title: Progress and perspectives on the role of RPE cell inflammatory responses in the development of age-related macular degeneration.
abstract: Age-related macular degeneration (AMD) is the leading cause of blindness in developed countries. The etiology of AMD remains poorly understood and no treatment is currently available for the atrophic form of AMD. Atrophic AMD has been proposed to involve abnormalities of the retinal pigment epithelium (RPE), which lies beneath the photoreceptor cells and normally provides critical metabolic support to these light-sensing cells. Cumulative oxidative stress and local inflammation are thought to represent pathological processes involved in the etiology of atrophic AMD. Studies of tissue culture and animal models reveal that oxidative stress-induced injury to the RPE results in a chronic inflammatory response, drusen formation, and RPE atrophy. RPE degeneration in turn causes a progressive degeneration of photoreceptors, leading to the irreversible loss of vision. This review describes some of the potential major molecular and cellular events contributing to RPE death and inflammatory responses. In addition, potential target areas for therapeutic intervention will be discussed and new experimental therapeutic strategies for atrophic AMD will be presented.
authors.affiliation: Retinal Disease Research, Department of Biological Sciences, Allergan, Inc., Irvine, CA, USA.
authors.forename: Suofu
authors.initials: S
authors.lastname: Qin
authors.forename: Gerard A
authors.initials: GA
authors.lastname: Rodrigues
references.citation: Proc Natl Acad Sci U S A. 2006 Sep 5;103(36):13480-4
references.pmid: 16938854
references.citation: Am J Ophthalmol. 2004 Sep;138(3):323-8
references.pmid: 15364212
references.citation: Mol Med. 2008 Jul-Aug;14(7-8):476-84
references.pmid: 18431461
references.citation: Semin Immunol. 2007 Feb;19(1):3-10
references.pmid: 17275324
references.citation: Proc Natl Acad Sci U S A. 2007 Oct 9;104(41):16227-32
references.pmid: 17884985
references.citation: Genet Epidemiol. 1994;11(1):51-67
references.pmid: 8013888
references.citation: Nat Med. 2007 Aug;13(8):913-9
references.pmid: 17632526
references.citation: Neurobiol Aging. 2005 Aug-Sep;26(8):1199-203
references.pmid: 15917104
references.citation: Nat Genet. 2008 Jul;40(7):892-6
references.pmid: 18511946
references.citation: Invest Ophthalmol Vis Sci. 2006 Jun;47(6):2709-15
references.pmid: 16723490
references.citation: Science. 2005 Apr 15;308(5720):419-21
references.pmid: 15761120
references.citation: Histol Histopathol. 2007 Dec;22(12):1301-8
references.pmid: 17701910
references.citation: Arch Ophthalmol. 1990 Oct;108(10):1442-7
references.pmid: 1699513
references.citation: Curr Opin Neurobiol. 1994 Aug;4(4):515-24
references.pmid: 7812140
references.citation: Nat Genet. 2006 Oct;38(10):1173-7
references.pmid: 16998489
references.citation: Proc Natl Acad Sci U S A. 2005 May 17;102(20):7227-32
references.pmid: 15870199
references.citation: J Biol Chem. 2004 Apr 23;279(17):17079-84
references.pmid: 14764599
references.citation: FASEB J. 2005 Oct;19(12):1592-601
references.pmid: 16195368
