IPF氧化损伤发病机制和抗氧化治疗进展

发布时间：2018-07-22 19:49

【摘要】：特发性肺纤维化(idiopathic pulmonary fibrosis, IPF)是一种原因不明的肺间质慢性弥漫性纤维化性疾病,以进行性呼吸困难、肺功能下降、预后差为特征,最终死于呼吸衰竭。近年来IPF的发病率呈上升趋势。肺内常见的氧化剂有超氧阴离子自由基、羟自由基、过氧化氢、一氧化氮、过氧化亚硝基阴离子,其中以羟自由基损伤力最强。抗氧化剂有维生素E、α-硫辛酸、还原型谷胱甘肽、超氧化物歧化酶、过氧化氢酶、谷胱甘肽过氧化物酶、血红素加氧酶1和硫氧还蛋白等。抗氧化剂可直接清除氧化剂或催化氧化剂反应生成其他物质而减轻氧化损伤。氧化损伤在IPF发病过程中有重要作用,保持氧化剂和抗氧化剂平衡可抑制IPF的发展。氧化剂通过以下机制促进IPF的发展。氧化剂如ROS可直接损伤蛋白质、DNA、脂类等生物大分子；活化NF-κB和AP-1,引起炎症因子基因表达,生成的IL-1、TNF-α反过来也可活化NF-κB,TGF-β.等也能增加ROS的生成,形成正反馈。TGF-β1减少有抑制肺纤维化作用的PGE2生成,而ROS能增多促纤维化的LT及TXA2生成,导致炎症损伤；ROS能刺激多种细胞表达TGF-β,进而活化成纤维细胞成为肌成纤维细胞,而成纤维细胞是合成细胞外基质的主要细胞；引起蛋白酶/抗蛋白酶失衡,如基质金属蛋白酶/金属蛋白酶抑制剂失衡导致细胞外基质过度沉积；ROS增多引起的肺泡上皮细胞凋亡导致了肺泡基底膜的破坏,募集成纤维细胞通过细胞外基质的沉积来修复损伤,细胞外基质持续沉积,最终破坏了正常肺结构。这些最终导致IPF的发生,因此纠正氧化/抗氧化失衡能减缓IPF发展,减轻肺纤维化程度。抗氧化治疗IPF是一个很有前景的研究方向。目前IPF尚无有效的治疗药物,且激素和免疫抑制剂疗效欠佳,亟需开发新药物或寻找新治疗手段。用于实验性治疗IPF的抗氧化剂分为三类：非酶类抗氧化剂、酶类抗氧化剂、中草药。虽然已开始应用NAC、盐酸氨溴索、硫辛酸等治疗IPF,但其疗效不确定,仍需进一步的临床试验。本文通过查阅国内外文献资料,介绍了体内常见氧化剂和抗氧化剂、IPF氧化损伤发病机制、IPF抗氧化治疗、总结和展望四个方面的研究进展,并附一篇综述介绍IPF的治疗进展。
[Abstract]:Idiopathic pulmonary fibrosis (idiopathic pulmonary fibrosis,) is a chronic diffuse fibrosis disease with unknown causes. It is characterized by progressive dyspnea, decreased pulmonary function and poor prognosis. The incidence of IPF is on the rise in recent years. The common oxidants in lung include superoxide anion radical, hydroxyl radical, hydrogen peroxide, nitric oxide and nitroso peroxide. Antioxidants include vitamin E, 伪 -lipoic acid, reduced glutathione, superoxide dismutase, catalase, glutathione peroxidase, heme oxygenase-1 and thioredoxin. Antioxidants can directly scavenge oxidants or catalyze oxidant reactions to produce other substances to reduce oxidative damage. Oxidative damage plays an important role in the pathogenesis of IPF. Maintaining the balance of oxidants and antioxidants can inhibit the development of IPF. Oxidants promote the development of IPF through the following mechanisms. Oxidants such as Ros can directly damage protein DNA, lipids and other biological macromolecules, activate NF- 魏 B and AP-1, induce the expression of inflammatory factor gene, and produce IL-1TNF- 伪, which in turn can activate NF- 魏 B and TGF- 尾. Ros can also increase the production of Ros, forming positive feedback. TGF- 尾 1 can reduce the production of PGE2, which can inhibit pulmonary fibrosis, while Ros can increase the production of LT and TXA2, resulting in inflammatory injury. Ros stimulates the expression of TGF- 尾 in a variety of cells and activates fibroblasts into myofibroblasts, which are the main cells that synthesize extracellular matrix. For example, the imbalance of matrix metalloproteinases / metalloproteinase inhibitors leads to excessive deposition of extracellular matrix Ros and apoptosis of alveolar epithelial cells, which leads to the destruction of alveolar basement membrane. Recruitment fibroblasts repair the damage through the deposition of extracellular matrix, and eventually destroy the normal lung structure. These ultimately lead to IPF, so correcting oxidation / oxidation imbalance can slow down the development of IPF and reduce the degree of pulmonary fibrosis. Antioxidant therapy for IPF is a promising research direction. At present, IPF has no effective therapy, and the effect of hormone and immunosuppressant is poor, so it is urgent to develop new drugs or to find new treatment methods. Antioxidants used for experimental treatment of IPF are classified into three categories: non-enzymatic antioxidants, Chinese herbal medicines. Although NAC, ambroxol hydrochloride and lipoic acid have been used in the treatment of IPF, the efficacy is uncertain and further clinical trials are needed. In this paper, the mechanism of common oxidants and antioxidants in vivo for oxidative injury of IPF and its antioxidation therapy are introduced, and the research progress in four aspects is summarized and prospected, and a review on the treatment of IPF is also given in this paper.
【学位授予单位】：山西医科大学
【学位级别】：硕士
【学位授予年份】：2012
【分类号】：R563.9

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