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Smoking & the pathogenesis of macular degeneration

Institution: University of California, Santa Barbara
Investigator(s): Lincoln Johnson, Ph.D.
Award Cycle: 2000 (Cycle 9) Grant #: 9RT-0071 Award: $99,500
Subject Area: General Biomedical Science
Award Type: Research Project Awards

Initial Award Abstract
Macular degeneration is the eye disease that is the leading cause of blindness in people over the age of 60 in this country. The disease causes the death of the light sensitive “photoreceptor” cells in a specialized part of the retina called the macula, thus the name macular degeneration. The macula is a small but very important part of the retina; it is responsible for “fine acuity vision”, the vision one uses when driving, reading, sewing, watching television or any activity requiring fine focus. Unfortunately, no treatment has been shown to be consistently effective in preventing macular degeneration or reversing the loss of vision caused by the disease.

A number of clinical studies have shown that people who smoke cigarettes are two to four times more likely to suffer loss of vision due to macular degeneration than are non-smokers. The studies detailed in this proposal will begin to determine why, at the most basic cellular and molecular levels, this is true. The studies will address one hypothesis that has been advanced to explain the relationship between smoking and macular degeneration, that of smoking-induced oxidative stress. We will determine experimentally whether oxidative stress causes abnormalities in the “retinal pigmented epithelial cells” of the eye. These “RPE” cells are important to the survival and well being of the photoreceptor cells of the retina, and dysfunction in these cells is regarded as a key element in the development of macular degeneration.

The goal of the studies is to assess whether, under experimental oxidative stress, RPE cells exhibit abnormal patterns of production of molecules that (1) form harmful deposits called drusen in the eyes of individuals with macular degeneration or (2) are involved in stimulating the growth of blood vessels in the neovascular or “wet” form of the disease. These studies will lead to a better understanding of the relationship between smoking and macular degeneration and have the potential to lead to the development of treatments that will reduce visual loss due to this devastating disease.

Final Report
Introduction. Age-related macular degeneration (AMD) is the leading cause of new blindness in elderly adults in this country and is the overall most common cause of blindness in the Western world. The results of a number of epidemiological studies show that smokers have a two to four fold increased likelihood of suffering of visual loss from AMD than do non-smokers. While the adverse effects of smoking on the risk of developing AMD is likely to involve multiple mechanisms, three hypotheses have been advanced as likely explanations for this association. These include smoking-induced (1) oxidative stress, (2) vascular insufficiency, and (3) immune/inflammatory response. The aim of these studies was to examine the effects oxidative stress on retinal pigmented epithelial (“RPE”) cells. RPE cells lie at the back of the eye and play numerous roles in ensuring the health and well being of the light-sensitive photoreceptor cells of the retina. Many of pathologic signs of macular degeneration stem from abnormalities in RPE cells.

Topic Addressed. These studies sought to determine whether experimentally induced oxidative stress causes changes in gene expression in RPE cells that are involved in the pathogenesis of AMD. They examined RPE cells for the expression of (1) Molecular components of drusen, abnormal extracellular deposits that are a hallmark of macular degeneration, and (2) Angiogenic factors that are likely to play a role in the induction of new blood vessel growth that causes the most severe exudative or “wet” form of AMD.

Research Progress. Changes in gene transcription for molecular components of drusen and angiogenic factors in RPE cells subjected to oxidative stress induced by hydrogen peroxide (H2O2) were examined using quantitative polymerase chain reaction (QPCR) technologies. For the angiogenic factors, increases in expression were observed for VEGF, PEDF and angiopoietin-1, whereas a decrease in the expression of angiogenin was observed. Of the drusen-associated molecules, Apo E and vitronectin showed increased expression; while those of CRP and C5 were both relatively low, CRP showing decreased expression. These analyses indicate that oxidatively stressed RPE cells have significantly altered expression patterns for angiogenic factors, as well as some drusen-associated molecules.

RPE cell cultures exposed to H2O2 and corresponding control cultures were also compared by DNA array analysis on a cytokine/growth factor DNA gene array. Of the 375 gene sequences represented in the array, 38 were expressed more highly in the oxidatively stressed cells than in controls. The expression of seven genes was determined to be reduced in the stressed cells. Included among the genes upregulated in response to oxidative stress were those for several angiogenic factors, including VEGF, angiogenin and angiopoietins 1, 2.

Future Directions. The data obtained in these investigations supports the theory that the secretion of angiogenic factors by RPE cells in response to oxidative stress may be involved in stimulating retinal neovascularization associated with the late stages of AMD. It is anticipated that further study will determine the molecular mechanisms underlying this response and perhaps serve as the basis for the development of treatment strategies aimed at reducing the production of harmful pro-angiogenic factors by RPE cells.