Table 2.
Examples of studies investigating the effect of inhibiting tumor necrosis factor or interleukins in AAA animal models.
| Ref | Animal | AAA Model | Aortic Diameter (Intervention vs. AAA Control) | Intervention | Intervention Started after AAA Induction | Dose/Frequency of Intervention | Assessment Period | Post-Intervention Cytokine Change | p Value (TNF or IL Inhibition vs. AAA Controls) | Mechanisms Implicated in Protection from AAA Development or Growth |
|---|---|---|---|---|---|---|---|---|---|---|
| Tumor Necrosis Factor-α | ||||||||||
| [28] | B6129SF2 mice | Periaortic application of CaCl2 | 9.8 ± 0.3 vs. 5.8 ± 0.1 mm |
TNF alpha gene knockout Infliximab |
NA Yes |
NA 10 μg/g body weight, once weekly |
6 weeks 6 weeks |
↓ ↓ |
<0.01 0.03 |
Reduced elastic fiber disruption, macrophage infiltration, and MMP-2 and MMP-9 expression in aortic tissue |
| [29] | Mx-1 Cre transgenic mice | Periaortic application of CaCl2 | 1.3 ± 0.1 vs. 0.8 ± 0.1 mm ^ | TACE gene knockout | No | 250 μg on alternate days, starting 2 weeks prior to the operation | 6 weeks | ↓ | 0.05 | Attenuated inflammation, oxidative stress, neoangiogenesis and extracellular matrix disruption |
| [30] | WKY | Elastase perfusion | 2.7 ± 0.1 vs. 1.4 ± 0.1 mm | TNF-BP | No | 1 mg/kg diluted in vehicle prior, 48 & 96 h | 6 days | ↓ | <0.01 | Elastin fragmentation and smooth muscle cell loss in the media of the aortic wall was prevented |
| Interleukin-1b/1R | ||||||||||
| [30] | WKY | Elastase perfusion | 2.3 ± 0.2 vs. 2.2 ± 0.3 mm | IL-1R-a | No | Dose: 100 mg/kg diluted in vehicle Frequency: 20 min prior to surgery, and every 8 h |
6 days | ↑ | >0.05 | NA |
| [32] | C57BL/6J mice | Periaortic application of CaCl2 | 58.2 ± 5.2 vs. 35.5 ± 3.5% ^ | Genetic deletion of IL1β | No | NA | 6 weeks | ↓ | 0.01 | NA |
| [34] | C57BL/6J mice | Ang-II infusion + IL-1Ra-deficient mice | 0.9 ± 0.1 vs. 0.5 ± 0.0 mm | IL-1β mAb | Yes | 7.5 mg/kg, twice a week | 14 days | ↓ | <0.01 | Prevented destruction of the elastic lamina and degeneration of SMCs in the abdominal aorta |
| [44] | C57BL/6J mice | Elastase perfusion | 110% increase in AAA cases vs. self-controls | IL-1β knockout | No | NA | 3, 7 and 14 days | ↓ | 0.05 | Attenuated ceramide synthesis in aortic infiltrated neutrophils prevents NETosis |
| [33] | C57BL/6J mice | Ang-II infusion + SMC selective Smad4 deletion in IL1-R1−/− |
1.2 ± 0.0 vs. 1.5 ± 0.1 mm | IL-1β antibody | No | 10 mg/kg body/weight, once weekly | 16 weeks | ↓ | <0.01 | Monocyte infiltration was blocked and aneurysm progression ameliorated |
| [35] | C57BL/6J mice | Elastase perfusion + IL-1β gene knockout | 38 ± 20.4 vs. 89.5 ± 13.1% 52.9 ± 3.2 vs. 82.4 ± 15.3% |
IL-1R gene knockout IL-1R antagonist (anakinra) |
No Yes |
Anakinra administered at day 3 post-AAA induction at 100 mg/kg per day |
