【作者】 王晓岩；

【导师】 迟宝荣；

【作者基本信息】 吉林大学 ， 内科学， 2009， 博士

【摘要】 支气管哮喘(bronchial asthma,简称哮喘)是由多种炎症介质、炎症细胞和细胞因子参与的一种气道慢性炎症性疾病,是当今世界范围内严重威胁人类健康的主要慢性疾病之一,近年来在许多国家的发病率呈上升趋势。中药喘息康颗粒(Chanxikang Keli,CXKKL)是吉林省中医药科学院呼吸科的经验方,具有温肺散寒,化痰平喘,临床主治哮喘,症见呼吸急促,喉中哮鸣有声,胸膈满闷等以寒哮等为主要临床表现者,在临床上取得了较好的疗效。本实验对中药喘息康颗粒治疗支气管哮喘的药效学及对哮喘豚鼠模型哮喘机制进行干预的研究,研究喘息康颗粒对支气管哮喘的药理作用,并初步探讨其机制。研究结果表明,喘息康颗粒能延长由组织胺和氯化乙酰胆碱混合液喷雾所致豚鼠哮喘的引喘潜伏期,增加小鼠气道内酚红排出量,减轻小鼠二甲苯耳水肿反应及角叉菜胶致大鼠足肿胀,减轻大鼠被动皮肤过敏反应,使二氧化硫引起小鼠咳嗽的潜伏期明显延长和咳嗽次数明显减少。另外,本实验还对哮喘豚鼠模型哮喘机制进行干预治疗研究,研究结果提示:喘息康颗粒能改善哮喘症状;减少外周血中嗜酸性粒细胞数;减轻哮喘豚鼠支气管周围肺组织的病理变化,降低豚鼠血清和肺泡灌洗液中IL-4含量,升高IFN-γ含量,与模型组比较具有极显著性差异;升高豚鼠血清中Eotaxin含量,降低豚鼠肺组织中MMP-9及TIMP-1含量,增强豚鼠肺组织中IFN-γ基因表达,抑制豚鼠肺组织中IL-4基因表达,从而发挥抗炎、平喘作用,取得较好的疗效。更多还原

