title: Cytokines in neovascular age-related macular degeneration: fundamentals of targeted combination therapy.
abstract: The neovascular form of age-related macular degeneration (AMD), called wet-AMD or choroidal neovascularisation, begins with damage to the outer retinal cells and retinal pigment epithelium (RPE), which elicits a cascade of inflammatory and angiogenic responses leading to neovascularisation under the macula. Studies showed that oxidative damage, chronic inflammation of the RPE and complement misregulation work at different steps of this disease. After established neovascularisation, several pro- and antiangiogenic agents start to play an important role. Vascular endothelial growth factors (VEGFs) are the most specific and potent regulators of angiogenesis, which are inhibited by intravitreal injections of ranibizumab, bevacizumab, VEGF Trap, pegaptanib sodium and other agents under investigation. Pigment epithelium-derived factor, on the other hand, shows neuroprotective and antiangiogenic activities. Hepatocyte growth factor (HGF) has a mitogenic effect on a wide range of epithelial and endothelial cells, and it is inhibited by an anti-HGF monoclonal antibody. Platelet-derived growth factor is a potent chemoattractant and mitogen for both fibroblasts and retinal RPE cells, which has been inhibited experimentally by VEGF Trap and human anti-platelet-derived growth factor-D monoclonal antibody. Fibroblast growth factor-2 has pleiotropic effects in different cell and organ systems, and it is blocked by anti-FGF antibodies, with a greater benefit regarding antiangiogenesis when combined treatment with anti-VEGF is performed. Tumour necrosis factor alpha is expressed in the retina and the choroid, and its blockade in choroidal neovascularisation includes the use of monoclonals such as infliximab. This paper reviews the most important cytokines involved in the pathogenesis of wet-AMD, with emphasis on potential combined therapies for disease control.
authors.affiliation: Department of Ophthalmology, Vision InstitutedIPEPO, Federal University of São Paulo, São Paulo, Brazil. dias_joaor@yahoo.com.br.
authors.forename: João Rafael
authors.initials: JR
authors.lastname: de Oliveira Dias
authors.forename: Eduardo Büchele
authors.initials: EB
authors.lastname: Rodrigues
authors.forename: Mauricio
authors.initials: M
authors.lastname: Maia
authors.forename: Octaviano
authors.initials: O
authors.lastname: Magalhães
authors.forename: Fernando Marcondes
authors.initials: FM
authors.lastname: Penha
authors.forename: Michel Eid
authors.initials: ME
authors.lastname: Farah
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use; D052157:Aptamers, Nucleotide / Q000627:therapeutic use; D000068258:Bevacizumab; D020256:Choroidal Neovascularization / Q000378:metabolism*; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D004359:Drug Therapy, Combination; D005136:Eye Proteins / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D017228:Hepatocyte Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D000069285:Infliximab; D058449:Intravitreal Injections; D058990:Molecular Targeted Therapy / Q000379:methods; D009414:Nerve Growth Factors / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D000069579:Ranibizumab; D040262:Receptors, Vascular Endothelial Growth Factor; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use; D015843:Serpins / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000378:metabolism; D057135:Wet Macular Degeneration / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D000099174:Pigment Epithelium-Derived Factor
chemical_list: D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D052157:Aptamers, Nucleotide; D000068258:Bevacizumab; D016207:Cytokines; D005136:Eye Proteins; D016222:Fibroblast Growth Factor 2; D017228:Hepatocyte Growth Factor; D000069285:Infliximab; D009414:Nerve Growth Factors; D010982:Platelet-Derived Growth Factor; D000069579:Ranibizumab; D040262:Receptors, Vascular Endothelial Growth Factor; D011993:Recombinant Fusion Proteins; D015843:Serpins; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; D000099174:Pigment Epithelium-Derived Factor; C533178:aflibercept; C495058:pegaptanib