PMID- 21386905 OWN - NLM STAT- MEDLINE DCOM- 20110901 LR - 20231213 IS - 1932-6203 (Electronic) IS - 1932-6203 (Linking) VI - 6 IP - 2 DP - 2011 Feb 28 TI - Cigarette smoke-related hydroquinone dysregulates MCP-1, VEGF and PEDF expression in retinal pigment epithelium in vitro and in vivo. PG - e16722 LID - 10.1371/journal.pone.0016722 [doi] LID - e16722 AB - BACKGROUND: Age-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 FINDINGS: MCP-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. CONCLUSION: We 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. FAU - Pons, Marianne AU - Pons M AD - Department of Ophthalmology, Miller School of Medicine, Bascom Palmer Eye Institute, University of Miami, Miami, Florida, United States of America. FAU - Marin-Castano, Maria E AU - Marin-Castano ME LA - eng GR - P30 EY014801/EY/NEI NIH HHS/United States GR - P30-EY14801/EY/NEI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20110228 PL - United States TA - PLoS One JT - PloS one JID - 101285081 RN - 0 (Ccl2 protein, mouse) RN - 0 (Chemokine CCL2) RN - 0 (Eye Proteins) RN - 0 (Hydroquinones) RN - 0 (Nerve Growth Factors) RN - 0 (Serpins) RN - 0 (Smoke) RN - 0 (Vascular Endothelial Growth Factor A) RN - 0 (pigment epithelium-derived factor) RN - 0 (vascular endothelial growth factor A, mouse) RN - XV74C1N1AE (hydroquinone) SB - IM MH - Aged MH - Aged, 80 and over MH - Animals MH - Cells, Cultured MH - Chemokine CCL2/genetics/metabolism MH - Choroidal Neovascularization/genetics/metabolism/pathology MH - Eye Proteins/genetics/metabolism MH - Female MH - Gene Expression Regulation/drug effects MH - Humans MH - Hydroquinones/*adverse effects/isolation & purification MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Middle Aged MH - Nerve Growth Factors/genetics/metabolism MH - Retinal Pigment Epithelium/*drug effects/*metabolism/pathology MH - Serpins/genetics/metabolism MH - Smoke/*adverse effects MH - Smoking/adverse effects/pathology MH - Nicotiana/chemistry MH - Vascular Endothelial Growth Factor A/genetics/metabolism PMC - PMC3046136 COIS- Competing Interests: The authors have declared that no competing interests exist. EDAT- 2011/03/10 06:00 MHDA- 2011/09/02 06:00 PMCR- 2011/02/28 CRDT- 2011/03/10 06:00 PHST- 2010/10/15 00:00 [received] PHST- 2010/12/23 00:00 [accepted] PHST- 2011/03/10 06:00 [entrez] PHST- 2011/03/10 06:00 [pubmed] PHST- 2011/09/02 06:00 [medline] PHST- 2011/02/28 00:00 [pmc-release] AID - PONE-D-10-03986 [pii] AID - 10.1371/journal.pone.0016722 [doi] PST - epublish SO - PLoS One. 2011 Feb 28;6(2):e16722. doi: 10.1371/journal.pone.0016722.