ABSTRACT Oxidative damage and inflammation are postulated to be involved in age-related macular degeneration (AMD). However, the molecular signal(s) linking oxidation to inflammation in this

late-onset disease is unknown. Here we describe AMD-like lesions in mice after immunization with mouse serum albumin adducted with carboxyethylpyrrole, a unique oxidation fragment of

docosahexaenoic acid that has previously been found adducting proteins in drusen from AMD donor eye tissues1 and in plasma samples2 from individuals with AMD. Immunized mice develop

antibodies to this hapten, fix complement component-3 in Bruch's membrane, accumulate drusen below the retinal pigment epithelium during aging, and develop lesions in the retinal

the molecular pathology of oxidative damage in the outer retina and the immune response contributing to AMD. Access through your institution Buy or subscribe This is a preview of

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IN GEOGRAPHIC ATROPHY: A REVIEW Article Open access 09 January 2022 UNRAVELLING THE THERAPEUTIC POTENTIAL OF IL-33 FOR ATROPHIC AMD Article Open access 16 September 2021 COMPLEMENT C5 IS

NOT CRITICAL FOR THE FORMATION OF SUB-RPE DEPOSITS IN _EFEMP1_ MUTANT MICE Article Open access 17 May 2021 REFERENCES * Crabb, J.W. et al. Drusen proteome analysis: an approach to the

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_J. Immunol._ 145, 4101–4107 (1990). CAS  PubMed  Google Scholar  Download references ACKNOWLEDGEMENTS J.G.H. and V.L.P. designed and initiated the experiments. L.L. and R.G.S. prepared the

CEP-MSA and CEP-BSA. R.L.U., V.L.P., K.G.S. and X.Y. immunized the mice. K.G.S. and X.Y. performed the protein chemistry and ELISA assays, as well as managing the day-to-day maintenance of

the mice. M.E.R. and J.G.H. performed all of the histological and electron microscopic analysis. V.L.B. performed the confocal microscopy. J.G.H. analyzed all of the data and wrote the

manuscript. R.G.S., R.L.U. and V.L.P. made critical comments and suggestions for revisions of the manuscript in response to the reviewers. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS *

Department of Ophthalmology, Cole Eye Institute (i31), Cleveland Clinic Lerner College of Medicine, Cleveland, 44195, Ohio, USA Joe G Hollyfield, Vera L Bonilha, Mary E Rayborn, Xiaoping

Yang, Karen G Shadrach, Rafael L Ufret & Victor L Perez * Department of Chemistry, Case Western Reserve University, Cleveland, 44106, Ohio, USA Liang Lu & Robert G Salomon Authors *

Joe G Hollyfield View author publications You can also search for this author inPubMed Google Scholar * Vera L Bonilha View author publications You can also search for this author inPubMed 

Google Scholar * Mary E Rayborn View author publications You can also search for this author inPubMed Google Scholar * Xiaoping Yang View author publications You can also search for this

author inPubMed Google Scholar * Karen G Shadrach View author publications You can also search for this author inPubMed Google Scholar * Liang Lu View author publications You can also search

for this author inPubMed Google Scholar * Rafael L Ufret View author publications You can also search for this author inPubMed Google Scholar * Robert G Salomon View author publications You

can also search for this author inPubMed Google Scholar * Victor L Perez View author publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS Supported by the

State of Ohio Biomedical Research and Technology Transfer Program, a Research Center Grant from the Foundation Fighting Blindness, and a Challenge Grant from Research to Prevent Blindness.

The project was also supported by grants R56EY10240, R01EY014240, R24EY015638 (J.G.H.), R21EY017153 (V.L.B.), R01GM21249 (R.G.S.) and K08EY014912 (V.L.P.) from the US National Institutes of

Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the US National Eye Institute of the National Institutes of Health.

We thank J.W. Crabb for valuable discussions, B. Anand-Apte for critical comments on the manuscript, N.S. Peachey for help with the statistical comparisons, R.L. Fairchild for providing the

Rag-deficient mice, Y. Li for help with the histology, K. Sayanagi and T. Yakamoto for the fundus photography and A. Vasanji for developing the image-analysis algorithm used to define the

areas of sub-RPE deposits. CORRESPONDING AUTHORS Correspondence to Joe G Hollyfield or Victor L Perez. ETHICS DECLARATIONS COMPETING INTERESTS The mouse model for age-related macular

degeneration described in this study is protected for commercialization by the Cleveland Clinic. J.G.H., R.G.S. and V.L.P. are the inventors. SUPPLEMENTARY INFORMATION SUPPLEMENTARY TEXT AND

FIGURES Supplementary Figs. 1–7 and Supplementary Table 1 (PDF 1014 kb) RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Hollyfield, J., Bonilha, V.,

Rayborn, M. _et al._ Oxidative damage–induced inflammation initiates age-related macular degeneration. _Nat Med_ 14, 194–198 (2008). https://doi.org/10.1038/nm1709 Download citation *

Received: 20 June 2007 * Accepted: 21 December 2007 * Published: 27 January 2008 * Issue Date: February 2008 * DOI: https://doi.org/10.1038/nm1709 SHARE THIS ARTICLE Anyone you share the

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