双巯氧吡啶(PTS2)在急性肺损伤中对毛细血管的作用分析.doc

PAGE 论文题目：双巯氧吡啶（PTS2）在急性肺损伤中 对毛细血管的作用 摘要 双巯氧吡啶（PTS2）是一种吡啶类植物碱，最早发现于陵水暗罗的根茎中。近期的研究已经证实了吡啶的金属配合物，尤其是巯氧吡啶锌具有很好的抗细菌和真菌感染的作用。并且吡啶的多种衍生物（包括PTS2）的抗恶性肿瘤的作用也已经得到证实。鉴于其药用价值，人工合成PTS2的方法技术也在不断的得到改进，现已能够大规模的进行工业合成。 本课题组前期工作发现PTS2能够通过抑制核转录因子STAT的活化而降低巨噬细胞内诱生型一氧化氮合酶（iNOS）和环加氧酶-2（COX-2）的表达，进而有效的降低内毒素休克导致的动物死亡率同时还能够显著减轻水肿、肺间质增厚、肺毛细血管损伤、出血和炎症细胞浸润、促炎因子表达及活性增加等主要的急性肺损伤（ALI）症状。巨噬细胞的活化和毛细血管通透性的改变是炎症初期的重要病理反应，对炎症的发展过程中起了至关重要的作用。在此基础上，本实验从肺毛细血管形态和功能的变化这一方面深入研究了PTS2抗ALI的作用机理。巨噬细胞被活化后，大量释放白细胞介素-1β（IL-1β）等细胞因子，它们能够影响内皮细胞的活动，使内皮表面黏附因子表达增加，内皮细胞发生凋亡。我们首先在小鼠身上进行实验，首先检测了肺泡灌洗液（BALF）中IL-1β的含量，发现IL-1β在受损伤肺的BALF中含量显著增加，而在正常和给药各组的BALF中含量很低。所以我们进一步检测了肺毛细血管的血浆蛋白通透性变化和血管内皮表面黏附分子-1（VCAM-1）的表达水平。结果显示PTS2可以明显降低油酸诱导的肺毛细血管通透性增高和内皮VCAM-1表达的上调。 关键词：PTS2 急性肺损伤 肺毛细血管 ABSTRACT Dipyrithione （PTS2）, which was first found in the rhizome of Polyalthia nemoralis A.DC., is a kind of plant alkaloid, belonging to pyridine family. Recent research indicated the anti-bacterium and anti-fungi effect of pyridine’s coordination compound with metal. Besides, many kinds of pyridine derivates including PTS2 have been confirmed to have anti-tumor effect. Considering about its pharmaceutic value, large-scale industrial synthesis has came into being, due to continual improvement of synthetic technology. Prior works in our lab has confirmed that PTS2 prevents animal dying from endotoxic shock induced by lipopolysaccharide (LPS) effectively by inhibiting the activation of STAT and impressing the expression of induced nitric oxide synthase (iNOS) and COX-2. At the same time, it can also reduce neutrophil accumulation, interstitial edema, congestion, endothelial integrity disruption, leakage of plasma protein as well as expression and activation of pro-inflammatory factors in the condition of acute lung injury (ALI). Activation of macrophage and change of microvascular permeability are important to the generation and development of inflammation. Based on these works, this paper exams the mechanism, by which PTS2 takes effect, in gr