title: Interleukin-8 administration enhances venous thrombosis resolution in a rat model.
abstract: BACKGROUND
  Therapy for deep vein thrombosis (DVT) resolution in those patients in whom a complication or contraindication to anticoagulation occurs is limited. As prior work suggests that thrombus maturation involves early influx of neutrophils (PMN) and neovascularization, we hypothesized that administering the proinflammatory/proangiogenic chemokine interleukin (IL)-8 might accelerate thrombus resolution.
  
  
  METHODS
  An established rodent model of DVT (inferior vena cava [IVC] ligation) was used whereby daily intravenous recombinant human IL-8 (1 microg) or vehicle control was administered, with sacrifice at 4 and 8 days. Prior to sacrifice and at harvest, duplex ultrasound of the DVT and femoral venous pressure measurements were performed. Thrombi were analyzed by immunohistochemical techniques for PMN, monocytes, and neovascularization; for chemokines, by enzyme-linked immunoassay; and fibrosis, by hydroxyproline assay and trichrome staining.
  
  
  RESULTS
  IL-8 accelerated thrombus dissolution 4 days after IVC ligation, with 6-fold increased thrombus blood flow by duplex ultrasound and a 23% increased absolute femoral venous pressure compared with controls (both P < 0.05). These findings may be partially explained by the fact that animals receiving IL-8, as compared with controls, had 2.5-fold greater thrombus neovascularization (with a trend continuing to 8 days) and increased PMN at 4 days. Thrombus vascular endothelial growth factor was significantly reduced at 8 days postligation, while monocyte chemotactic protein-1 and macrophage inflammatory protein-1alpha were not altered by IL-8 administration. At 8 days post-IVC-ligation, fibrosis was 12-fold greater with IL-8 treatment compared with controls.
  
  
  CONCLUSIONS
  A proinflammatory/proangiogenic thrombus milieu, as conferred by IL-8, enhances thrombus resolution and underscores the important relationship between neovascularity and inflammation.
authors: Section of Vascular Surgery, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA. henke@umich.edu
authors: P K
authors: PK
authors: Henke
authors: T W
authors: TW
authors: Wakefield
authors: A M
authors: AM
authors: Kadell
authors: M J
authors: MJ
authors: Linn
authors: M R
authors: MR
authors: Varma
authors: M
authors: M
authors: Sarkar
authors: A
authors: A
authors: Hawley
authors: J B
authors: JB
authors: Fowlkes
authors: R M
authors: RM
authors: Strieter
mesh_terms: D000818:Animals; D018925:Chemokines / Q000378:metabolism; D016228:Endothelial Growth Factors / Q000378:metabolism; D005355:Fibrosis; D006973:Hypertension / Q000209:etiology / Q000503:physiopathology; D016209:Interleukin-8 / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007958:Leukocyte Count; D008222:Lymphokines / Q000378:metabolism; D008297:Male; D018919:Neovascularization, Physiologic / Q000187:drug effects; D009504:Neutrophils / Q000187:drug effects / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012039:Regional Blood Flow / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D014690:Venous Pressure / Q000187:drug effects; D020246:Venous Thrombosis / Q000188:drug therapy* / Q000503:physiopathology
chemical_list: D018925:Chemokines; D016228:Endothelial Growth Factors; D016209:Interleukin-8; D008222:Lymphokines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors