title: Complement activation via alternative pathway is critical in the development of laser-induced choroidal neovascularization: role of factor B and factor H.
abstract: The objective of this study was to explore the role of classical, lectin, and alternative pathways of complement activation in laser-induced choroidal neovascularization (CNV). The classical and alternative pathways were blocked in C57BL/6 mice by small interfering RNAs (siRNA) directed against C1q and factor B, respectively. C4(-/-) mice developed CNV similar to their wild-type controls and inhibition of C1q by siRNA had no effect on the development of CNV. In contrast, CNV was significantly inhibited (p < 0.001) in C5(-/-) mice and C57BL/6 mice treated with factor B siRNA. Inhibition of the alternative pathway by factor B siRNA resulted in decreased levels of membrane attack complex and angiogenic factors-vascular endothelial growth factor and TGF-beta2. Furthermore, factor B was up-regulated in complement sufficient C57BL/6 mice at day 1 postlaser and remained elevated at day 7. Significantly reduced levels of factor H were observed at day 3 in these animals. In conclusion, our results demonstrate that activation of the factor B-dependent alternative pathway, but not the classical or lectin pathways, was essential for the development of CNV in mouse model of laser-induced CNV. Thus, specific blockade of the alternative pathway may represent a therapeutically relevant strategy for the inhibition of CNV.
authors.affiliation: Department of Ophthalmology, Jones Eye Institute, Pat and Willard Walker Eye Research Center, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA. pbora@uams.edu
authors.forename: Nalini S
authors.initials: NS
authors.lastname: Bora
authors.forename: Sankaranarayanan
authors.initials: S
authors.lastname: Kaliappan
authors.forename: Purushottam
authors.initials: P
authors.lastname: Jha
authors.forename: Qin
authors.initials: Q
authors.lastname: Xu
authors.forename: Jeong-Hyeon
authors.initials: JH
authors.lastname: Sohn
authors.forename: Dhara B
authors.initials: DB
authors.lastname: Dhaulakhandi
authors.forename: Henry J
authors.initials: HJ
authors.lastname: Kaplan
authors.forename: Puran S
authors.initials: PS
authors.lastname: Bora
mesh_terms: D000818:Animals; D020256:Choroidal Neovascularization / Q000235:genetics / Q000276:immunology* / Q000517:prevention & control; D015922:Complement C1q / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D003181:Complement C4 / Q000172:deficiency / Q000235:genetics; D003182:Complement C5 / Q000172:deficiency / Q000235:genetics; D011415:Complement Factor B / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D017242:Complement Factor H / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D015938:Complement Membrane Attack Complex / Q000378:metabolism; D003170:Complement Pathway, Alternative / Q000235:genetics / Q000276:immunology*; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D007275:Injections, Intravenous; D007834:Lasers; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D034741:RNA, Small Interfering / Q000008:administration & dosage; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D053781:Transforming Growth Factor beta2; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000096:biosynthesis
chemical_list: D003181:Complement C4; D003182:Complement C5; D015938:Complement Membrane Attack Complex; D034741:RNA, Small Interfering; D016212:Transforming Growth Factor beta; D053781:Transforming Growth Factor beta2; D042461:Vascular Endothelial Growth Factor A; D015922:Complement C1q; D017242:Complement Factor H; D011415:Complement Factor B