慢性阻塞性肺疾病和缺氧性肺动脉高压的发病机理及药物防治研究

Study on Pathogenesis of Chronic Obstructive Pulmonary Diseases and Hypoxic Pulmonary Hypertension and me Preventive and Therapeutic Effects of Medicine

目的研究慢性阻塞性肺疾病(COPD)和缺氧性肺动脉高压的发病机理及中药814、肺舒灵的防治作用。方法建立弹性酶、吸烟、细菌感染、缺氧及脂多糖诱发COPD、肺动脉高压鼠模型及体外肺泡巨噬细胞、肺泡Ⅱ型上皮细胞培养,利用形态定量病理学、电镜、病理生理、免疫组化及分子生物学技术检测。结果 1、814、肺舒灵对COPD造成的气道、肺、肺小动脉的病理性结构改建有抑制(减轻)作用,降低肺动脉高压。2、814、肺舒灵能保护肺血管内皮细胞;抑制肺泡巨噬细胞肿瘤坏死因子TNF-α的产生和一氧化氮合酶NOS的异常表达;促进肺泡巨噬细胞发生凋亡。3、通过培养细胞的免疫组化,West-ern,Northern杂交检测,提示814可拮抗TNF-α对肺表面活性物质A、B、mRAN表达的抑制,并证明表面活性物质的基因表达变化与肺气肿病变的发生发展相关。提示内源性表面活性物质系统的改善有助于肺气肿的减轻。4.COPD及肺动脉高压肺组织中基质金属蛋白酶MMP-9、MMP-12 mRNA表达增强,肺舒灵有抑制MMP表达增强,防治COPD的作用。结论 814、肺舒灵对动物实验性COPD、缺氧性肺动脉高压有明显防治作用。其主要作用机理可能是保护肺血管内皮细胞,抑制肺泡巨噬细胞TNF-α的产生和iNOS的表达,减少炎症因子,从而起到防治COPD的作用。

Objective To investigate the pathogenesis of Chronic Obstructive pulmonary diseases (COPD) and Hypoxic pulmonary hypertension (HPH) and the preventive and therapeutic effects of Chinese herbal medicine - 814 and Feishuling.Methods The animal (hemsters or Wistar rate) models of COPD and HPH in duced by elastase, smoking, bacteria infective, E.Coli lipopolysaccharide and hypoxia were establi Shed.Cell culture of alveolar macrophages and typy Ⅱ lipneumocytes in vitro is conducted.The Lung Samples were observeted and measured by morphometric analysis under the Olympus light microscope and the electromicroscope, and the pathophysiology, immunohistochemistry and molecularbiology tests were performed.Results 1.Chinese herbs - 814 and Feishuling were obviously able to decrease HPH and bronchial, pulmonary arterial and pulmonary structural remodeling in COPD.2.814 and Feishuling were able to protect pulmonary endothelial cells, to inhibit abnormal expression of TNF - α mRNA and NOS, to promoto apoptosis of the alveolar macrophages in cultural alveolar macrophages .3.814 could antagonize the suppression of TNF - α on expression of pulmonary surfactant A - mRNA and B mRNA in cultural alveolar type Ⅱ epithelial cells.4.The expression of matrix metalloproteinase ( MMP) - 9, 12, mRNA increased significantly in alveolar macrophages and Feshuling had inhibiting effects on expression of MMP9, 12 in alveolar macrophages and lung tissue with COPD and HPH in immunohistochemistry.In Conclusion, Chinese herbs - 814 and Feshuling might significantly have preventive and therapeutic effects for COPD in animal experiments. Their major operative mechanism might be to protect pulmonary endothelial cells and to inhibit production of TNF - αof alveolar macrophages in COPD and HPH.