title: Anti-angiogenesis effect of the novel anti-inflammatory and pro-resolving lipid mediators.
abstract: OBJECTIVE
  Resolvins and lipoxins are lipid mediators generated from essential polyunsaturated fatty acids that are the first dual anti-inflammatory and pro-resolving signals identified in the resolution phase of inflammation. Here the authors investigated the potential of aspirin-triggered lipoxin (LX) A4 analog (ATLa), resolving (Rv) D1, and RvE1, in regulating angiogenesis in a murine model.
  
  
  METHODS
  ATLa and RvE1 receptor expression was tested in different corneal cell populations by RT-PCR. Corneal neovascularization (CNV) was induced by suture or micropellet (IL-1 beta, VEGF-A) placement. Mice were then treated with ATLa, RvD1, RvE1, or vehicle, subconjunctivally at 48-hour intervals. Infiltration of neutrophils and macrophages was quantified after immunofluorescence staining. The mRNA expression levels of inflammatory cytokines, VEGFs, and VEGFRs were analyzed by real-time PCR. CNV was evaluated intravitally and morphometrically.
  
  
  RESULTS
  The receptors for LXA4, ALX/Fpr-rs-2 and for RvE1, ChemR23 were each expressed by epithelium, stromal keratocytes, and infiltrated CD11b(+) cells in corneas. Compared to the vehicle-treated eye, ATLa-, RvD1-, and RvE1-treated eyes had reduced numbers of infiltrating neutrophils and macrophages and reduced mRNA expression levels of TNF-alpha, IL-1 alpha, IL-1 beta, VEGF-A, VEGF-C, and VEGFR2. Animals treated with these mediators had significantly suppressed suture-induced or IL-1 beta-induced hemangiogenesis (HA) but not lymphangiogenesis. Interestingly, only the application of ATLa significantly suppressed VEGF-A-induced HA.
  
  
  CONCLUSIONS
  ATLa, RvE1, and RvD1 all reduce inflammatory corneal HA by early regulation of resolution mechanisms in innate immune responses. In addition, ATLa directly inhibits VEGF-A-mediated angiogenesis and is the most potent inhibitor of NV among this new genus of dual anti-inflammatory and pro-resolving lipid mediators.
authors.affiliation: Department of Ophthalmology, Schepens Eye Research Institute, Harvard Medical School, 20 Staniford Street, Boston, MA 02114, USA.
authors.forename: Yiping
authors.initials: Y
authors.lastname: Jin
authors.forename: Makoto
authors.initials: M
authors.lastname: Arita
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhang
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Saban
authors.forename: Sunil K
authors.initials: SK
authors.lastname: Chauhan
authors.forename: Nan
authors.initials: N
authors.lastname: Chiang
authors.forename: Charles N
authors.initials: CN
authors.lastname: Serhan
authors.forename: Reza
authors.initials: R
authors.lastname: Dana
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D016510:Corneal Neovascularization / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D016207:Cytokines / Q000235:genetics; D004195:Disease Models, Animal; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D015536:Down-Regulation; D015118:Eicosapentaenoic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D019084:Fluorescent Antibody Technique, Indirect; D044045:Lipoxins / Q000494:pharmacology*; D008264:Macrophages / Q000502:physiology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009504:Neutrophils / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D044042:Receptors, Formyl Peptide / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics; D042582:Vascular Endothelial Growth Factor C / Q000235:genetics; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics
chemical_list: C489638:16-(4-fluoro)phenoxylipoxin A4 methyl ester; D020533:Angiogenesis Inhibitors; D016207:Cytokines; C469988:Fpr1 protein, mouse; D044045:Lipoxins; D012333:RNA, Messenger; D044042:Receptors, Formyl Peptide; D042461:Vascular Endothelial Growth Factor A; D042582:Vascular Endothelial Growth Factor C; C518399:resolvin D1; C467480:vascular endothelial growth factor A, mouse; C467483:vascular endothelial growth factor C, mouse; D004281:Docosahexaenoic Acids; D015118:Eicosapentaenoic Acid; D040301:Vascular Endothelial Growth Factor Receptor-2; C499823:5S,12R,18R-trihydroxy-6Z,8E,10E,14Z,16E-eicosapentaenoic acid