references.citation: J Clin Invest. 2006 Feb;116(2):378-85
references.pmid: 16453022
references.citation: Science. 2005 Apr 15;308(5720):385-9
references.pmid: 15761122
references.citation: Int Rev Cytol. 2000;196:245-313
references.pmid: 10730217
references.citation: Proc Natl Acad Sci U S A. 1993 Sep 1;90(17):7915-22
references.pmid: 8367443
references.citation: Invest Ophthalmol Vis Sci. 2001 Sep;42(10):2419-25
references.pmid: 11527959
references.citation: Vision Res. 2002 Feb;42(4):487-95
references.pmid: 11853765
references.citation: Eye (Lond). 1998;12 ( Pt 4):679-85
references.pmid: 9850264
references.citation: Arch Ophthalmol. 1985 May;103(5):694-703
references.pmid: 4039560
references.citation: J Clin Invest. 1997 Feb 1;99(3):457-68
references.pmid: 9022079
references.citation: Rejuvenation Res. 2006 Summer;9(2):256-63
references.pmid: 16706653
references.citation: Invest Ophthalmol Vis Sci. 1999 Aug;40(9):1927-35
references.pmid: 10440245
references.citation: Arch Ophthalmol. 1993 Apr;111(4):514-8
references.pmid: 8470986
references.citation: Am J Epidemiol. 2005 Jun 1;161(11):1013-9
references.pmid: 15901621
references.citation: Nature. 2006 Mar 9;440(7081):237-41
references.pmid: 16407889
references.citation: Proc Natl Acad Sci U S A. 2006 Jul 25;103(30):11282-7
references.pmid: 16844785
references.citation: Invest Ophthalmol Vis Sci. 2007 Feb;48(2):858-65
references.pmid: 17251488
references.citation: Surv Ophthalmol. 2007 Jan;52 Suppl 1:S79-90
references.pmid: 17240260
references.citation: Invest Ophthalmol Vis Sci. 2007 Aug;48(8):3846-53
references.pmid: 17652760
references.citation: Exp Eye Res. 1998 Apr;66(4):411-9
references.pmid: 9593635
references.citation: J Biomed Sci. 2004 Jan-Feb;11(1):37-48
references.pmid: 14730208
references.citation: J Immunol. 2006 Aug 1;177(3):1872-8
references.pmid: 16849499
references.citation: Proc Natl Acad Sci U S A. 2006 Oct 31;103(44):16182-7
references.pmid: 17060630
references.citation: Invest Ophthalmol Vis Sci. 2008 Aug;49(8):3649-58
references.pmid: 18316698
references.citation: Arch Ophthalmol. 2003 Nov;121(11):1621-4
references.pmid: 14609922
references.citation: Infect Immun. 2008 Apr;76(4):1358-67
references.pmid: 18268029
references.citation: Invest Ophthalmol Vis Sci. 2008 Nov;49(11):4795-800
references.pmid: 18599571
references.citation: Am J Ophthalmol. 1997 Feb;123(2):199-206
references.pmid: 9186125
references.citation: Vision Res. 2003 Dec;43(28):2983-90
references.pmid: 14611934
references.citation: J Cell Physiol. 2005 Feb;202(2):570-8
references.pmid: 15316929
references.citation: Am J Pathol. 2008 May;172(5):1325-31
references.pmid: 18372426
references.citation: J Clin Invest. 2005 Oct;115(10):2793-800
references.pmid: 16167083
references.citation: Cell. 1999 Jun 25;97(7):889-901
references.pmid: 10399917
references.citation: Invest Ophthalmol Vis Sci. 2003 Aug;44(8):3578-85
references.pmid: 12882810
references.citation: Invest Ophthalmol Vis Sci. 2005 Dec;46(12):4393-401
references.pmid: 16303925
references.citation: Br J Ophthalmol. 1996 Jan;80(1):9-14
references.pmid: 8664242
references.citation: J Cell Physiol. 2006 Jan;206(1):119-25
references.pmid: 15965958
references.citation: Vision Res. 2008 Feb;48(3):360-5
references.pmid: 17892891
references.citation: Invest Ophthalmol Vis Sci. 1999 Oct;40(11):2598-607
references.pmid: 10509655
references.citation: J Neurosci Res. 1999 Sep 15;57(6):789-800
references.pmid: 10467250
references.citation: Proc Natl Acad Sci U S A. 2002 Nov 12;99(23):14682-7
references.pmid: 12391305
references.citation: J Immunol. 2006 Jul 15;177(2):1272-81
references.pmid: 16818787
references.citation: Ophthalmology. 1999 Mar;106(3):564-9
references.pmid: 10080215
references.citation: Proc Natl Acad Sci U S A. 2004 Jul 13;101(28):10446-51
references.pmid: 15229324
references.citation: Ophthalmology. 1999 May;106(5):910-9
references.pmid: 10328389
references.citation: Optom Vis Sci. 1998 Jul;75(7):476-84
references.pmid: 9703035
references.citation: Graefes Arch Clin Exp Ophthalmol. 2005 Jul;243(7):646-52
references.pmid: 15657773
references.citation: Nat Med. 2003 Nov;9(11):1390-7
references.pmid: 14566334
references.citation: J Clin Invest. 2007 Oct;117(10):2920-8
references.pmid: 17909628
references.citation: N Engl J Med. 2007 Aug 9;357(6):553-61
references.pmid: 17634448
references.citation: J Leukoc Biol. 1999 Sep;66(3):391-400
references.pmid: 10496308
references.citation: J Immunol. 2002 May 15;168(10):5233-9
references.pmid: 11994480
references.citation: Graefes Arch Clin Exp Ophthalmol. 2005 Nov;243(11):1080-90
references.pmid: 15909160
references.citation: J Neurochem. 2008 May;105(4):1187-97
references.pmid: 18182060
references.citation: J Exp Med. 1995 Jun 1;181(6):2119-27
references.pmid: 7760001
references.citation: Clin Exp Immunol. 2003 Feb;131(2):248-53
references.pmid: 12562384
references.citation: Arch Ophthalmol. 2002 Nov;120(11):1551-8
references.pmid: 12427071
references.citation: Arch Ophthalmol. 1999 Mar;117(3):329-39
references.pmid: 10088810
references.citation: Proc Natl Acad Sci U S A. 2005 Aug 16;102(33):11846-51
references.pmid: 16081535
references.citation: Ophthalmologica. 2007;221(3):143-52
references.pmid: 17440275
references.citation: Ann Epidemiol. 2008 Aug;18(8):647-56
references.pmid: 18652983
references.citation: Proc Natl Acad Sci U S A. 2006 Feb 14;103(7):2328-33
references.pmid: 16452172
references.citation: Arch Ophthalmol. 2007 Sep;125(9):1225-32
references.pmid: 17846363
references.citation: Invest Ophthalmol Vis Sci. 2003 Aug;44(8):3669-74
references.pmid: 12882822
references.citation: Hum Mol Genet. 2007 Aug 15;16(16):1986-92
references.pmid: 17576744
references.citation: Nat Clin Pract Rheumatol. 2007 Jul;3(7):382-90
references.pmid: 17599072
references.citation: Arch Ophthalmol. 2004 Apr;122(4):564-72
references.pmid: 15078675
references.citation: Invest Ophthalmol Vis Sci. 2003 Aug;44(8):3663-8
references.pmid: 12882821
references.citation: Exp Eye Res. 2000 Apr;70(4):441-9
references.pmid: 10865992
references.citation: Invest Ophthalmol Vis Sci. 2005 Feb;46(2):683-91
references.pmid: 15671300
references.citation: Invest Ophthalmol Vis Sci. 2001 May;42(6):1356-62
references.pmid: 11328751
references.citation: Ophthalmology. 1997 Jan;104(1):7-21
references.pmid: 9022098
references.citation: J Immunol. 1999 Mar 15;162(6):3212-9
references.pmid: 10092772
references.citation: J Biol Chem. 2003 Oct 24;278(43):42027-35
references.pmid: 12923198
references.citation: Br J Ophthalmol. 2005 Jan;89(1):107-12
references.pmid: 15615757
references.citation: Arch Ophthalmol. 2001 Oct;119(10):1417-36
references.pmid: 11594942
references.citation: Invest Ophthalmol Vis Sci. 2006 Nov;47(11):5098-105
references.pmid: 17065531
references.citation: Hum Mol Genet. 2008 Apr 1;17(7):971-7
references.pmid: 18084039
references.citation: Exp Eye Res. 2005 May;80(5):595-606
references.pmid: 15862166
references.citation: Exp Eye Res. 2006 Oct;83(4):824-33
references.pmid: 16822505
references.citation: Am J Pathol. 2002 Oct;161(4):1515-24
references.pmid: 12368224
references.citation: Mol Vis. 2003 Mar 11;9:60-73
references.pmid: 12632036
references.citation: N Engl J Med. 2001 Apr 5;344(14):1058-66
references.pmid: 11287977
references.citation: Invest Ophthalmol Vis Sci. 2003 Aug;44(8):3586-92
references.pmid: 12882811
references.citation: Invest Ophthalmol Vis Sci. 2001 Oct;42(11):2714-20
references.pmid: 11581220
references.citation: J Photochem Photobiol B. 1993 Aug;19(3):201-4
references.pmid: 8229462
references.citation: Life Sci. 2006 Jul 4;79(6):545-50
references.pmid: 16504212
references.citation: Prog Retin Eye Res. 2001 Jan;20(1):29-48
references.pmid: 11070367
references.citation: Proc Natl Acad Sci U S A. 2007 Jun 26;104(26):11026-31
references.pmid: 17578916
references.citation: Aust N Z J Ophthalmol. 1998 Nov;26(4):277-81
references.pmid: 9843254
references.citation: Bioorg Med Chem Lett. 2006 Oct 1;16(19):5088-92
references.pmid: 16876401
references.citation: Biochem Biophys Res Commun. 2006 Apr 7;342(2):372-8
references.pmid: 16483542
references.citation: Retina. 1988;8(3):177-81
references.pmid: 2852836
references.citation: Invest Ophthalmol Vis Sci. 1989 Aug;30(8):1691-9
references.pmid: 2759786
references.citation: Invest Ophthalmol Vis Sci. 2008 Aug;49(8):3666-70
references.pmid: 18408184
references.citation: Aust N Z J Ophthalmol. 1995 Nov;23(4):293-8
references.pmid: 11980075
references.citation: Exp Eye Res. 2006 May;82(5):840-8
references.pmid: 16364296
references.citation: Toxicol Appl Pharmacol. 2005 Apr 15;204(2):122-34
references.pmid: 15808518
references.citation: Exp Eye Res. 2003 Apr;76(4):463-71
references.pmid: 12634111
references.citation: Hum Mol Genet. 2008 Jun 15;17(12):1821-4
references.pmid: 18325906
references.citation: Exp Eye Res. 2007 Apr;84(4):635-45
references.pmid: 17292886
references.citation: Invest Ophthalmol Vis Sci. 2001 Jun;42(7):1646-52
references.pmid: 11381073
references.citation: Nat Genet. 2007 Oct;39(10):1200-1
references.pmid: 17767156
references.citation: Proc Natl Acad Sci U S A. 2006 Mar 7;103(10):3896-901
references.pmid: 16505355
references.citation: Br J Ophthalmol. 1993 Oct;77(10):657-61
references.pmid: 8218037
references.citation: Trends Immunol. 2008 Aug;29(8):380-7
references.pmid: 18602340
references.citation: Prog Retin Eye Res. 2001 Nov;20(6):705-32
references.pmid: 11587915
references.citation: Exp Eye Res. 2001 Dec;73(6):887-96
references.pmid: 11846519
