title: Novel mechanism of aortic aneurysm development in mice associated with smoking and leukocytes.
abstract: OBJECTIVE
  The purpose of this study was to evaluate potential mechanisms promoting abdominal aortic aneurysm development with tobacco smoke (TS) exposure.
  
  
  RESULTS
  Experiments used the elastase perfusion model of abdominal aortic aneurysms with smoke-free controls. The effect of TS exposure was evaluated in C57/Bl6 mice, after broad-spectrum matrix metalloproteinase inhibition with doxycycline and in mice deficient in matrix metalloproteinase-9, matrix metalloproteinase-12, Cathepsin-S, and Neutrophil Elastase. Preparations of washed marrow, spleen, and peripheral blood leukocytes were transferred to smoke-free mice from 6-week TS-exposed mice or smoke-free mice. All mice were euthanized 14 days after elastase perfusion, and the percentage of change in aortic diameter (%Δ aortic diameter) was calculated. Electron microscopy of aortic tissue from animals exposed to TS without elastase exposure did not demonstrate any ultrastructural changes. Neither doxycycline nor any specific elastase deficiency was effective at preventing an increase in %Δ aortic diameter in TS-exposed animals. Smoke exposure for 6 weeks increased the %Δ aortic diameter after a smoke-free interval of up to 6 weeks before elastase perfusion. Leukocyte preparations from TS-exposed mice localized to abdominal aortic aneurysms and increased the %Δ aortic diameter in smoke-free mice.
  
  
  CONCLUSIONS
  The effect of TS on the development of abdominal aortic aneurysms is not dependent on the activity of elastolytic enzymes and persists for long periods despite cessation of TS. Alterations in leukocyte response to aortic injury appear to mediate this effect.
authors.affiliation: Department of Surgery, Section of Vascular Surgery, Washington University School of Medicine, St Louis, MO 63110, USA.
authors.forename: Jianping
authors.initials: J
authors.lastname: Jin
authors.forename: Batool
authors.initials: B
authors.lastname: Arif
authors.forename: Francisca
authors.initials: F
authors.lastname: Garcia-Fernandez
authors.forename: Terri L
authors.initials: TL
authors.lastname: Ennis
authors.forename: Elaine C
authors.initials: EC
authors.lastname: Davis
authors.forename: Robert W
authors.initials: RW
authors.lastname: Thompson
authors.forename: John A
authors.initials: JA
authors.lastname: Curci
mesh_terms: D000818:Animals; D001012:Aorta, Abdominal / Q000473:pathology / Q000503:physiopathology / Q000648:ultrastructure; D017544:Aortic Aneurysm, Abdominal / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology*; D002403:Cathepsins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D002452:Cell Count; D004195:Disease Models, Animal; D004318:Doxycycline / Q000494:pharmacology; D019272:Leukocyte Elastase / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D007963:Leukocytes, Mononuclear / Q000473:pathology* / Q000502:physiology*; D008297:Male; D053508:Matrix Metalloproteinase 12 / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D020780:Matrix Metalloproteinase 9 / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D020782:Matrix Metalloproteinases / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012907:Smoking / Q000009:adverse effects*
chemical_list: D002403:Cathepsins; D019272:Leukocyte Elastase; C028217:cathepsin S; D020782:Matrix Metalloproteinases; D020780:Matrix Metalloproteinase 9; D053508:Matrix Metalloproteinase 12; D004318:Doxycycline