Regulation of epithelium-specific Ets-like factors ESE-1 and ESE-3 in airway epithelial cells： potential roles in airway inflammation

Airway inflammation is the hallmark of many respiratory disorders, such as asthma and cystic fibrosis. Changes in airway gene expression triggered by inflammation play a key role in the pathogenesis of these diseases. Genetic linkage studies suggest that ESE-2 and ESE-3, which encode epithelium-specific Ets-domain-containing transcription factors, are candidate asthma susceptibility genes. We report here that the expression of another member of the Ets family transcription factors ESE-1, as well as ESE-3, is upregulated by the inflammatory cytokines interleukin-1β （IL-1β） and tumor necrosis factor-α （TNF-α） in bronchial epithelial cell lines. Treatment of these cells with IL-1β and TNF-α resulted in a dramatic increase in mRNA expression for both ESE-1 and ESE-3. We demonstrate that the induced expression is mediated by activation of the transcription factor NF-κB. We have characterized the ESE-1 and ESE-3 promoters and have identified the NF-κB binding sequences that are required for the cytokine-induced expression. In addition, we also demonstrate that ESE-1 upregulates ESE-3 expression and downregulates its own induction by cytokines. Finally, we have shown that in E/f3 （homologous to human ESE-1） knockout mice, the expression of the inflammatory cytokine interleukin-6 （IL-6） is downregulated. Our findings suggest that ESE-1 and ESE-3 play an important role in airway inflammation.

Effect of intratracheally administered BCG-DNA on murine model of asthma

Objective: To investigate the effect of intratracheally administered BCG DNA on a murine model of asthma. Methods: BALB/C mice were divided into 4 groups: normal control group, asthma model group, BCG DNA administered before OVA sensitization group, BCG DNA administered after OVA challenge group. The asthma models were developed by immunizing BALB/C mice with OVA. A total of 100 μg BCG DNA was intratracheally administered before OVA sensitization and after OVA challenge. WBC count and eosinophil percentage (EOS%) in bronchoalveolar lavage fluid (BALF) were measured. Changes of IL 4 , IL 5,IL 12, IFN γ in BALF were determined by ELISA. Pulmonary inflammation was observed on normal pathological slides and the proliferation and mucus secretion of goblet cells stained by AB PAS were also observed. Results: IL 4 , IL 5,IL 12, IFN γ in BALF of normal control group were(32.3±5.7)pg/ml,(15.6±3.9)pg/ml,(80±8.5)pg/ml,(153.2±9.4)pg/ml respectively. IL 4,IL 5 in BALF of asthma model group increased to (299±15.6)pg/ml and (206.7±9.3)pg/ml, while IL 12 and IFN γ decreased to (20.4±4.1)pg/ml and (51.6±5.5) pg/ml respectively. BCG DNA administered intratracheally before OVA sensitization and after OVA challenge significantly increased IL 12 [(71.6±8.3)pg/ml,(67.8±8.1pg/ml)] and IFN γ [(119.0±11.3)pg/ml,(114.7±10.1)pg/ml] in the BALF. Meanwhile, BCG DNA decreased IL 4 [(82.1±6.1)pg/ml,(86.3±5.9)pg/ml] and IL 5 [(32.3±4.6)pg/ml,(37.4±5.3)pg/ml]. Eosinophil level in BALF was inhibited and the pulmonary inflammation was dramatically relieved compared to asthma model group. Conclusion: Intratracheally administered BCG DNA can induce IL 12 and IFN γ secretion,inhibit Th2 response which can relieve allergic airway inflammation and provide a new way in the treatment and prevention of asthma.

