Inhibition of Interleukin-1β Decreases Aneurysm Formation and Progression in a Novel Model of Thoracic Aortic Aneurysms

Background-Thoracic aortic aneurysms (TAAs) are common, but experimental TAA models are limited and the role of interleukin-1 beta (IL-1 beta) is undetermined. Methods and Results-IL-1 beta protein was measured in human TAAs and control aortas, and IL-1 beta protein was increased +/-20-fold in human TAAs. To develop an experimental model of TAAs, 8-to10-week-old male C57Bl/6 mice (wild type [WT]) underwent thoracotomy with application of periadventitial elastase (WT TAA) or saline (WT control; n=30 per group). Elastase treatment to thoracic aortas resulted in progressive dilation until day 14 with maximal dilation of 99.6+/-24.7% compared with 14.4+/-8.2% for WT saline control (P< 0.0001). WT TAAs demonstrated elastin fragmentation, smooth muscle cell loss, macrophage infiltration, and increased IL-1 beta expression. Next, TAAs were induced in mice deficient of IL-1 beta (IL-1 beta knockout) or IL-1 receptor (IL-1R knockout; n=10 each). Genetic deletion of IL-1 beta and IL-1R significantly decreased thoracic aortic dilation (IL-1 beta knockout=54.2+/-16.8% and IL-1R knockout=62.6+/-17.2% versus WT TAA=104.7+/-23.8%; P< 0.001 for both). IL-1 beta knockout and IL-1R knockout aortas demonstrated preserved elastin and smooth muscle cells with fewer inflammatory cells. Correspondingly, IL-1 beta and IL-1R knockout aortas had decreased inflammatory cytokine and matrix metalloproteinase 9 expression. Separately, WT mice pretreated with either IL-1R antagonist anakinra (100 mg/kg per day) or vehicle alone (control) underwent elastase treatment. Pretreatment of WT mice with anakinra attenuated TAA formation (control: 99.2+/-15.5% versus anakinra: 68.3+/-19.2%; P< 0.005). Finally, to investigate treatment of small TAAs, WT mice were treated with anakinra 3 days after TAA induction. Anakinra treatment in WT mice with small TAAs reduced aortic dilation on day 14 (control treatment: 89.1+/-18.6% versus anakinra treatment: 59.7+/-25.7%; P= 0.01). Conclusions-Periadventitial application of elastase to murine thoracic aortas reproducibly produced aneurysms with molecular and histological features consistent with TAA disease. Genetic and pharmacological inhibition of IL-1 beta decreased TAA formation and progression, indicating that IL-1 beta may be a potential target for TAA treatment.