14 days | NA | NA | Decreased macrophage and elastin fragmentation |
| Interleukin-6 | ||||||||||
| [37] | C57BL/6J mice | Periaortic application of CaCl2 | 0.9 ± 0.0 vs. 1.1 ± 0.0 mm | murine anti-IL-6R | Prior and post induction | 0.25 mg MR16-1 every week | 6 weeks | ↓ | <0.01 | Suppressed STAT3 activation and AAA expansion |
| [36] | C57BL/6J mice | Elastase perfusion | 50 ± 20.9 vs. 82.7 ± 25.1 mm ^ | Anti-IL-6 antibody | Yes | 4 mg/kg, initiated at day 3 |
14 days | ↓ | <0.03 | Reduced AAA progression |
| [39] | C57BL/6J mice | Elastase perfusion | 101.2 ± 20.1 vs. 101.2 ± 18.4% ^ | IL-6 knockout | No | NA | 14 days | ↔ (Unchanged) | 0.73 | NA |
| [38] | C57BL/6J mice | elastase + anti-TGF-β model | 1.6 ± 0.3 vs. 1.9 ± 0.5 | sgp130Fc | Yes | 10µg thrice a week initiated on the day of experiment | 7 days | ↓ | <0.01 | Increased collagen content of the arterial wall |
| Interleukin-12/23 | ||||||||||
| [40] | C57BL/6J mice | Ang-II infusion | 1.4 ± 0.1 vs. 1.1 ± 0.1 mm ^ | IL-12p40 knockout | No | 150 μL 2 timesat 3-day interval | 14 days | ↓ | <0.01 | Augmented TGFβ2-mediated MMP2 expression |
| [41] | C57BL/6J mice | Elastase perfusion | 0.5 ± 0.1 vs. 0.7 ± 0.1 mm | IL-12p40/IL-23p19 mAb | Yes | 250 μg on days 3 and 8 | 14 days | ↓ | <0.001 | Reduced M1 and M2 macrophages |
| Interleukin-17 | ||||||||||
| [43] | ApoE−/− mice | Ang-II infusion | 1.4 ± 0.1 vs. 1.7 ± 0.1 mm | IL-17A siRNA | No | 3μg/kg | 28 days | ↓ | 0.05 | Reduced VEGFA, MMP-2, MMP-9 and JAK2 protein levels. |
| [42] | C57BL/6J mice | Elastase perfusion | 89.4 ± 7.4 vs. 141.1 ± 16.1% | IL-17−/− | No | NA | 14 days | ↓ | <0.05 | Reduced MCP-1, RANTES, KC, TNF-α, MIP-1α and IFN-γ |
AAA—abdominal aortic aneurysm, ApoE—apolipoprotein E, Ang-II—angiotensin-II, CaCl2—calcium chloride, CD—cluster of differentiation, ECM—extracellular matrix, IFNγ—interferon gamma, IL—interleukin, JAK—Janus kinase, kg—kilogram, KC—keratinocyte-derived chemokine, MMP—matrix metalloproteinases, MCP—monocyte chemoattractant protein, MSC—mesenchymal stem cells, MIP1α—macrophage inflammatory protein 1 alpha, mAb—monoclonal antibody, μL—microlitre, mg—milligram, μg—microgram, NA—not available; NR—not reported, ND—non-detectable, NETosis—neutrophil extracellular traps, RANTES—regulated upon activation normal T cell expressed and presumably secreted, STAT—signal transducer and activator of transcription, SMAD4—mothers against decapentaplegic homolog 4, siRNA—small interfering ribonucleic acid, SMC—smooth muscle cell, TNFα—tumor necrosis factor alpha, TN-BP—TNF binding protein, TACE—TNF-alpha converting enzyme, TGFβ—transforming growth factor beta, VEGF—vascular endothelial growth factor, WKY—Wistar–Kyoto, IL-1R-a—interleukin 1 receptor a, %—percentage. ^ Mean ± SD of aortic diameter calculated using ImageJ [45] for graphs and using a validated method [46] for median values.