疏风解痉方辨证治疗儿童咳嗽变异性哮喘45例

目的：观察疏风解痉方辨证治疗儿童咳嗽变异性哮喘（CVA）的临床疗效及对血清总IgE和嗜酸性粒细胞（EOS）及哮喘细胞因子的影响.方法：90例CVA患儿随机按数字表法分为对照组和中药组各45例,并设健康对照组15例.对照组采用孟鲁司特钠咀嚼片,4～5岁者4 mg,6 ～12岁者5 mg,每晚睡前使用.中药组在对照组治疗的基础上加用疏风解痉方,1剂/d.两组疗程均为4周.记录治疗前后咳嗽频率、咳嗽程度、咳嗽性质、气急及咽痒等主要症状评分,检测治疗前后血清总IgE、外周血嗜酸性粒细胞（EOS）、肿瘤坏死因子-α（TNF-α）、白细胞介素-4（IL-4）、白细胞介素-10 （IL-10）和干扰素-γ（IFN-γ）等水平.结果：中药组疾病疗效总有效率为93.33％,优于对照组的77.78％ （P ＜0.05）;治疗后中药组咳嗽频率、咳嗽程度、咳嗽性质、气急及咽痒等主要症状评分均低于对照组（P＜0.01）;治疗后中药组血清总IgE,TNF-α,IL-4和EOS水平低于对照组（P＜0.01）,中药组IL-10和IFN-γ水平高于对照组（P＜0.01）.结论：疏风解痉方辨证治疗儿童咳嗽变异性哮喘可改善症状,提高疗效,并能调节细胞因子水平,减轻气道的高反应性.

Effects of interleukin-18 on airway inflammation and the Th1/Th2 cytokine imbalance in guinea pig asthmatic model

In order to investigate the effects of interleukin-18 （IL-18） on airway inflammation and the Th1/Th2 cytokine balance in guinea pig asthmatic model as well as its possible mechanisms, the asthmatic model was established by intraperitoneal injection of ovalbumin （OVA） and aerosol challenges into guinea pigs, and 30 treated animals were randomly divided into three groups of 10 animals in each groups, in which group A served as the asthmatic model, group B as the controls and group C as the group treated with IL-18. The counting and categorization of the inflammatory cells in bronchoalveolar lavage fluid （BALF） were performed by using light microscopy, and the contents of cytokines （ IFN-γ, IL- 2, IL-4 and IL-5） were assayed by means of the ELISA kit. The experimental results showed that the numbers of eosinophils （ESO） in BALF of group A, B and C were （97.70 ± 58.03） × 10^6/L, （11.68 × 9.95） × 10^6/L and （28.62 ± 10.46） × 10^6/L, respectively, in which the number of eosinophils in group A was significantly higher than those of group B and C. Also, the number of neutrophils in BALF of group A was even higher than those in group B and C. In addition, the contents of IFN-7 and IL-2 in group A were lower than those in group B and C, but the contents of IL-4 as well as IL-5 were rather higher than those in group B and C. It is evident from the above observations that IL-18 can effectively inhibit the asthmatic inflammatory cells in BALF with an imbalance of the Thl/Th2 cytokines, thus offer- ing the experimental basis for the clinical application of IL-18 in the prevention and treatment of asthma.

Effect of moxibustion at Feishu(BL 13)on airway inflammation in asthma model rats

