Andrographolide抑制LPS/IFN-gamma誘導大鼠血管平滑肌細胞發炎反應之機轉探討

近來的研究中發現動脈粥狀硬化不再被認為是一種脂肪堆積所造成的疾病，而是一種內皮失去功能、內皮下發炎反應以及血管平滑肌細胞的癒後有關的慢性發炎病程。本篇論文在於探討穿心蓮萃取物andrographolide (3-(2-(decahydro-6-hydroxy-5-(hydroxymethyl)-5,8a-dimethyl-2-methylene-1-napthalenyl)ethylidene)dihydro-4-hydroxy-2(3H)-furanone)抑制大鼠血管平滑肌細胞發炎的藥理機轉。在本篇研究中我們發現andrographolide(20及50 ?嵱)以濃度相關性的降低脂多醣體(lipopolysaccharide，LPS)以及干擾素(interferon-??)在大鼠血管平滑肌細胞中所引發的發炎因子，包含誘導型一氧化氮合成酵素以及基質金屬蛋白水解酶，訊息核醣核酸及蛋白質的生成。之後進一步探討andrographolide抑制細菌脂多糖體與干擾素合併誘導血管平滑肌細胞發炎的分子機轉。發現andrographolide抗發炎的效果是經由影響NF-?羠進入細胞核內進，而抑制轉錄因子NF-?羠訊息之活化。之後我們更進一步觀察andrographolide在動物實驗中，對於施以氣球擴張術後的大鼠頸動脈，是否能降低其血管新內膜的過度增生，發現andrographolide(5 mg/kg/day)可以明顯的減少氣球擴張術造成的血管內膜增生的情形。本研究發現，andrographolide可以藉由抑制轉錄因子NF-?羠之活化而降低下游發炎相關基因的表現，將來在臨床上對於動脈粥狀硬化疾病以及氣球擴張術後的血管再阻塞是具有開發潛力的藥物。

關鍵字

動脈粥狀硬化；發炎反應；轉錄因子NF-kappaB

並列摘要

In the recent study, atherosclerosis was no longer considered a disorder of lipid accumulation, but a disease process characterized by the dynamic interaction between endothelial dysfunction, subendothelial inflammation and the ‘wound healing response’ of the vascular smooth muscle cells. Andrographolide is a bicyclic diterpenoid lactone isolated from leaves of Andrographis paniculata. In the present study, we investigated the effects and mechanisms of andrographolide on the inflammatory effect induced by bacterial lipopolysaccharide (LPS) and interferon-?? (IFN-??) on cultured primary vascular smooth muscle cells (VSMCs). We found that andrographolide (20 and 50 ?嵱) exerted a concentration-dependently inhibited the inflammatory mediator expression including nitric oxide (NO) production, iNOS mRNA and protein expression upon stimulation by LPS (50 ?慊/mL)/IFN-?? (100 unit/mL) on VSMCs. On the other hand, andrographolide (20 and 50?嵱) concentration-dependently suppressed matrix metalloproteinase-9 not only expression but also activation on VSMCs, which are stimulated by LPS and IFN-???|?nAnd the continued research focused on the molecular mechanism of andrographolide inhibitory effect on LPS with Interferon-?? induced vascular smooth muscle cells inflammation. We found that andrographolide attenuated inflammatory effect by inhibiting NF-?羠 tranlocation therefore down-regulated transcription factor NF-?羠 signal activation. Moreover, we found that andrographolide (5 mg/kg/day) inhibited the thrombus and neointimal formation after angioplasty at prevention of neointimal hyperplasia in rats. Our research indicated that, by the down-regulation of the NF-?羠 target genes which are critical in thrombosis and inflammation, such as andrographolide, may be therapeutically valuable for preventing and treating thrombotic arterial diseases, including neointimal hyperplasia in arterial restenosis.

並列關鍵字

atherosclerosis ； inflmmation ； NF-kappaB

參考文獻

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Andrographolide抑制LPS/IFN-gamma誘導大鼠血管平滑肌細胞發炎反應之機轉探討

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