resolvin-d1 and Corneal-Neovascularization

Stromal keratitis (SK) is a chronic immunopathological lesion of the eye, caused by HSV-1 infection, and a common cause of vision impairment in humans. The inflammatory lesions in the cornea are primarily caused by neutrophils with the active participation of CD4

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antiviral Agents; Aspirin; Chemokine CCL2; Chemokine CXCL2; Corneal Neovascularization; Corneal Stroma; Docosahexaenoic Acids; Female; Gene Expression Regulation; Herpes Simplex; Herpesvirus 1, Human; Humans; Interleukins; Keratitis, Herpetic; Matrix Metalloproteinase 9; Mice; Mice, Inbred BALB C; MicroRNAs; Neutrophils; Severity of Illness Index; Signal Transduction; Th1 Cells; Th17 Cells; Vascular Endothelial Growth Factor A

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.. 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.. 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.. 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.

Topics: Angiogenesis Inhibitors; Animals; Corneal Neovascularization; Cytokines; Disease Models, Animal; Docosahexaenoic Acids; Down-Regulation; Eicosapentaenoic Acid; Fluorescent Antibody Technique, Indirect; Lipoxins; Macrophages; Male; Mice; Mice, Inbred BALB C; Neutrophils; Receptors, Formyl Peptide; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor C; Vascular Endothelial Growth Factor Receptor-2