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INTRODUCTION:Interleukin-1β (IL-1β) is a proinflammatory cytokine elevated in both human and experimental abdominal aortic aneurysms (AAAs). IL-1β signals the inflammatory cascade through binding the interleukin-1 receptor (IL-1R). The study objective was to evaluate pharmacologic opposition of IL-1β signaling using the recombinant IL-1R antagonist anakinra for prevention and treatment of experimental AAAs.
METHODS:To evaluate AAA prevention with anakinra, 4 groups of 8-10 week old male C57Bl/6 mice (n=7/group) had continuous release osmotic pumps filled with escalating doses of anakinra placed subcutaneously. Three days after anakinra pump placement, all mice underwent aortic elastase perfusion. Maximal aortic dilation was measured 14 days following elastase perfusion. Aortic samples were evaluated with immunohistochemistry for macrophages, neutrophils, and elastin. IL-1β protein levels were measured by ELISA. To determine if treatment with anakinra could inhibit aneurysm progression once an AAA was initiated or a small AAA existed, 8-10 week old male C57Bl/6 mice underwent elastase perfusion followed by osmotic pump placement 3 days or 7 days afterwards (n=7/group for day 3 and 5/group for day 7). Pumps were filled with anakinra or vehicle as a control. Aortic dilation was measured at harvest, and tissue was analyzed with immunohistochemistry for macrophages, neutrophils, elastin, and IL-1β.
RESULTS:Increasing doses of anakinra resulted in a stepwise attenuation in aortic dilation with mean aortic dilations of 86.3 ± 5.7% for vehicle only, 74.9 ± 5.9% for 10 mg/kg/day anakinra, 56.8 ± 3.3% for 30 mg/kg/day anakinra, and 48.3 ± 4.6% for 100 mg/kg/day anakinra (p<0.05 for 30 mg/kg/day and 100 mg/kg/day versus vehicle by ANOVA). Escalating doses of anakinra pretreatment also corresponded with a dose dependent decrease in macrophage and neutrophil infiltration, as well as elastin degradation compared to vehicle treated mice at 14 days. Aortic dilation significantly correlated with IL-1β protein levels [R=0.575 (95% CI: 0.203 to 0.802), p<0.01]. Treatment with anakinra starting 3 or 7 days following elastase exposure significantly reduced aortic dilation compared to vehicle alone. Treatment starting 3 days following elastase resulted in 43.7 ± 8.3% dilation vs. 86.4 ± 3.5% dilation with vehicle alone, p<0.0005. Anakinra treatment starting 7 days after elastase exposure reduced aortic dilation from 82.4±6.9% with vehicle alone to 52.9±1.4%, p<0.005. Aortas treated with anakinra demonstrated less macrophage and neutrophil infiltration, less elastin degradation, and less IL-1β.
CONCLUSIONS:IL-1β signaling was critical for AAA formation, and inhibition of its corresponding receptor through receptor antagonism with anakinra attenuated AAA formation, macrophage and neutrophil infiltration, and elastin degradation. Furthermore, delayed initiation of IL-1R antagonism following early aneurysm formation inhibited AAA progression, suggesting that IL-1β pathway antagonism may function as a novel treatment strategy for AAAs.