Objective:To observe the effect of moxibustion at Feishu(BL 13)on related inflammatory cells and inflammatory factors in the bronchoalveolar lavage fluid of asthma model rats,and to explore the mechanism of moxibustion in treating asthma.Methods:A total of 48 Sprague-Dawley(SD)rats were randomly divided into a normal group,a model group,a moxibustion group and a medication group,with 12 rats in each group.Except for the normal group,the rats in the other three groups were subjected to ovalbumin sensitization to stimulate the asthma.At the same time,rats in the moxibustion group received moxibustion at bilateral Feishu(BL 13),and rats in the medication group received dexamethasone by intragastric administration.Rats in the normal and the model groups only received the same fixation and normal saline by intragastric administration.After the interventions,the inspiratory resistance,the expiratory resistance,and the pulmonary compliance were measured for rats in each group;the numbers of the inflammatory cells in the bronchoalveolar lavage fluid were counted;the levels of the involved inflammatory factors in bronchoalveolar lavage fluid were detected;the pathological morphologies of the lung tissues were observed under light microscope.Results:After modeling,compared with the normal group,the rats in the model group showed obvious asthma attack-like response,significantly increased inspiratory resistance and expiratory resistance(both P<0.01),and significantly reduced pulmonary compliance(P<0.01);thickened tracheal wall and the narrowed tracheal lumen observed under the light microscope;infiltration of inflammatory cells and increased eosinophils in and around the tracheal wall;significantly increased total number of inflammatory cells and proportion of eosinophils in the bronchoalveolar lavage fluid(all P<0.01);significantly reduced levels of interleukin(IL)-10,IL-12 and interferon(IFN)-γ(all P<0.01),and significantly increased levels of IL-4,IL-5 and tumor necrosis factor(TNF)-α(all P<0.01)in the bronchoalveolar lavage fluid.After intervention,compared with the model group,rats in the moxibustion and the medication groups showed significantly reduced asthma-like reaction,pathological morphological damage of lung tissue,inspiratory resistance and expiratory resistance(all P<0.01);significantly increased pulmonary compliance(P<0.01);significantly reduced total number of inflammatory cells,proportion of eosinophils,levels of IL-4,IL-5 and TNF-αin the bronchoalveolar lavage fluid(P<0.05 or P<0.01),while significantly increased IL-12 and IFN-γlevels(all P<0.01)in the bronchoalveolar lavage fluid;rats in the medication group also showed a significantly reduced IL-10 level in the bronchoalveolar lavage fluid(P<0.01);there was no statistically significant difference between the moxibustion and the medication groups(all P>0.05).Conclusion:Both moxibustion at Feishu(BL 13)and intragastric administration of dexamethasone can improve the asthma attack-like symptoms of ovalbumin-sensitized rats;regulating the inflammatory cell numbers and the inflammatory factor contents in the lung may be one mechanism of moxibustion in treating asthma.

Regulatory T cells and asthma

Asthma is a chronic disease of airway inflammation due to excessive T helper cell type 2 （Th2） response. Present treatment based on inhalation of synthetic glucocorticoids can only control Th2-driven chronic eosinophilic inflammation, but cannot change the immune tolerance of the body to external allergens. Regulatory T cells （Tregs） are the main negative regulatory cells of the immune response. Tregs play a great role in regulating allergic, auto- immune, graft-versus-host responses, and other immune responses. In this review, we will discuss the classification and biological characteristics, the established immunomodulatory mechanisms, and the characteristics of induced differentiation of Tregs. We will also discuss the progress of TregS in the field of asthma. We believe that further studies on the regulatory mechanisms of Tregs will provide better treatments and control strategies for asthma.

Effects of Wuwei Dilong Decoction on Inflammatory Cells and Cytokines in Asthma Model Guinea Pigs

Objective： To explore the effects and the mechanism of Wuwei Dilong Decoction （五味地龙汤 Schisandra Fruit and Earthworm Decoction） for treatment of asthma. Methods： The asthma guinea pig model was established with spray of ovalbumin （OVA）. Fifteen days later, the guinea pigs were administered by intra-gastric perfusion of Wuwei Dilong Decoction once a day for 8 consecutive days. Blood samples were taken for testing the total leucocytes, eosinophil （EOS）, lymphocytes, interferon-γ （IFN-γ） and leukotriene B4 （LTB4）. Results： In the asthma model group, the total leucocytes, EOS and lymphocytes were all increased, with significant differences as compared with the different dosage Wuwei Dilong Decoction groups （P〈0.01 or P〈0.05）. The serum LTB4 in the asthma model group was significantly increased and IFN-γ decreased. After administration of Wuwei Dilong Decoction of the large, medium and small dosages, LTB4 decreased, while IFN-7 increased （P〈0.05 or P〈0.01）. Conclusion： Wuwei Dilong Decoction can inhibit infiltration and diffusion of the inflammatory cells in the asthma model guinea pigs, and regulate LTB4 and IFN-γ, which is probably one of the important mechanisms of Wuwei Dilong Decoction for relieving asthma.