Abstract
BackgroundAge-related macular degeneration (AMD) is the leading cause of legal blindness in the elderly population. Debris (termed drusen) below the retinal pigment epithelium (RPE) have been recognized as a risk factor for dry AMD and its progression to wet AMD, which is characterized by choroidal neovascularization (CNV). The underlying mechanism of how drusen might elicit CNV remains undefined. Cigarette smoking, oxidative damage to the RPE and inflammation are postulated to be involved in the pathophysiology of the disease. To better understand the cellular mechanism(s) linking oxidative stress and inflammation to AMD, we examined the expression of pro-inflammatory monocyte chemoattractant protein-1 (MCP-1), pro-angiogenic vascular endothelial growth factor (VEGF) and anti-angiogenic pigment epithelial derived factor (PEDF) in RPE from smoker patients with AMD. We also evaluated the effects of hydroquinone (HQ), a major pro-oxidant in cigarette smoke on MCP-1, VEGF and PEDF expression in cultured ARPE-19 cells and RPE/choroids from C57BL/6 mice.Principal FindingsMCP-1, VEGF and PEDF expression was examined by real-time PCR, Western blot, and ELISA. Low levels of MCP-1 protein were detected in RPE from AMD smoker patients relative to controls. Both MCP-1 mRNA and protein were downregulated in ARPE-19 cells and RPE/choroids from C57BL/6 mice after 5 days and 3 weeks of exposure to HQ-induced oxidative injury. VEGF protein expression was increased and PEDF protein expression was decreased in RPE from smoker patients with AMD versus controls resulting in increased VEGF/PEDF ratio. Treatment with HQ for 5 days and 3 weeks increased the VEGF/PEDF ratio in vitro and in vivo.ConclusionWe propose that impaired RPE-derived MCP-1-mediated scavenging macrophages recruitment and phagocytosis might lead to incomplete clearance of proinflammatory debris and infiltration of proangiogenic macrophages which along with increased VEGF/PEDF ratio favoring angiogenesis might promote drusen accumulation and progression to CNV in smoker patients with dry AMD.
Highlights
Age-related macular degeneration (AMD) is the main cause of untreatable blindness among older adults in the developed world and has a devastating impact on quality of life [1,2,3,4]
We propose that impaired retinal pigment epithelium (RPE)-derived monocyte chemoattractant protein-1 (MCP-1)-mediated scavenging macrophages recruitment and phagocytosis might lead to incomplete clearance of proinflammatory debris and infiltration of proangiogenic macrophages which along with increased vascular endothelial growth factor (VEGF)/pigment epithelial derived factor (PEDF) ratio favoring angiogenesis might promote drusen accumulation and progression to choroidal neovascularization (CNV) in smoker patients with dry AMD
Until now, there is no report in the literature examining VEGF and PEDF expression in RPE from AMD patients or evaluating whether or not cigarette smoke-related HQ-induced oxidative stress has the potential to dysregulate the VEGF/PEDF balance in RPE cells. Given their critical role in AMD and that oxidative damage to the RPE and inflammation appear to be central in the pathogenesis of the disease, we studied the effect of different HQ concentrations and durations of exposure on the regulation of MCP-1, VEGF and PEDF expression in RPE in vitro and in vivo
Summary
Age-related macular degeneration (AMD) is the main cause of untreatable blindness among older adults in the developed world and has a devastating impact on quality of life [1,2,3,4]. A fraction of patients with drusen will develop wet AMD, the most rapidly progressing form which accounts for 80 to 90% of cases of severe vision loss related to the disease. Our understanding of the two forms of AMD has increased substantially, yet there is still much debate as to why and how the disease progresses and what sequence of cellular events lead to the progression of dry to wet AMD. Debris (termed drusen) below the retinal pigment epithelium (RPE) have been recognized as a risk factor for dry AMD and its progression to wet AMD, which is characterized by choroidal neovascularization (CNV). To better understand the cellular mechanism(s) linking oxidative stress and inflammation to AMD, we examined the expression of pro-inflammatory monocyte chemoattractant protein-1 (MCP-1), pro-angiogenic vascular endothelial growth factor (VEGF) and anti-angiogenic pigment epithelial derived factor (PEDF) in RPE from smoker patients with AMD. We evaluated the effects of hydroquinone (HQ), a major prooxidant in cigarette smoke on MCP-1, VEGF and PEDF expression in cultured ARPE-19 cells and RPE/choroids from C57BL/6 mice
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