Indomethacin inhibits expansion of experimental aortic aneurysms via inhibition of the cox2 isoform of cyclooxygenase
Indomethacin inhibits expansion of experimental aortic aneurysms via inhibition of the cox2 isoform of cyclooxygenase
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DOI：
10.1016/s0741-5214(99)70216-8
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发表时间：
1999-05-01
影响因子：
4.3
通讯作者：
Reilly, JM
中科院分区：
文献类型：
--
作者：
Miralles, M;Wester, W;Reilly, JM
目的：COX1或COX2亚型环氧合酶控制前列腺素E-2(PGE2)的合成，而前列腺素E-2调节基质金属蛋白酶-9(MMP9)的表达。PGE2和MMP9在主动脉瘤中升高。在动物模型上研究了非特异性环氧合酶抑制剂吲哚美辛抑制动脉瘤扩张的机制和时间进程。方法：用生理盐水和弹性蛋白酶对40只大鼠进行主动脉灌流。弹性蛋白酶处理的动物不接受治疗(n=82)或接受消炎痛治疗(n=73)。在主动脉灌流时和处死大鼠时测量主动脉直径。结果：对照组大鼠主动脉内径变化不大。所有仅使用弹性蛋白酶的动物都出现了动脉瘤(第14天最大主动脉直径为5.27±2.37 mm)。吲哚美辛显著降低了主动脉扩张率(最大主动脉直径，3.45±1.11 mm；P<；.001vs.弹性酶组)。酶联免疫吸附试验显示，PGE2合成与主动脉扩张平行，吲哚美辛使PGE2合成减少。组织学上，弹性酶组的主动脉弹性蛋白构筑遭到破坏，但经消炎痛处理后仍得以保存。COX1和COX2的原位杂交显示COX2表达，但不表达COX1，免疫组织化学显示COX2与主动脉壁相关的巨噬细胞共定位。结论：消炎痛抑制动脉瘤生长，其作用机制可能是通过抑制COX2亚型环氧合酶，从而减少PGE2和MMP9的合成。
Purpose: Cyclooxygenase, either the cox1 or cox2 isoform, controls synthesis of prostaglandin E-2 (PGE2), which regulates expression of matrix metalloprotease-9 (MMP-9). PGE2 and MMP-9 are elevated in aortic aneurysms. The mechanisms and time course of the inhibition of aneurysm expansion with a nonspecific cyclooxygenase inhibitor, indomethacin, were determined in an animal model.Methods: Rats underwent aortic perfusion with saline (n = 40) as controls or with elastase. Elastase-treated animals received no treatment (n = 82) or received indomethacin (n = 73). Aortic diameters were determined at the time of aortic perfusion and when the rats were killed. The aortas mere harvested and used for whole organ culture, substrate gel zymography, or histologic analysis.Results: The control group demonstrated Little change in aortic diameter. All the elastase-only animals developed aneurysms (maximal aortic diameter, 5.27 +/- 2.37 mm on day 14). Indomethacin markedly decreased the rate of aortic expansion (maximum aortic diameter, 3.45 +/- 1.11 mm; P < .001 vs the elastase-only group). The enzyme-linked immunosorbent assay of aortic explant culture media showed that PGE2 synthesis paralleled aortic expansion, and indomethacin decreased PGE2 synthesis. Histologically, the aortic elastin architecture mas destroyed in the elastase group, but was preserved with indomethacin treatment. In situ, hybridization for cox1 and cox2 showed that cox2, but not cox1, was expressed and was co-localized by immunohistochemistry to macrophages associated with the aortic wall. Decreased levels of MMP-9 activity with indomethacin were shown by means of substrate zymography MMP-9 was also localized to macrophages.Conclusion: Indomethacin attenuates aneurysm growth, and its effects are mediated via inhibition of the cox2 isoform of cyclooxygenase, which decreases PGE2 and MMP-9 synthesis.