微囊蛋白1及细胞内钙离子在TGF-β1诱导哮喘大鼠气道平滑肌增殖中的作用

目的探讨微囊蛋白1、细胞内钙离子在转化生长因子β1(TGF-β1)诱导哮喘大鼠气道平滑肌细胞(ASMCs)增殖中的作用。方法离体培养大鼠ASMCs,并分为正常组、哮喘组、TGF-β1干预组、TGF-β1+β-环糊精(β-CD)干预组,CCK-8法检测各组细胞的增殖水平;Western blot法检测各组微囊蛋白1含量;流式细胞仪检测各组ASMCs胞内钙离子荧光强度。结果哮喘组OD值较正常组明显增加(P<0.05),TGF-β1组OD值较正常组、哮喘组明显增加(P<0.05),TGF-β1+β-CD组OD值较TGF-β1组明显增加(P<0.05)。TGF-β1组较正常组和哮喘组微囊蛋白1含量减少(P<0.05),TGF-β1+β-CD组较TGF-β1组微囊蛋白1含量减少(P<0.05)。TGF-β1组较正常组和哮喘组胞内钙离子荧光强度增加(P<0.05),TGF-β1+β-CD组较TGF-β1组胞内钙离子荧光强度增加(P<0.05)。相关关系分析示细胞增殖水平与微囊蛋白1含量呈负相关(r=-0.51,P<0.05),细胞增殖水平与钙离子荧光强度呈正相关(r=0.60,P<0.05),微囊蛋白1含量与钙离子荧光强度呈负相关(r=-0.87,P<0.05)。结论微囊蛋白1可以抑制TGF-β1诱导的ASMCs增殖,这种抑制作用可能部分是通过减少胞内游离钙离子来实现的。

基于网络药理学探讨小儿止哮平喘颗粒治疗支气管哮喘的作用机制

目的运用网络药理学探讨小儿止哮平喘颗粒治疗支气管哮喘的作用机制。方法通过TCMSP和SymMap数据库筛选小儿止哮平喘颗粒的活性成分及其作用靶点,通过NCBI Gene、GeneCards、TTD、KEGG、MalaCards、PharmGKB、OMIM等数据库筛选支气管哮喘的疾病相关靶点,获取活性成分作用靶点与疾病相关靶点的交集靶点(共同靶点),即小儿止哮平喘颗粒治疗支气管哮喘的潜在作用靶点。运用Cytoscape3.2.1软件构建“中药-成分-靶点-疾病”网络,将上述共同靶点导入String数据库,获取数据后在Cytoscape3.2.1软件中构建“成分靶点-疾病靶点”(T-D)网络,利用Metascape数据库进行GO和KEGG通路富集分析。结果共筛选得到289个活性成分及470个潜在作用靶点;获得豆甾-4-烯-3-酮、白矢车菊素、丹参醌酚I、飞燕草素、(E)-(4-甲基亚苄基)-(4-苯基三唑-1-基)胺、油酸等核心活性成分;RAC-α丝氨酸/苏氨酸蛋白激酶(RAC-alpha serine/threonine-protein kinase,AKT1)、p53蛋白(cellular tumor antigen p53,TP53)、黏着连接蛋白β1(cateninβ1,CTNNβ1)、转录因子激活蛋白-1(transcription factor AP-1,JUN)、Harvery鼠肉瘤病毒癌基因(GTPase HRas,HRAS)、生长因子受体结合蛋白2(growth factor receptor-bound protein 2,GRB2)、过氧化物酶体增殖激活受体γ(peroxisome proliferator-activated receptor gamma,PPARG)等核心靶点;筛选得到AGE-RAGE信号通路、钙信号通路、cAMP信号通路、TNF信号通路、PI3K-Akt信号通路等关键信号通路。结论小儿止哮平喘颗粒可通过多成分、多靶点调控多种通路达到治疗小儿支气管哮喘的作用,为其分子机制研究奠定了一定的基础。

Bronchoalveolar Lavage and Histologic Characterization of Inhaled Heparin in Asthmatic Guinea Pigs

Objective: To survey the effects of inhaled heparin on airway inflammation inguinea pigs with asthma and investigate the possible mechanism of inhaled heparin in the treatmentof asthma. Methods: The asthma in guinea pigs induced by ovalbumin was treated with inhaled heparin.The changes of cellularities in bronchoalveolar lavage (BAL) fluid and the airway walls wereexamined. Histologic examinations were also done in the guinea pig controls. Results: The number ofeosinophils, lymphocytes, and ciliated epithelial cells in the BAL fluid from the group treated withheparin was significantly lower than that of the group of asthma controls (P<0.01). Within theairway watts of the heparin treated group, the eosinophil infiltration was less prominent than thatof the group of asthma controls (P<0.001) and the number of mast cell was significantly higher thanthat of the group of asthma controls (P<0.01). Histologic examination showed that airway damages inthe heparin treated group were mild. Conclusion: Heparin can inhibit airway inflammation andalleviate airway damage in guinea pigs with asthma.

