栓菌水提物中剂量（120mg/kg）能降低血中嗜酸性粒细胞（Eos）及血清中IgE含量,减少BALF中Eos,降低血清及肺组织匀浆中IL-4含量,提高IFN-γ/IL-4,减轻模型的病理改变;石油醚提取物高剂量（24mg/kg）能降低血中Eos和血清中IgE、TNF-α、IL-1、IL-6含量,减少肺组织炎症细胞浸润;抗氧化结果显示,香栓菌各层提取物均有不同程度的抗氧化能力,并呈现一定的量效关系,同时水提取物的抗氧化效果最显著。本文为深入研究香栓菌子实体对呼吸系统疾病的治疗提供了重要试验依据。     

Th22细胞与支气管哮喘

支气管哮喘是一种临床上常见的呼吸道疾病,研究发现CD4＋T细胞在哮喘的发病过程中起重要作用。Th22细胞是最近发现的一类CD4＋T细胞功能亚群之一,其主要效应因子IL-22在炎症性疾病、组织修复、创口愈合及自身免疫性疾病中起重要作用,但其具体机制尚未完全清楚。从Th22的细胞因子来源、生物学特性、分化和调控出发,简要探讨Th22细胞与哮喘之间的可能关系。     

Wound repair and proliferation of bronchial epithelial cells regulated by CTNNAL1

Adhesion molecules play vital roles in airway hyperresponsiveness (AHR) or airway inflammation. Our previous study indicated that adhesion molecule catenin alpha-like 1 (CTNNAL1) is relevant closely to asthma susceptibility, but its biological function or significance is still unclear. In the present study, we observed the temporal and spatial distribution of CTNNAL1 expression in mouse lung tissue with the OVA-sensitized asthma model and found that the level of CTNNAL1 mRNA showed a prominent negative correlation with pulmonary resistance (R(L)). To study the function of CTNNAL1 in airway, effects of CTNNAL1 on proliferation and wound repair activity of human bronchial epithelial cells (HBEC) was investigated with antisense oligonucleotide (ASO) technique. The results showed that: (1) CTNNAL1 ASO could decelerate the repairing velocity and proliferation of HBEC; (2) CTNNAL1 expression was increased on the edge cells of mechanic wounded area in culture; (3) extracellular matrix component fibronectin (Fn) obviously promoted wound repair activity and proliferation of HBEC, which could be blocked by CTNNAL1 ASO; (4) Western blot showed that Fn could promote FAK phosphorylation, which also be inhibited by CTNNAL1 ASO. In conclusion, the level of CTNNAL1 mRNA expression is highly correlated to airway resistance; CTNNAL1 may contribute to the wound repair and proliferation of HBEC. Furthermore, it may serve to Fn mediated cell-extracellular adhesion and its signal transduction.     

Immunoresolvents in asthma and allergic diseases: Review and update

Asthma and allergic diseases are inflammatory conditions developed by excessive reaction of the immune system against normally harmless environmental substances. Although acute inflammation is necessary to eradicate the damaging agents, shifting to chronic inflammation can be potentially detrimental. Essential fatty-acids-derived immunoresolvents, namely, lipoxins, resolvins, protectins, and maresins, are anti-inflammatory compounds that are believed to have protective and beneficial effects in inflammatory disorders, including asthma and allergies. Accordingly, impaired biosynthesis and defective production of immunoresolvents could be involved in the development of chronic inflammation. In this review, recent evidence on the anti-inflam]matory effects of immunoresolvents, their enzymatic biosynthesis routes, as well as their receptors are discussed.