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Inhibition of interleukin-1? decreases aneurysm formation and progression in a novel model of thoracic aortic aneurysms.

ABSTRACT: Thoracic aortic aneurysms (TAAs) are common, but experimental TAA models are limited and the role of interleukin-1? (IL-1?) is undetermined.IL-1? protein was measured in human TAAs and control aortas, and IL-1? protein was increased ?20-fold in human TAAs. To develop an experimental model of TAAs, 8- to 10-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? expression. Next, TAAs were induced in mice deficient of IL-1? (IL-1? knockout) or IL-1 receptor (IL-1R knockout; n=10 each). Genetic deletion of IL-1? and IL-1R significantly decreased thoracic aortic dilation (IL-1? knockout=54.2±16.8% and IL-1R knockout=62.6±17.2% versus WT TAA=104.7±23.8%; P<0.001for both). IL-1? knockout and IL-1R knockout aortas demonstrated preserved elastin and smooth muscle cells with fewer inflammatory cells. Correspondingly, IL-1? 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).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? decreased TAA formation and progression, indicating that IL-1? may be a potential target for TAA treatment.

SUBMITTER: Johnston WF

PROVIDER: S-EPMC5097450 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Inhibition of interleukin-1β decreases aneurysm formation and progression in a novel model of thoracic aortic aneurysms.

Johnston William F WF Salmon Morgan M Pope Nicolas H NH Meher Akshaya A Su Gang G Stone Matthew L ML Lu Guanyi G Owens Gary K GK Upchurch Gilbert R GR Ailawadi Gorav G

Circulation 20140901 11 Suppl 1

<h4>Background</h4>Thoracic aortic aneurysms (TAAs) are common, but experimental TAA models are limited and the role of interleukin-1β (IL-1β) is undetermined.<h4>Methods and results</h4>IL-1β protein was measured in human TAAs and control aortas, and IL-1β protein was increased ≈20-fold in human TAAs. To develop an experimental model of TAAs, 8- to 10-week-old male C57Bl/6 mice (wild type [WT]) underwent thoracotomy with application of periadventitial elastase (WT TAA) or saline (WT control; n= ...[more]

PMID: 25200056

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Project description:Abdominal aortic aneurysms (AAAs) are characterized by chronic inflammatory cell infiltration. The present extended immunohistochemistry study aimed to characterize inflammation in AAA and aortic control samples. In specific, the composition of the infiltrating immune cells and the expression of five inflammasome components in these immune cells were evaluated, in order to characterize their role in AAA development. A total of 104 biopsies from 48 AAA patients and 40 healthy specimens from organ donors were evaluated for their grade of inflammation. Infiltrating leukocytes were characterized by specific markers (CD3, CD20 and CD68), intramural localization and inflammasome protein expression [NLR family pyrin domain containing 3 (NLRP3), absent in melanoma 2 (AIM2), apoptosis?associated speck?like protein containing a caspase recruitment domain (ASC), Caspase?1 and Caspase?5]. Macrophages, B and T lymphocytes were detected to a similar extent in grade 1, 2 and 3 AAA specimens, whereas in control samples, B and T lymphocytes were rarely observed in grade 1 lesions. Expression frequencies of NLRP3, AIM2 and Caspase?5 were significantly higher in grade 1 lesions of AAA samples compared with grade 1 lesions in control samples. Finally, AIM2, ASC, and Caspase?5 displayed significantly lower expression frequencies in grade 3 compared with grade 2 AAA specimens, and all inflammasome components were less frequently detected in grade 3 than in grade 1 lesions of AAA. This indicates that inflammasome activities decrease with AAA progression in infiltrating leukocytes. No statistically significant association was found for grade 2 and grade 3 lesions and total leukocyte count, C?reactive protein levels, maximal aortic diameter, plasma cholesterol level or biomechanical parameters (derived from finite element analysis) of the respective patients. Overall, the aortic wall of AAA contained lymphocytes and macrophages with different states of activity. The present data suggested that therapeutic inhibition of specific inflammasome components might counteract AAA development and progression.

Dataset Information

Inhibition of interleukin-1? decreases aneurysm formation and progression in a novel model of thoracic aortic aneurysms.

Publications

Inhibition of interleukin-1β decreases aneurysm formation and progression in a novel model of thoracic aortic aneurysms.

Similar Datasets

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