title: Genetic and pharmacologic disruption of interleukin-1β signaling inhibits experimental aortic aneurysm formation.
abstract: OBJECTIVE
  Abdominal aortic aneurysms (AAAs) are common, but their exact pathogenesis remains unknown and no specific medical therapies are available. We sought to evaluate interleukin-1β (IL-1β) and interleukin-1 receptor (IL-1R) in an experimental AAA model to identify novel therapeutic targets for AAA treatment.
  
  
  RESULTS
  IL-1β mRNA and protein levels were significantly elevated in abdominal aortas of 8- to 12-week-old male C57Bl/6 mice after elastase aortic perfusion (wild-type [WT]) compared with saline perfusion. Mice with genetic deletion of IL-1β (IL-1β knockout [KO]) or IL-1R (IL-1R KO) that underwent elastase perfusion demonstrated significant protection against AAA formation, with maximal aortic dilations of 38.0±5.5% for IL-1β KO and 52.5±4.6% for IL-1R KO, compared with 89.4±4.0% for WT mice (P<0.005). Correspondingly, IL-1β KO and IL-1R KO aortas had reduced macrophage and neutrophil staining with greater elastin preservation compared with WT. In WT mice pretreated with escalating doses of the IL-1R antagonist anakinra, there was a dose-dependent decrease in maximal aortic dilation (R=-0.676; P<0.0005). Increasing anakinra doses correlated with decreasing macrophage staining and elastin fragmentation. Lastly, WT mice treated with anakinra 3 or 7 days after AAA initiation with elastase demonstrated significant protection against AAA progression and had decreased aortic dilation compared with control mice.
  
  
  CONCLUSIONS
  IL-1β is critical for AAA initiation and progression, and IL-1β neutralization through genetic deletion or receptor antagonism attenuates experimental AAA formation. Disrupting IL-1β signaling offers a novel pathway for AAA treatment.
authors.affiliation: Department of Surgery, University of Virginia, Charlottesville, VA, USA.
authors.forename: William F
authors.initials: WF
authors.lastname: Johnston
authors.forename: Morgan
authors.initials: M
authors.lastname: Salmon
authors.forename: Gang
authors.initials: G
authors.lastname: Su
authors.forename: Guanyi
authors.initials: G
authors.lastname: Lu
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Stone
authors.forename: Yunge
authors.initials: Y
authors.lastname: Zhao
authors.forename: Gary K
authors.initials: GK
authors.lastname: Owens
authors.forename: Gilbert R
authors.initials: GR
authors.lastname: Upchurch
authors.forename: Gorav
authors.initials: G
authors.lastname: Ailawadi
mesh_terms: D000818:Animals; D001012:Aorta, Abdominal / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D017544:Aortic Aneurysm, Abdominal / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D004108:Dilatation, Pathologic; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004549:Elastin / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein / Q000494:pharmacology*; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors* / Q000172:deficiency* / Q000235:genetics; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010196:Pancreatic Elastase; D012333:RNA, Messenger / Q000378:metabolism; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors* / Q000172:deficiency* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors
chemical_list: D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D012333:RNA, Messenger; D017472:Receptors, Interleukin-1; D004549:Elastin; D010196:Pancreatic Elastase