【Abstract】 Bronchial asthma are a variety of inflammatory mediators, inflammatory cells and cytokines involved, is a chronic airway inflammatory disease charactered by reversible airway obstruction, airway hyper responsiveness, airway remodeling ,which is a serious threat to human health in the worldwide, as one of the major chronic diseases. In recent years, the incidence tended to rise in many countries. Bronchial asthma is quite common in Western countries, worsening ability to work, and difficult to cure. Seriously disturbed people’s lives, so it’s important to prevent and treat for the urgent asthma.The exact cause of asthma incidence and pathogenesis has not yet been clarified. Generally, it is believed that the pathogenesis of asthma and genetic, immunological, and environment caused by the interaction of various factors. In recent years, because of the rapid development of modern industries, atmospheric environmental degradation, combined with smoking and other unhealthy lifestyle, as well as social, psychological and other factors, the incidence of asthma has been rising. However, the complexity of the disease etiology, pathogenic factors of the occurrence are the basic factors are the basis of diseases, most of that is a genetic disease, genetic and environmental factors affected by the dual impact of asthma in recent years, so the study of genetic factors the more and more. Trigger asthma and also more complex, and many allergens, infection factors, environmental factors, dietary factors, occupational factors, drug factors, exercise factors, psychological factors, endocrine factors and so on. However, the nature of asthma is chronic allergic airway inflammation.Asthma is characterized by the inflammation of eosinophils (EOS) accumulation in the bronchial tissue and cause activation of the reversible airway obstruction, airway allergic inflammation (AAI) and airway hyperresponsiveness (BHR). Study shows that a large number of Th subsets Th1 and Th2 cross-regulation exist between the relationship, Th1 and Th2 imbalance in the pathogenesis of bronchial asthma has an important role in the performance of functions relative to Th1 suppression, Th2 function of the relative hyperfunction. Thl cells and immune regulation of cellular immune function of anti-inflammatory, Th2 cells regulate humoral immunity and allergic features, both the destruction of the balance as soon as the attack will cause asthma, IFN-γ, IL-4, respectively, are Thl, Th2 cells characteristic cytokines, IFN-γand IL-4 ratio of the response in the body cells Thl/Th2 balance. Matrix metalloproteinases (matrix metalloproteinases, MMPs) are a group of structurally similar MMPs matrix degradation, matrix protease inhibitors (tissue inhibitor of metalloproteinase, TIMPs) can inhibit MMPs. MMP-9 and its inhibitor TIMP-1 is one of the most important members, may be involved in asthmatic airway inflammation, smooth muscle and airway wall remodeling of extracellular matrix deposition.At present, the modern medical treatment of the disease mainly glucocorticoid,β2 receptor agonist, disodium cromoglycate, anticholinergic drugs, etc. To ease the acute attack of asthma can get better effect, but the whole body of patients with asthma without immune dysfunction obvious regulatory role. Bronchial asthma is a systemic immune dysfunction disorders, Chinese medicine in the treatment of asthma treatment for this, uphold, can play a unique advantage and role of a more prominent research value and broad development prospects.Chinese medicine granules are breathing Jilin Academy of Traditional Chinese Medicine experience respiratory side with lung temperature and cold-dispelling, phlegm Pingchuan role in achieving a better clinical efficacy, but its mechanism has not been very clear.Chinese medicine CXKKL treatment of bronchial asthma and the efficacy of asthma guinea pig model of asthma intervention in the role of mechanisms have been studied using molecular biology and immunohistochemical techniques from the level of gene and protein dynamics in observing, studying, breathing granules of the pharmacological effects of bronchial asthma and to explore its mechanism.The following is the study outcomes:1.CXKKL to extend by histamine and acetylcholine chloride spray caused by the mixture of guinea pig asthma asthma latency, delay the onset of asthma. 2.CXKKL mice can increase the output phenolsulfonphthalein airway to facilitate the discharge of sputum, and thus has a role in expectoration; sulfur dioxide can cause coughing in mice and significantly prolong the incubation period significantly reduced the number of cough, wheezing that has the town of Granules cough expectorant effects.3.CXKKL can reduce the xylene ear edema reaction in mice and carrageenan induced rat paw swelling and reduce passive cutaneous anaphylaxis in rat shows that breathing Granules with anti-inflammatory, reducing the role of inflammatory exudation.4.From the improvement of pathological changes in lung tissue, bronchial asthma model group of inflammatory lesions in lung tissue and dexamethasone group and comparison group were CXKKL increase to the minimum lesion dexamethasone group, CXKKL second group. Preliminary proof of their asthma bronchitis disease when there is inhibition of cell infiltration.5.Guinea pig asthma Change Level results showed that: compared with normal control group, asthma model group, CXKKL group and dexamethasone group was significantly higher asthma Level; compared with the asthma model group, CXKKL group and dexamethasone group has to reduce the trend of asthma symptoms, but without statistical significance.6.Guinea pig peripheral blood eosinophil count showed that the change: compared with normal control group, asthma model group, CXKKL group and dexamethasone group the blood significantly increased the number of Eos has a very significant difference; with the model group: CXKKL group and dexamethasone group, the number of Eos was significantly reduced, with a very significant difference. To prove that when the asthma bronchitis there is inhibition of cell infiltration disease.7.CXKKL group and dexamethasone group of guinea pigs shortness of breath, not the entire respiratory rhythm, breathing rate and so on than the model group reduced, compared with the model group was significantly prolonged incubation period of asthma, with a very significant difference. Prove that the improvement of asthma symptoms have a role.8.CXKKL can reduce the peripheral blood and BALF of IL-4 and Eotaxin levels and in lung tissue expression of IL-4mRNA decreased; In contrast to make IFN-γsignificantly increased in lung tissues of IFN-γmRNA expression was significantly lower, suggesting that its inhibiting Th2 cell differentiation and promote Th1 cell differentiation, correcting Th1/Th2 imbalance has important significance. And can reduce the lung tissue of MMP-9 and TIMP-1, thereby inhibiting the airway inflammation of bronchial asthma and the role of airway remodeling.Innovation of the study:1.Study the efficacy and mechanism CXKKL confirmed asthma CXKKL to extend the incubation period of asthma, delay the onset of asthma, and has antitussive, expectorant, anti-inflammatory, reducing the role of inflammatory exudation.2.Application of RT-PCR technology CXKKL observed in lung tissue of IL-4mRNA and IFN-γmRNA expression, CXKKL treatment of the mechanism of bronchial asthma. CXKKL and can reduce the lung tissue of MMP-9 and TIMP-1, thereby inhibiting the airway inflammation of bronchial asthma and airway remodeling.更多还原