references.citation: Prog Lipid Res. 1983;22(2):79-131
references.pmid: 6348799
references.citation: Invest Ophthalmol Vis Sci. 1992 Nov;33(12):3394-9
references.pmid: 1428712
references.citation: Free Radic Biol Med. 2006 Feb 15;40(4):660-9
references.pmid: 16458197
references.citation: Nat Med. 2008 Feb;14(2):194-8
references.pmid: 18223656
references.citation: Invest Ophthalmol Vis Sci. 2007 Apr;48(4):1900-5
references.pmid: 17389526
references.citation: Invest Ophthalmol Vis Sci. 2005 Nov;46(11):4302-10
references.pmid: 16249512
references.citation: Hum Mol Genet. 2008 May 1;17(9):1299-305
references.pmid: 18203751
references.citation: Invest Ophthalmol Vis Sci. 2007 Aug;48(8):3827-36
references.pmid: 17652758
references.citation: Nat Genet. 2006 Apr;38(4):458-62
references.pmid: 16518403
references.citation: J Cell Physiol. 2006 Sep;208(3):516-26
references.pmid: 16741961
references.citation: Curr Eye Res. 2002 Dec;25(6):373-9
references.pmid: 12789545
references.citation: Invest Ophthalmol Vis Sci. 2007 Mar;48(3):1355-61
references.pmid: 17325184
references.citation: Proc Natl Acad Sci U S A. 1992 Dec 1;89(23):11249-53
references.pmid: 1454803
references.citation: Cell Mol Life Sci. 2004 Jul;61(13):1664-74
references.pmid: 15224189
references.citation: Am J Clin Nutr. 1995 Dec;62(6 Suppl):1448S-1461S
references.pmid: 7495246
references.citation: FASEB J. 2004 Mar;18(3):562-4
references.pmid: 14715704
references.citation: Surv Ophthalmol. 2000 Sep-Oct;45(2):115-34
references.pmid: 11033038
references.citation: Prog Retin Eye Res. 2003 Sep;22(5):683-703
references.pmid: 12892646
references.citation: Invest Ophthalmol Vis Sci. 2005 Mar;46(3):979-87
references.pmid: 15728556
references.citation: Neurobiol Aging. 2007 May;28(5):639-47
references.pmid: 16697488
references.citation: Invest Ophthalmol Vis Sci. 1996 Dec;37(13):2724-35
references.pmid: 8977488
references.citation: Science. 2005 Apr 15;308(5720):421-4
references.pmid: 15761121
references.citation: Eur J Pharmacol. 2007 May 7;562(1-2):12-9
references.pmid: 17321517
references.citation: Exp Cell Res. 1994 Sep;214(1):242-9
references.pmid: 8082727
references.citation: Invest Ophthalmol Vis Sci. 1995 Jun;36(7):1271-9
references.pmid: 7775104
references.citation: Invest Ophthalmol Vis Sci. 2005 Apr;46(4):1140-6
references.pmid: 15790871
references.citation: Invest Ophthalmol Vis Sci. 2008 Apr;49(4):1679-85
references.pmid: 18385091
references.citation: Invest Ophthalmol Vis Sci. 1992 May;33(6):1909-18
references.pmid: 1582797
references.citation: Am J Ophthalmol. 2002 Sep;134(3):411-31
references.pmid: 12208254
references.citation: Invest Ophthalmol Vis Sci. 2007 Sep;48(9):4328-34
references.pmid: 17724224
references.citation: Exp Eye Res. 2006 Jan;82(1):99-110
references.pmid: 16019000
references.citation: Graefes Arch Clin Exp Ophthalmol. 1993;231(1):34-40
references.pmid: 8428678
references.citation: Nat Med. 2000 Apr;6(4):435-42
references.pmid: 10742151
references.citation: J Biol Chem. 2007 Aug 3;282(31):22414-25
references.pmid: 17558024
references.citation: FASEB J. 2005 Oct;19(12):1683-5
references.pmid: 16099945
references.citation: Nature. 2008 Mar 6;452(7183):103-7
