Department of Pharmacology & Experimental Therapeutics, Division of Pathological Sciences, Kyoto Pharmaceutical University, Kyoto, Japan.
Life Sci. 2013 Oct 6;93(12-14):441-7. doi: 10.1016/j.lfs.2013.07.021. Epub 2013 Jul 27.
We examined changes in the expression of a pro-angiogenic factor, vascular endothelial growth factor (VEGF), and an anti-angiogenic factor, endostatin, as well as matrix metalloproteinase (MMP)-2 and MMP-9 in the rat small intestine after administration of indomethacin and investigated the roles of these factors in the healing of indomethacin-induced small intestinal ulcers.
Male SD rats were given indomethacin (10mg/kg) p.o. and euthanized at various time points (3-24h and 2-7days) after the administration. To impair the healing of these lesions, low-dose of indomethacin (2mg/kg) was given p.o. once daily for 6days starting 1day after ulceration. Levels of VEGF, endostatin, MMP-2 and MMP-9 were determined by Western blotting.
The expression of both VEGF and endostatin was upregulated after the ulceration. Repeated administration of low-dose indomethacin impaired the ulcer healing with a decrease of VEGF expression and a further increase of endostatin expression, resulting in a marked decrease in the ratio of VEGF/endostatin expression. The levels of MMP-2 and MMP-9 were both significantly increased after the ulceration, but these responses were suppressed by the repeated indomethacin treatment. The healing of these ulcers was significantly delayed by the repeated administration of MMP inhibitors such as ARP-101 and SB-3CT.
The results confirm the importance of the balance between pro-angiogenic and anti-angiogenic activities in the healing of indomethacin-induced small intestinal damage and further suggest that the increased expression of MMP-2 and MMP-9 is another important factor for ulcer healing in the small intestine.
我们研究了在给予吲哚美辛后，血管内皮生长因子（VEGF）和血管生成抑制因子内皮抑素以及基质金属蛋白酶（MMP）-2 和 MMP-9 在大鼠小肠中的表达变化，并探讨了这些因子在吲哚美辛诱导的小肠溃疡愈合中的作用。
雄性 SD 大鼠给予吲哚美辛（10mg/kg）口服，并在给药后不同时间点（3-24h 和 2-7d）处死。为了损害这些病变的愈合，在溃疡形成后第 1 天开始每天给予低剂量吲哚美辛（2mg/kg）口服，共 6 天。通过 Western blot 测定 VEGF、内皮抑素、MMP-2 和 MMP-9 的水平。
溃疡形成后，VEGF 和内皮抑素的表达均上调。重复给予低剂量吲哚美辛可损害溃疡愈合，导致 VEGF 表达减少和内皮抑素表达进一步增加，从而导致 VEGF/内皮抑素表达的显著降低。溃疡形成后 MMP-2 和 MMP-9 的水平均显著增加，但这些反应被重复吲哚美辛处理所抑制。重复给予 MMP 抑制剂如 ARP-101 和 SB-3CT 可显著延迟这些溃疡的愈合。
这些结果证实了在吲哚美辛诱导的小肠损伤愈合过程中促血管生成和抗血管生成活性之间的平衡的重要性，并进一步表明 MMP-2 和 MMP-9 的表达增加是小肠溃疡愈合的另一个重要因素。
