title: Neutrophil depletion inhibits experimental abdominal aortic aneurysm formation.
abstract: BACKGROUND
  Neutrophils may be an important source of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9), two matrix-degrading enzymes thought to be critical in the formation of an abdominal aortic aneurysm (AAA). The purpose of this investigation was to test the hypothesis that neutrophil depletion would limit experimental AAA formation by altering one or both of these enzymes.
  
  
  RESULTS
  Control, rabbit serum-treated (RS; n=27) or anti-neutrophil-antibody-treated (anti-PMN; n=25) C57BL/6 mice underwent aortic elastase perfusion to induce experimental aneurysms. Anti-PMN-treated mice became neutropenic (mean, 349 cells/microL), experiencing an 84% decrease in the circulating absolute neutrophil count (P<0.001) before elastase perfusion. Fourteen days after elastase perfusion, control mice exhibited a mean aortic diameter (AD) increase of 104+/-14% (P<0.0001), and 67% developed AAAs, whereas anti-PMN-treated mice exhibited a mean AD increase of 42+/-33%, with 8% developing AAAs. The control group also had increased tissue neutrophils (20.3 versus 8.6 cells per 5 high-powered fields [HPFs]; P=0.02) and macrophages (6.1 versus 2.1 cells per 5 HPFs, P=0.005) as compared with anti-PMN-treated mice. There were no differences in monocyte chemotactic protein-1 or macrophage inflammatory protein-1alpha chemokine levels between groups by enzyme-linked immunosorbent assay. Neutrophil collagenase (MMP-8) expression was detected only in the 14-day control mice, with increased MMP-8 protein levels by Western blotting (P=0.017), and MMP-8-positive neutrophils were seen almost exclusively in this group. Conversely, there were no statistical differences in MMP-2 or MMP-9 mRNA expression, protein levels, enzyme activity, or immunostaining patterns between groups. When C57BL/6 wild-type (n=15) and MMP-8-deficient mice (n=17) were subjected to elastase perfusion, however, ADs at 14 days were no different in size (134+/-7.9% versus 154+/-9.9%; P=0.603), which suggests that MMP-8 serves only as a marker for the presence of neutrophils and is not critical for AAA formation.
  
  
  CONCLUSIONS
  Circulating neutrophils are an important initial component of experimental AAA formation. Neutrophil depletion inhibits AAA development through a non-MMP-2/9-mediated mechanism associated with attenuated inflammatory cell recruitment.
authors: Jobst Vascular Research Laboratories, Department of Surgery, Section of Vascular Surgery, University of Michigan, Ann Arbor, USA.
authors: Jonathan L
authors: JL
authors: Eliason
authors: Kevin K
authors: KK
authors: Hannawa
authors: Gorav
authors: G
authors: Ailawadi
authors: Indranil
authors: I
authors: Sinha
authors: John W
authors: JW
authors: Ford
authors: Michael P
authors: MP
authors: Deogracias
authors: Karen J
authors: KJ
authors: Roelofs
authors: Derek T
authors: DT
authors: Woodrum
authors: Terri L
authors: TL
authors: Ennis
authors: Peter K
authors: PK
authors: Henke
authors: James C
authors: JC
authors: Stanley
authors: Robert W
authors: RW
authors: Thompson
authors: Gilbert R
authors: GR
authors: Upchurch
mesh_terms: D000818:Animals; D019268:Antibodies, Antineutrophil Cytoplasmic / Q000008:administration & dosage / Q000494:pharmacology; D017544:Aortic Aneurysm, Abdominal / Q000209:etiology / Q000517:prevention & control*; D008212:Lymphocyte Depletion; D020778:Matrix Metalloproteinase 2 / Q000235:genetics; D020784:Matrix Metalloproteinase 8 / Q000032:analysis; D020780:Matrix Metalloproteinase 9 / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D009503:Neutropenia / Q000139:chemically induced; D009504:Neutrophils / Q000201:enzymology; D010196:Pancreatic Elastase / Q000008:administration & dosage; D012333:RNA, Messenger / Q000032:analysis
chemical_list: D019268:Antibodies, Antineutrophil Cytoplasmic; D012333:RNA, Messenger; D010196:Pancreatic Elastase; D020778:Matrix Metalloproteinase 2; D020784:Matrix Metalloproteinase 8; D020780:Matrix Metalloproteinase 9