Doxycycline inhibition of aneurysmal degeneration in an elastase-induced rat model of abdominal aortic aneurysm: Preservation of aortic elastin associated with suppressed production of 92 kD gelatinase
Doxycycline inhibition of aneurysmal degeneration in an elastase-induced rat model of abdominal aortic aneurysm: Preservation of aortic elastin associated with suppressed production of 92 kD gelatinase
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DOI：
10.1016/s0741-5214(96)70279-3
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发表时间：
1996-02-01
影响因子：
4.3
通讯作者：
Thompson, RW
中科院分区：
文献类型：
--
作者：
Petrinec, D;Liao, SX;Thompson, RW
目的：基质金属蛋白酶 (MMP) 局部产生的增加是腹主动脉瘤 (AAA) 结构蛋白降解的潜在机制。通过弹性蛋白酶诱导的 AAA 啮齿动物模型，我们确定使用抑制 MMP 的四环素进行药物治疗是否可能限制体内实验性 AAA 的发展。方法：48 只 Wistar 大鼠接受 50 U 猪胰腺弹性蛋白酶腹主动脉灌注 2 小时，然后皮下注射强力霉素（25 毫克/天；n = 24）或盐溶液载体（n = 24）。在进行弹性蛋白酶灌注之前和之后以及在第0、2、7或14天处死大鼠之前测量主动脉直径，并将AAA定义为主动脉直径增加至灌注前的至少两倍。死亡时，主动脉组织要么灌注固定用于组织学评估，要么提取用于底物酶谱评估。结果：第 0 天或第 2 天时，各组之间的主动脉直径没有差异，但在第 7 天和 14 天用多西环素治疗的动物中主动脉直径显着较小（平均值 +/- SEM，p < 0.01）。第 2 天后，AAA 的发生率从 83%（用盐水溶液治疗的 12 只大鼠中的 10 只）降低至 8%（用多西环素治疗的 12 只大鼠中的 1 只）。通过组织学评估，多西环素可防止主动脉弹性蛋白的结构恶化，而不会减少炎症细胞的流入。在经盐水溶液处理的对照组中观察到主动脉钉产生的 92 kD 明胶酶增加，在用多西环素处理的动物中被显着抑制。结论：用抑制 MMP 的四环素处理可抑制体内实验性 AAA 的发展。这种抑制可能是由于选择性阻断浸润炎症细胞中的弹力分解基质金属蛋白酶（MMP）表达。然而，需要额外的实验来充分描述这个过程。
Purpose: Increased local production of matrix metalloproteinases (MMPs) is a potential mechanism underlying structural protein degradation in abdominal aortic aneurysms (AAA). With an elastase-induced rodent model of AAA, we determined whether pharmacologic treatment with an MMP-inhibiting tetracycline might limit the development of experimental AAA in vivo.Methods: Forty-eight Wistar rats underwent a 2-hour perfusion of the abdominal aorta with 50 U porcine pancreatic elastase and were then treated with either subcutaneous doxycycline (25 mg/day; n = 24) or saline solution vehicle (n = 24). Aortic diameter was measured before and after elastase perfusion was performed and before the rats were killed at 0, 2, 7, or 14 days, and AAAs were defined as an increase in aortic diameter to at least twice that before perfusion. At death the aortic tissues were either perfusion-fixed for histologic evaluation or extracted for substrate zymographic evaluation.Results: Aortic diameter was not different between groups at 0 or 2 days, but it was significantly less in animals treated with doxycycline at both 7 and 14 days (mean +/- SEM, p < 0.01). After day 2 the incidence of AAA was reduced from 83% (10 of 12 rats treated with saline solution) to 8% (1 of 12 animals treated with doxycycline). By histologic assessment doxycycline prevented the structural deterioration of aortic elastin without decreasing the influx of inflammatory cells. Increased aortic Nail production of 92 kD gelatinase observed in a saline solution-treated control group was markedly suppressed in animals treated with doxycycline.Conclusions: Treatment with an MMP-inhibiting tetracycline inhibits the development of experimental AAA in vivo. This inhibition may be due to selective blockade of elastolytic MMP expression in infiltrating inflammatory cells. Additional experiments, however, are necessitated to fully delineate this process.