IT IS GASTROESOPHAGEAL REFLUX DISEASE, NOT ASTHMA: A CASE REPORT

THE incidence of gastroesophageal reflux disease （GERD） is high in Western nations. Its extraesophageal manifestations such as asthma, paroxysmal laryngospasm, and excessive throat phlegm,

Asthma and gastroesophageal reflux disease: Effect of long-term pantoprazole therapy

AIM： To define the prevalence of gastroesophageal reflux disease （GERD） in mild persistent asthma and to value the effect of pantoprazole therapy on asthmatic symptoms.METHODS： Seven of thirty-four asthmatic patients without GERD served as the non-GERD control group. Twenty-seven of thirty-four asthmatic patients had GERD （7/27 also had erosive esophagitis, sixteen of them presented GERD symptoms. An upper gastrointestinal endoscopy was performed in all the subjects to obtain five biopsy specimens from the lower 5 cm of the esophagus. Patients were considered to have GERD when they had a dilation of intercellular space （DIS）〉0.74 μm at transmission electron microscopy. Patients with GERD were treated with pantoprazole, 80 mg/day. Forced expiratory volume in one second （FEV1） was performed at entry and after 6 mo of treatment. Asthmatic symptoms were recorded. The required frequency of inhaling rapid acting β2-agonists was self-recorded in the patients＇ diaries.RESULTS： Seven symptomatic patients presented erosive esophagitis. Among the 18 asymptomatic patients, 11 presented DIS, while all symptomatic patients showed ultrastructural esophageal damage. Seven asymptomatic patients did not present DIS. At entry the mean of FEV1 was 1.91 L in symptomatic GERD patients and 1.88 L in asymptomatic GERD patients. After the treatment, 25 patients had a complete recovery of DIS and reflux symptoms. Twenty-three patients presented a regression of asthmatic symptoms with normalization of FEV1. Four patients reported a significant improvement of symptoms and their FEV1 was over 80%.CONCLUSION： GERD is a highly prevalent condition in asthma patients. Treatment with pantoprazole （80 mg/day） determines their improvement and complete regression.

Respiratory Distress Resulting from Gastroesophageal Reflux Is not Asthma,but Laryngotracheal Irritation,Spasm,even Suffocation

ESPITE the strong association between gastroesophageal reflux disease （GERD） and asthma has been undisputedly established and widely recognized by experts in advanced countries. Yet few topics in medicine are as controversial as the causal relationship between GERD and asthma： some argue that GERD causes asthma, while others think the other way around is true, still quite a few believe that bronchodilator medications are to blame. This controversy continues to be a conundrum or more piece of the puzzle.1 We would like to share two thoughts which might be a belated revelation with scholars and experts and invite them for further cooperative studies： the GERD-derived respiratory distress is not asthma, but GERD pure and simple; and the pathogenesis of respiratory distress is not asthma, but laryngotracheal irritation/spasm/suffocation.

IL-23 signaling enhances Th2 polarization and regulates allergic airway inflammation

IL-23/IL-17 axis is an important regulator in various inflammatory diseases. However, the role of IL-23 in allergic airway inflammation is not well understood. In this study, we show that in an allergen-induced asthma model, mice with transgenic overexpression of IL-23R exhibited increased airway infiltration of eosinophils and Th2 cytokine production, whereas those deficient in IL-23 displayed reduced airway inflammation. In vitro, IL-23-IL-23R signaling promoted GATA-3 expression and enhanced Th2 cytokine expression. Conversely, in the absence of this signal, Th2 cell differentiation was partially inhibited. Therefore, IL-23 signaling may regulate allergic asthma through modulation of Th2 cell differentiation.

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.

