title: Inhibition of interleukin-1β decreases aneurysm formation and progression in a novel model of thoracic aortic aneurysms.
abstract: BACKGROUND
  Thoracic aortic aneurysms (TAAs) are common, but experimental TAA models are limited and the role of interleukin-1β (IL-1β) is undetermined.
  
  
  RESULTS
  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=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-1β expression. Next, TAAs were induced in mice deficient of IL-1β (IL-1β knockout) or IL-1 receptor (IL-1R knockout; n=10 each). Genetic deletion of IL-1β and IL-1R significantly decreased thoracic aortic dilation (IL-1β 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-1β knockout and IL-1R knockout aortas demonstrated preserved elastin and smooth muscle cells with fewer inflammatory cells. Correspondingly, IL-1β 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-1β decreased TAA formation and progression, indicating that IL-1β may be a potential target for TAA treatment.
authors.affiliation: From the Division of Thoracic and Cardiovascular Surgery (W.F.J., M.S., N.H.P., A.M., M.L.S., G.A.), Division of Vascular and Endovascular Surgery (G.S., G.L., G.R.U.), Department of Molecular Physiology and Biological Physics, Robert M. Berne Cardiovascular Research Center (G.K.O., G.R.U.), and Department of Biomedical Engineering (G.A.), University of Virginia, Charlottesville, VA.
authors.forename: William F
authors.initials: WF
authors.lastname: Johnston
authors.affiliation: From the Division of Thoracic and Cardiovascular Surgery (W.F.J., M.S., N.H.P., A.M., M.L.S., G.A.), Division of Vascular and Endovascular Surgery (G.S., G.L., G.R.U.), Department of Molecular Physiology and Biological Physics, Robert M. Berne Cardiovascular Research Center (G.K.O., G.R.U.), and Department of Biomedical Engineering (G.A.), University of Virginia, Charlottesville, VA.
authors.forename: Morgan
authors.initials: M
authors.lastname: Salmon
authors.affiliation: From the Division of Thoracic and Cardiovascular Surgery (W.F.J., M.S., N.H.P., A.M., M.L.S., G.A.), Division of Vascular and Endovascular Surgery (G.S., G.L., G.R.U.), Department of Molecular Physiology and Biological Physics, Robert M. Berne Cardiovascular Research Center (G.K.O., G.R.U.), and Department of Biomedical Engineering (G.A.), University of Virginia, Charlottesville, VA.
authors.forename: Nicolas H
authors.initials: NH
authors.lastname: Pope
authors.affiliation: From the Division of Thoracic and Cardiovascular Surgery (W.F.J., M.S., N.H.P., A.M., M.L.S., G.A.), Division of Vascular and Endovascular Surgery (G.S., G.L., G.R.U.), Department of Molecular Physiology and Biological Physics, Robert M. Berne Cardiovascular Research Center (G.K.O., G.R.U.), and Department of Biomedical Engineering (G.A.), University of Virginia, Charlottesville, VA.
authors.forename: Akshaya
authors.initials: A
authors.lastname: Meher
authors.affiliation: From the Division of Thoracic and Cardiovascular Surgery (W.F.J., M.S., N.H.P., A.M., M.L.S., G.A.), Division of Vascular and Endovascular Surgery (G.S., G.L., G.R.U.), Department of Molecular Physiology and Biological Physics, Robert M. Berne Cardiovascular Research Center (G.K.O., G.R.U.), and Department of Biomedical Engineering (G.A.), University of Virginia, Charlottesville, VA.
authors.forename: Gang
authors.initials: G
authors.lastname: Su
authors.affiliation: From the Division of Thoracic and Cardiovascular Surgery (W.F.J., M.S., N.H.P., A.M., M.L.S., G.A.), Division of Vascular and Endovascular Surgery (G.S., G.L., G.R.U.), Department of Molecular Physiology and Biological Physics, Robert M. Berne Cardiovascular Research Center (G.K.O., G.R.U.), and Department of Biomedical Engineering (G.A.), University of Virginia, Charlottesville, VA.
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Stone
authors.affiliation: From the Division of Thoracic and Cardiovascular Surgery (W.F.J., M.S., N.H.P., A.M., M.L.S., G.A.), Division of Vascular and Endovascular Surgery (G.S., G.L., G.R.U.), Department of Molecular Physiology and Biological Physics, Robert M. Berne Cardiovascular Research Center (G.K.O., G.R.U.), and Department of Biomedical Engineering (G.A.), University of Virginia, Charlottesville, VA.
authors.forename: Guanyi
authors.initials: G
authors.lastname: Lu
authors.affiliation: From the Division of Thoracic and Cardiovascular Surgery (W.F.J., M.S., N.H.P., A.M., M.L.S., G.A.), Division of Vascular and Endovascular Surgery (G.S., G.L., G.R.U.), Department of Molecular Physiology and Biological Physics, Robert M. Berne Cardiovascular Research Center (G.K.O., G.R.U.), and Department of Biomedical Engineering (G.A.), University of Virginia, Charlottesville, VA.
authors.forename: Gary K
authors.initials: GK
authors.lastname: Owens
authors.affiliation: From the Division of Thoracic and Cardiovascular Surgery (W.F.J., M.S., N.H.P., A.M., M.L.S., G.A.), Division of Vascular and Endovascular Surgery (G.S., G.L., G.R.U.), Department of Molecular Physiology and Biological Physics, Robert M. Berne Cardiovascular Research Center (G.K.O., G.R.U.), and Department of Biomedical Engineering (G.A.), University of Virginia, Charlottesville, VA.
authors.forename: Gilbert R
authors.initials: GR
authors.lastname: Upchurch
authors.affiliation: From the Division of Thoracic and Cardiovascular Surgery (W.F.J., M.S., N.H.P., A.M., M.L.S., G.A.), Division of Vascular and Endovascular Surgery (G.S., G.L., G.R.U.), Department of Molecular Physiology and Biological Physics, Robert M. Berne Cardiovascular Research Center (G.K.O., G.R.U.), and Department of Biomedical Engineering (G.A.), University of Virginia, Charlottesville, VA. gorav@virginia.edu.
authors.forename: Gorav
authors.initials: G
authors.lastname: Ailawadi
mesh_terms: D000368:Aged; D000818:Animals; D017545:Aortic Aneurysm, Thoracic / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology / Q000517:prevention & control*; D020170:Caspase 1 / Q000502:physiology; D015897:Comorbidity; D004195:Disease Models, Animal; D018450:Disease Progression; D004353:Drug Evaluation, Preclinical; D005260:Female; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein / Q000494:pharmacology / Q000627:therapeutic use*; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics; D008264:Macrophages / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000473:pathology; D010196:Pancreatic Elastase / Q000633:toxicity; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics; D013908:Thoracotomy
chemical_list: D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D017472:Receptors, Interleukin-1; D010196:Pancreatic Elastase; D020170:Caspase 1
keywords: aneurysm; animal models of human disease; inflammation; interleukin-1; interleukin-1 receptor antagonist protein