Effect of Ciprofloxacin on Susceptibility to Aortic Dissection and Rupture in Mice - PubMed (original) (raw)

Effect of Ciprofloxacin on Susceptibility to Aortic Dissection and Rupture in Mice

Scott A LeMaire et al. JAMA Surg. 2018.

Abstract

Importance: 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.

Objective: 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.

Results: 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.

Conclusions and relevance: 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.

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Conflict of interest statement

Conflict of Interest Disclosures: None reported.

Figures

Figure 1.

Figure 1.. Increased Susceptibility to Challenge-Induced Aortic Aneurysm and Dissection (AAD) Formation in Mice That Received Ciprofloxacin

Wild-type mice were either unchallenged or challenged with a high-fat diet for 8 weeks and infused with angiotensin II during the last 4 weeks. Unchallenged and challenged mice received vehicle or ciprofloxacin during the last 4 weeks. A, Representative images of excised aortas showing gross differences between aortas from challenged mice that received vehicle and challenged mice that received ciprofloxacin. B, Comparison of aortic diameters in each aortic segment showing that aortic diameters were increased in both male and female challenged mice that received vehicle and were even further increased in challenged mice that received ciprofloxacin. C, Comparison of aortic lesion severity showing that the overall incidences of aortic dilatation, AAD (aneurysm, dissection, and rupture), severe AAD (dissection and rupture), and rupture were significantly increased in challenged mice that received ciprofloxacin compared with challenged mice that received vehicle. D, Kaplan-Meier survival analysis showing reduced survival in challenged mice that received ciprofloxacin compared with challenged mice that received vehicle.

Figure 2.

Figure 2.. Increased Susceptibility to Challenged-Induced Aortic Aneurysm and Dissection (AAD) Formation in Both the Thoracic and Abdominal Aortic Segments of Mice That Received Ciprofloxacin

Wild-type mice were either unchallenged or challenged with a high-fat diet for 8 weeks and infused with angiotensin II during the last 4 weeks. Unchallenged and challenged mice were given vehicle or ciprofloxacin during the last 4 weeks. A-D, Comparison of the incidences of aortic dilatation, AAD (aneurysm, dissection, and rupture), severe AAD (dissection and rupture), and rupture in the ascending aorta (A), aortic arch (B), descending thoracic aorta (C), and suprarenal abdominal aorta (D). The severity of aortic lesions was increased in challenged mice that received ciprofloxacin compared with challenged mice that received vehicle.

Figure 3.

Figure 3.. Similar Adverse Effects of Ciprofloxacin on Aortic Aneurysm and Dissection (AAD) Development in Male and Female Mice

Wild-type mice were either unchallenged or challenged with a high-fat diet for 8 weeks and infused with angiotensin II during the last 4 weeks. Unchallenged and challenged mice were given vehicle or ciprofloxacin during the last 4 weeks. Comparison of the overall incidences of aortic dilatation, AAD (aneurysm, dissection, and rupture), severe AAD (dissection and rupture), and rupture in all aortic segments showing that ciprofloxacin treatment enhanced challenged-induced AAD formation and severity similarly in male and female mice.

Figure 4.

Figure 4.. Decreased Lysyl Oxidase (LOX) Protein Expression and Increased Matrix Metalloproteinase (MMP) Expression and Activity in the Aortic Wall of Challenged Mice That Received Ciprofloxacin

A, Representative images of Verhoeff–Van Gieson elastin staining and quantification showing the destruction of elastic lamellar architecture in the aortic wall of challenged mice that received ciprofloxacin. Representative images of immunofluorescence staining and quantification showing compromised LOX expression, especially in the medial layer (B), and increased MMP-9 expression in the aortic wall of challenged mice that received ciprofloxacin (C). DAPI indicates 4’,6-diamidino-2-phenylindole; SM22α, 22-kDa smooth muscle cell.

Figure 5.

Figure 5.. Increased Apoptosis and Necroptosis in the Aortic Wall of Challenged Mice That Received Ciprofloxacin

A, Representative terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling (TUNEL)–stained images of the aortic wall and quantification. Apoptosis was significantly increased, particularly in the lesion areas, of challenged mice that received ciprofloxacin. Representative images of immunofluorescence staining and quantification showing the presence of receptor-interacting protein kinase 3 (RIP3) (B) and mixed lineage kinase domain-like (MLKL) (C) in aortic smooth muscle cells of challenged mice that received ciprofloxacin. DAPI indicates 4’,6-diamidino-2-phenylindole; SM22α, 22-kDa smooth muscle cell.

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