HOUSE DUST MITE ALLERGEN (Derp1 AND Blot5) LEVELS IN ASTHMATICS' HOME IN HONGKONG

To measure Derp1 and Blot5 allergen levels in asthmatics’ homes in Hongkong. Methods Seventy houses were enrolled for a mite indoor environment study. Dust samples were obtained from two sites of each patients’ house: bed and floor. Derp1 and Blot5 levels were quantified by a two-site monoclonal antibody-based ELISA technique. Results The levels of Derp1 allergens found in bed (geometric mean (GM) 3.43 μg/g of dust; 95%CI, 1.89-4.96 μg/g) and on the floor (GM 1.12 μg/g of dust; 95%CI, 0.71-1.53 μg/g) indicated significant differences (P = 0.005). However, the levels of Blot5 allergens found in bed (GM 19.00 μg/g of dust; 95%CI, 0.89-38.90 μg/g) and on the floor (GM 6.14 μg/g of dust; 95%CI, 0.40-11.90 μg/g) showed no statistically significant difference. In addition, in regards to the exposure index for Derp1 and Blot5 allergens found in bed and on the floor, 17.6% in bed and 8.6% on the floor had levels of Blot5 ≥ 10 μg/g of dust, higher than those obtained for Derp1 (7.2% and 0% in bed and on the floor respectively, P < 0.05); higher percentages in bed and on the floor (25.0% and 35.7%) were observed for levels of Blot5 = 0 μg/g of dust as compared with Derp1 in bed and on the floor (4.3% and 14.5% respectively, P < 0.05). Conclusions Derp1 and Blot5 are the major allergens found in this regional study, Blot5 is a more potent allergen in Hongkong, probably reflecting the high level of exposure to Blomia tropicalis (Bt). Bt and Dermatophagoides pteronyssinus(Dp) allergens should be included for precise diagnosis and effective immuno-therapeutic treatment of mite allergy in Hong-kong.

Effect of omeprazole and domperidone on adult asthmatics with gastroesophageal reflux

AIM： To study the effect of combined omeprazole（Ome） and domperidone（Dom） therapy on asthma symptoms and pulmonary function in asthmatics with gastroesoph- ageal reflux. METHODS： We selected 198 asthmatics with gastro- esophageal reflux diagnosed by 24-h esophageal pH moni- toring to receive Ome 20 mg twice daily and Dom 10 mg three times daily or placebo for 16 wk （1：1 double-blind randomization）. Spirometry was done at baseline and after 16 wk of treatment. The primary outcome measures were： mean daily daytime and nighttime asthma symptom scores. Mean daily reflux symptom scores, albuterol use as rescue medication （number of puffs）, daytime and nighttime peak expiratory flow rate （PEFR）, postbronchodilator forced expiratory volume in 1 second （FEVl） and postbronchodilator forced vital capacity （FVC） were secondary outcome measures. RESULTS： Comparison of mean change from baseline between antireflux therapy and placebo groups revealed significant reduction in daytime asthma symptom score （17.4% vs 8.9 %）, nighttime asthma symptom score （19.6% vs 5.4%）, reflux symptom score （8.7% vs 1.6%） and rescue medication use （23.2% vs 3.1%） after antireflux therapy compared to mean change in placebo group （P 〈 0.001）. There was significant improvement in morning PEFR （7.9% vs 0.2%）, evening PEFR （9.8% vs 0.5%）, FEW （11.1% vs 3.78%） and FVC （9.3%vs 1.52%） in the antireflux therapy group compared to placebo on comparng the mean change from baseline after 16 wk （P 〈 0.01） CONCLUSION： Combined therapy with Ome and Dom in adult asthmatics with gastroesophageal reflux may be beneficial by reducing asthma symptoms, rescuing medi- cation use, and improving pulmonary function.

Sirolimus-related pulmonary toxicity mimicking 'asthma like' symptoms

Sirolimus is an immunosuppressant with expanding use in pediatric organ transplantation, dermatology and rheumatology. We report two cases of children who developed asthma like symptoms and were diagnosed with interstitial lung disease, which responded to discontinuation of sirolimus. Pediatricians should be aware about the pulmonary side effects of sirolimus.

Airborne Pollen Grains Of Afyon, Turkey

The airborne pollen grains of Afyon have been studied for a two_year period (1999-2000) with a Durham sampler. A total of 14 367 pollen grains belonging to 40 taxa have been identified and recorded with some unidentified ones. Of them, 6 732 were identified in 1999 and 7 635 in 2000. Of the total pollen grains, 69.67% were arboreal, 26.64% non_arboreal and 3.68 % unidentified. The majority of the investigated pollen grains were from Pinus, Gramineae, Cupressaceae, Platanus , Chenopodiaceae/Amaranthaceae, Quercus, Ailanthus, Moraceae, Juglans , Salix, Cedrus and Rosaceae. The highest level of pollen grains was in May.

