Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas.
Department of Cardiovascular Surgery, Texas Heart Institute, Houston.
JAMA Surg. 2018 Sep 1;153(9):e181804. doi: 10.1001/jamasurg.2018.1804. Epub 2018 Sep 19.
Fluoroquinolones are among the most commonly prescribed antibiotics. Recent clinical studies indicated an association between fluoroquinolone use and increased risk of aortic aneurysm and dissection (AAD). This alarming association has raised concern, especially in patients with AAD with risk of rupture and in individuals at risk for developing AAD.
To examine the effect of ciprofloxacin on AAD development in mice.
DESIGN, SETTING, AND PARTICIPANTS: In a mouse model of moderate, sporadic AAD, 4-week-old male and female C57BL/6J mice were challenged with a high-fat diet and low-dose angiotensin infusion (1000 ng/min/kg). Control unchallenged mice were fed a normal diet and infused with saline. After randomization, challenged and unchallenged mice received ciprofloxacin (100 mg/kg/d) or vehicle through daily gavage during angiotensin or saline infusion. Aortic aneurysm and dissection development and aortic destruction were compared between mice. The direct effects of ciprofloxacin on aortic smooth muscle cells were examined in cultured cells.
No notable aortic destruction was observed in unchallenged mice that received ciprofloxacin alone. Aortic challenge induced moderate aortic destruction with development of AAD in 17 of 38 mice (45%) and severe AAD in 9 (24%) but no rupture or death. However, challenged mice that received ciprofloxacin had severe aortic destruction and a significantly increased incidence of AAD (38 of 48 [79%]; P = .001; χ2 = 10.9), severe AAD (32 of 48 [67%]; P < .001; χ2 = 15.7), and rupture and premature death (7 of 48 [15%]; P = .01; χ2 = 6.0). The increased AAD incidence was observed in different aortic segments and was similar between male and female mice. Compared with aortic tissues from challenged control mice, those from challenged mice that received ciprofloxacin showed decreased expression of lysyl oxidase, an enzyme that is critical in the assembly and stabilization of elastic fibers and collagen. These aortas also showed increased matrix metalloproteinase levels and activity, elastic fiber fragmentation, and aortic cell injury. In cultured smooth muscle cells, ciprofloxacin treatment significantly reduced lysyl oxidase expression and activity, increased matrix metalloproteinase expression and activity, suppressed cell proliferation, and induced cell death. Furthermore, ciprofloxacin-a DNA topoisomerase inhibitor-caused nuclear and mitochondrial DNA damage and the release of DNA into the cytosol, subsequently inducing mitochondrial dysfunction, reactive oxygen species production, and activation of the cytosolic DNA sensor STING, which we further showed was involved in the suppression of lysyl oxidase expression and induction of matrix metalloproteinase expression.
Ciprofloxacin increases susceptibility to aortic dissection and rupture in a mouse model of moderate, sporadic AAD. Ciprofloxacin should be used with caution in patients with aortic dilatation, as well as in those at high risk for AAD.
氟喹诺酮类药物是最常被开的抗生素之一。最近的临床研究表明，氟喹诺酮类药物的使用与主动脉瘤和夹层（AAD）的风险增加有关。这种令人震惊的关联引起了关注，尤其是在有破裂风险的 AAD 患者和有发生 AAD 风险的个体中。
研究环丙沙星对小鼠 AAD 发展的影响。
设计、地点和参与者：在中度散发性 AAD 的小鼠模型中，4 周龄雄性和雌性 C57BL/6J 小鼠接受高脂肪饮食和低剂量血管紧张素输注（1000ng/min/kg）的挑战。对照未受挑战的小鼠喂食正常饮食并输注生理盐水。随机分组后，受挑战和未受挑战的小鼠在血管紧张素或生理盐水输注期间每天通过灌胃接受环丙沙星（100mg/kg/d）或载体。比较了两组小鼠的主动脉瘤和夹层发展以及主动脉破坏情况。还在培养的细胞中研究了环丙沙星对主动脉平滑肌细胞的直接影响。
单独使用环丙沙星的未受挑战的小鼠未观察到明显的主动脉破坏。主动脉受到挑战后，中度主动脉破坏，38 只小鼠中有 17 只（45%）发展为 AAD，9 只（24%）发展为严重 AAD，但没有破裂或死亡。然而，接受环丙沙星治疗的受挑战小鼠发生严重的主动脉破坏，AAD 的发生率显著增加（38 只中有 48 只[79%]；P=0.001；χ2=10.9）、严重 AAD（32 只中有 48 只[67%]；P<0.001；χ2=15.7）和破裂和过早死亡（7 只中有 48 只[15%]；P=0.01；χ2=6.0）。在不同的主动脉段都观察到 AAD 发生率增加，而且在雄性和雌性小鼠之间相似。与受挑战的对照小鼠的主动脉组织相比，接受环丙沙星治疗的受挑战小鼠的赖氨酰氧化酶表达降低，赖氨酰氧化酶是弹性纤维和胶原蛋白组装和稳定所必需的酶。这些主动脉还显示出基质金属蛋白酶水平和活性增加、弹性纤维断裂和主动脉细胞损伤。在培养的平滑肌细胞中，环丙沙星治疗显著降低了赖氨酰氧化酶的表达和活性，增加了基质金属蛋白酶的表达和活性，抑制了细胞增殖，并诱导了细胞死亡。此外，环丙沙星（一种 DNA 拓扑异构酶抑制剂）引起核和线粒体 DNA 损伤以及 DNA 释放到细胞质中，随后诱导线粒体功能障碍、活性氧产生和细胞质 DNA 传感器 STING 的激活，我们进一步表明 STING 参与了赖氨酰氧化酶表达的抑制和基质金属蛋白酶表达的诱导。
环丙沙星增加了中度散发性 AAD 小鼠模型中主动脉夹层和破裂的易感性。在有主动脉扩张的患者以及有发生 AAD 风险的患者中，应谨慎使用环丙沙星。