references.pmid: 18288107
references.citation: JAMA. 1996 Oct 9;276(14):1141-6
references.pmid: 8827966
references.citation: J Clin Invest. 1996 Sep 1;98(5):1210-7
references.pmid: 8787684
references.citation: Clin Cancer Res. 1995 Oct;1(10):1133-8
references.pmid: 9815904
references.citation: Prog Retin Eye Res. 2001 May;20(3):385-414
references.pmid: 11286898
references.citation: Expert Opin Emerg Drugs. 2006 Nov;11(4):725-40
references.pmid: 17064228
references.citation: Invest Ophthalmol Vis Sci. 2004 Oct;45(10):3713-20
references.pmid: 15452081
references.citation: Surv Ophthalmol. 1995 Mar-Apr;39(5):367-74
references.pmid: 7604360
references.citation: Invest Ophthalmol Vis Sci. 1991 Aug;32(9):2462-72
references.pmid: 1714427
references.citation: Invest Ophthalmol Vis Sci. 1990 Dec;31(12):2520-8
references.pmid: 2176183
references.citation: J Cell Sci. 2001 Jan;114(Pt 1):199-205
references.pmid: 11112703
references.citation: Prog Retin Eye Res. 2001 Jul;20(4):469-529
references.pmid: 11390257
references.citation: Am J Pathol. 1994 Feb;144(2):393-403
references.pmid: 7508686
references.citation: FASEB J. 2000 May;14(7):835-46
references.pmid: 10783137
references.citation: Mol Vis. 1999 Nov 03;5:32
references.pmid: 10562656
references.citation: Curr Eye Res. 2001 Nov;23(5):320-5
references.pmid: 11910520
references.citation: Physiol Rev. 2005 Jul;85(3):845-81
references.pmid: 15987797
references.citation: Proc Natl Acad Sci U S A. 2004 Jun 1;101(22):8491-6
references.pmid: 15152078
references.citation: Nat Med. 2006 Mar;12(3):317-23
references.pmid: 16474398
references.citation: Br J Ophthalmol. 2004 Jun;88(6):776-81
references.pmid: 15148211
references.citation: Tissue Eng. 2004 Nov-Dec;10(11-12):1617-22
references.pmid: 15684670
references.citation: Curr Mol Med. 2007 Dec;7(8):758-65
references.pmid: 18331234
references.citation: Eur J Ophthalmol. 1998 Oct-Dec;8(4):199-206
references.pmid: 9891890
references.citation: Proc Natl Acad Sci U S A. 2007 Aug 7;104(32):13152-7
references.pmid: 17670936
references.citation: Invest Ophthalmol Vis Sci. 2007 Apr;48(4):1801-7
references.pmid: 17389514
references.citation: Blood. 1998 Sep 1;92(5):1661-7
references.pmid: 9716594
references.citation: Mol Vis. 2003 May 14;9:184-90
references.pmid: 12764254
references.citation: Invest Ophthalmol Vis Sci. 2002 Oct;43(10):3292-8
references.pmid: 12356837
references.citation: J Neuroimmunol. 2004 Aug;153(1-2):7-15
references.pmid: 15265658
references.citation: Eye (Lond). 2005 Sep;19(9):935-44
references.pmid: 16151432
references.citation: Exp Eye Res. 2006 Oct;83(4):834-40
references.pmid: 16764856
references.citation: Invest Ophthalmol Vis Sci. 2006 Sep;47(9):3912-8
references.pmid: 16936104
references.citation: Invest Ophthalmol Vis Sci. 2003 Apr;44(4):1775-82
references.pmid: 12657621
references.citation: Invest Ophthalmol Vis Sci. 2001 Jun;42(7):1660-8
references.pmid: 11381075
references.citation: PLoS Med. 2006 Aug;3(8):e310
references.pmid: 16903779
references.citation: Eye (Lond). 1995;9 ( Pt 6):763-71
references.pmid: 8849547
references.citation: Invest Ophthalmol Vis Sci. 1998 Mar;39(3):592-602
references.pmid: 9501871