THE ASSOCIATION BETWEEN TUMOR NECROSIS FACTORαGENE POLYMORPHISM AND ASTHMA

Objective.In this study,we investigated the hypothesis that tumor necrosis factor(TNF)α-308gene polymorphism might be of the genetic predisposition to asthma and asthma phenotypes.Methods.TNFα-308gene polymorphism was genotyped in221random unrelated Northern Chinese population(comprising125asthmatics and96healthy controls)and52individuals from12asthmatic families with Han ethnic by using polymerase chain reaction(PCR)-restriction fragment length polymor-phism(RFLP).Methacholine(Mch)broncho-challenge test,bronchial reversibility test and lung function were underwent in all asthmatics.Results.TNFα-3082homozygosity was present at a significantly higher frequency in asthmatics than that in controls(20.8%vs11.4%,P<0.05,OR2.259),the TNF allele2was also higher in asthmatics compared with controls(0.42vs0.33,P<0.01).TNFα-3082homozygosity was an weak independent risk factor for asthma etiology(OR0.226,P<0.05).Moreover,patients carrying TNFα-3082homozy-gosity had less responsive to inhaledβ 2 -agonist in20minutes than patients carrying other two genotypes(24.1%vs29.5%vs38.8%,P<0.05).Linkage analysis didn’t support that TNFαgene was linked to asthma (Likelihood of odds,LOD<1)based on familial data.Conclusion These results suggest that TNFα-3082homozygosity may be of a component contribut-ing to the genetic predisposition to asthma ,and airway responsiveness toβ2 -agonist.

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.

Asthma in pregnancy

Asthma affects approximately 8% of women during pregnancy. Pregnancy results in a variable course for asthma control, likely contributed to by physiological changes affecting the respiratory, immune, and hor-monal systems. While asthma during pregnancy has been associated with an increased risk of maternal and fetal complications including malformations, available data also suggest that active asthma management and monitoring can decrease the risk of adverse outcomes. The diagnosis, disease classifcation, and goals for asthma management in the pregnant woman are the same as for nonpregnant patients. However, evidence shows that pregnant asthmatics are more likely to be under-treated, resulting in asthma exacerbations occurring in approximately one third and hospitalization in one tenth of patients. Pharmacotherapeutic management of asthma exacerbations in pregnant patients follows stan-dard treatment guidelines. In contrast, the principles of asthma maintenance therapy are slightly modified in the pregnant patient. Patients and practitioners may avoid use of asthma medications due to concern for a risk of fetal complications and malformations. A variable amount of information is available regarding the risk of a given asthma medication to cause adverse fetal out-comes, and it is preferable to use an inhaled product. Nevertheless, based on available data, the majority of asthma medications are regarded as safe for use during pregnancy. And, any increased risk to either the mother or fetus from medication use appears to be small compared to that associated with poor asthma control.

Association between interleukin-4 polymorphisms and asthma

Objective:To perform a systematic review and meta analysis on the association of C-589T and C-590T polymorphisms of IL-4 with asthma and to estimate allele frequencies, the magnitude of the gene effect as well as the possible mode of inheritance. Methods: A genetic model-free approach was used to perform a meta analysis. Heterogeneity, sensitivity analysis and publication bias were also explored. Results: Our meta analysis summarized the evidence to date regarding the association of C-589T and C-590T polymorphisms in the promoter region of IL-4 gene with asthma. For C-590T, the results showed a significant recessive genetic model, and the CC genotype was about 24% less likely to have asthma than the genotype CT and TT. Although there was evidence suggesting a recessive genetic model for C-589T, the recessive model was not statistically significant. Conclusion: This meta analysis suggests that there may be an important effect of single nucleotide polymorphisms (SNPs) in the promoter region of IL-4 gene on the pathogenesis of asthma.

Remission of bronchial asthma after viral clearance in chronic hepatitis C

A 53-year-old man with a history of blood transfusion at the age of 20 was admitted to our hospital because of liver dysfunction. He had bronchial asthma when he was 18 years old, which naturally resolved within 2 years. However, his bronchial asthma recurred at the age of 45 and was treated with oral theophylline. He was diagnosed as having chronic hepatitis C based on the histological and clinical findings, and then interferon (IFN) therapy was administered. The frequency of bronchial asthma attack was gradually decreasing after IFN therapy with marked improvement of hypereosinophilia. He achieved sustained viral response (SVR) and his bronchial asthma did not worsen even after the cessation of IFN. Hepatitis C virus (HCV) infection and IFN therapy were considered in the remission of asthma in this case. HCV infection could be the cause of bronchial asthma, especially in patients with late appearance of asthma.

Camel milk could be helpful in the treatment of asthma

Asthma is a chronic inflammatory disease with excessive irritability and airway narrowing and inflammation plays an important role in it.There are 300 million asthmatic people in the world currently.Main treatments for asthma include two groups of bronchodilators and inflammation controllers.Researches was continued in order to reach new treatments to reduce drug side effects and treatment-resistant cases or the types associated with weak treatment response.Today,World Health Organization recommends the application of traditional medicine especially in underdeveloped countries because of insufficient health resources and spread of diseases.Iranian traditional medicine(ITM)or Persian medicine is one of the oldest comprehensive traditional medicines with thousands years history which could help us to manage different diseases.The aim of this hypothesis is to investigate the camel milk as a complementary treatment of asthma because this chronic disease is sometimes resistant or response weakly to the treatment.In this article,the administration of camel milk in lung inflammatory diseases was studied by searching the PubMed and Scopus scientific databases.The results of this study indicated that camel milk due to having anti-inflammatory,immunomodulatory and anti-oxidant effects could decrease the levels of inflammatory factors such as tumor necrosis factorα,interleukin-17(IL-17),IL-6,IL-1B and transforming growth factor-β1 in a human and animal samples with inflammatory diseases.Besides,based on ITM,camel milk was used in treatment patients with asthma.But,clinical studies are needed to validate the effectiveness of camel milk in asthma and its mechanisms.

Relationship between Chlamydia pneumoniae infection and occurrence of bronchial asthma

Objective: To study the relationship between Chlamydia pneumoniae (C. pneumoniae) infection and asthma exacerbation. Methods: A prospective study of C. pneumoniae infection was conducted in 75 patients with asthma and 63 patients with respiratory tract infection, and 100 blood donors served as controls. The presence of infection was convinced by the polymerase chain reaction and direct immunofluorescence assay for C. pneumoniae DNA from throat swab specimens and micro-immunofluorescence testing for C. pneu-moniae-specific IgG, IgM and IgA antibodies. Results: Prevalence of specific IgG in asthma patients (81. 3%) was higher than that of the blood donors (68. 0%, P<0. 05) and was not significantly different from respiratory tract infection patients (68. 0%, P>0. 05). The acute C. pneumoniae infection rate of symptomatic asthma patients (59. 4%) was markedly higher than that of respiratory tract infection patients (34. 9% , P<0. 05). The average titer of C. pneumoniae IgG instead of IgA in asthma patients (48. 38±6. 94) was significantly higher than respiratory tract infection patients (24. 70±8. 77, P<0. 05). Other pathogens were identified in 12 of 21 (57. 1%) asthma patients with C. pneumoniae. The symptoms of 7 asthma patients with C. pneumoniae infection were improved through antibiotic treatment. Conclusion: The findings suggest a possible role of C. pneumoniae infection in asthma.

CIRCULATING INTERCELLULAR ADHESION MOLECULE 1 LEVELS IN SERA OF BRONCHIAL ASTHMA

Objective The aim of the study was to determine whether bronchial asthma was associated with increased levels of soluble intercellular adhesion molecule 1(sICAM 1) in serum, which might be valuble data for the effective therapy of these patients Patients and methods The concentrations of sICAM 1 were determined in sera of healthy donors and asthmatic patients using a sensitive enzyme immunoassay Results The mean(±SD) levels of serum sICAM 1 of 26 asthmatic patients (205±72 0 μg/L)was significantly higher than that of the 30 healthy volunteers (154±63 9 μg/L,P<0 01) There was no much difference between the serum levels in 12 patients suffering from atopic asthma and the levels in 14 patients with nonatopic asthma The serum concentrations of sICAM 1 were higher during asthma attacks than that during remissions in the same patients (P<0 05) Conclusion These results suggest that sICAM 1 may play a certain role in the pathophysiology of bronchial asthma,and might be signals for successful treatment