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Cigarette Smoke-Related Hydroquinone Dysregulates MCP-1, VEGF and PEDF Expression in Retinal Pigment Epithelium in Vitro and in Vivo  [PDF]
Marianne Pons,Maria E. Marin-Casta?o
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0016722
Abstract: 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.
Biological Effects of Cigarette Smoke in Cultured Human Retinal Pigment Epithelial Cells  [PDF]
Alice L. Yu, Kerstin Birke, Johannes Burger, Ulrich Welge-Lussen
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0048501
Abstract: The goal of the present study was to determine whether treatment with cigarette smoke extract (CSE) induces cell loss, cellular senescence, and extracellular matrix (ECM) synthesis in primary human retinal pigment epithelial (RPE) cells. Primary cultured human RPE cells were exposed to 2, 4, 8, and 12% of CSE concentration for 24 hours. Cell loss was detected by cell viability assay. Lipid peroxidation was assessed by loss of cis-parinaric acid (PNA) fluorescence. Senescence-associated ?-galactosidase (SA-?-Gal) activity was detected by histochemical staining. Expression of apolipoprotein J (Apo J), connective tissue growth factor (CTGF), fibronectin, and laminin were examined by real-time PCR, western blot, or ELISA experiments. The results showed that exposure of cells to 12% of CSE concentration induced cell death, while treatment of cells with 2, 4, and 8% CSE increased lipid peroxidation. Exposure to 8% of CSE markedly increased the number of SA-?-Gal positive cells to up to 82%, and the mRNA expression of Apo J, CTGF, and fibronectin by approximately 3–4 fold. Treatment with 8% of CSE also increased the protein expression of Apo J and CTGF and the secretion of fibronectin and laminin. Thus, treatment with CSE can induce cell loss, senescent changes, and ECM synthesis in primary human RPE cells. It may be speculated that cigarette smoke could be involved in cellular events in RPE cells as seen in age-related macular degeneration.
Alternative Complement Pathway Deficiency Ameliorates Chronic Smoke-Induced Functional and Morphological Ocular Injury  [PDF]
Alex Woodell, Beth Coughlin, Kannan Kunchithapautham, Sarah Casey, Tucker Williamson, W. Drew Ferrell, Carl Atkinson, Bryan W. Jones, B?rbel Rohrer
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0067894
Abstract: Background Age-related macular degeneration (AMD), a complex disease involving genetic variants and environmental insults, is among the leading causes of blindness in Western populations. Genetic and histologic evidence implicate the complement system in AMD pathogenesis; and smoking is the major environmental risk factor associated with increased disease risk. Although previous studies have demonstrated that cigarette smoke exposure (CE) causes retinal pigment epithelium (RPE) defects in mice, and smoking leads to complement activation in patients, it is unknown whether complement activation is causative in the development of CE pathology; and if so, which complement pathway is required. Methods Mice were exposed to cigarette smoke or clean, filtered air for 6 months. The effects of CE were analyzed in wildtype (WT) mice or mice without a functional complement alternative pathway (AP; CFB?/?) using molecular, histological, electrophysiological, and behavioral outcomes. Results CE in WT mice exhibited a significant reduction in function of both rods and cones as determined by electroretinography and contrast sensitivity measurements, concomitant with a thinning of the nuclear layers as measured by SD-OCT imaging and histology. Gene expression analyses suggested that alterations in both photoreceptors and RPE/choroid might contribute to the observed loss of function, and visualization of complement C3d deposition implies the RPE/Bruch's membrane (BrM) complex as the target of AP activity. RPE/BrM alterations include an increase in mitochondrial size concomitant with an apical shift in mitochondrial distribution within the RPE and a thickening of BrM. CFB?/? mice were protected from developing these CE-mediated alterations. Conclusions Taken together, these findings provide clear evidence that ocular pathology generated in CE mice is dependent on complement activation and requires the AP. Identifying animal models with RPE/BrM damage and verifying which aspects of pathology are dependent upon complement activation is essential for developing novel complement-based treatment approaches for the treatment of AMD.
Age and disease-related structural changes in the retinal pigment epithelium  [cached]
Vera L Bonilha
Clinical Ophthalmology , 2008,
Abstract: Vera L BonilhaCole Eye Institute, The Cleveland Clinic, Cleveland, OH, USAAbstract: As the retinal pigment epithelium (RPE) ages, a number of structural changes occur, including loss of melanin granules, increase in the density of residual bodies, accumulation of lipofuscin, accumulation of basal deposits on or within Bruch’s membrane, formation of drusen (between the basal lamina of the RPE and the inner collagenous layer of Bruch’s membrane), thickening of Bruch’s membrane, microvilli atrophy and disorganization of the basal infoldings. Although these changes are well known, the basic mechanisms involved in them are frequently poorly understood. These age-related changes progress slowly and vary in severity in different individuals. These changes are also found in age-related macular degeneration (AMD), a late onset disease that severely impacts the RPE, but they are much more pronounced than during normal aging. However, the changes in AMD lead to severe loss of vision. Given the many supporting functions which the RPE serves for the retina, it is important to decipher the age-related changes in this epithelium in order to understand age-related changes in vision.Keywords: retinal pigment epithelium, aging, age-related macular degeneration (AMD), ocular disorders, retinal disease
Age-Related Changes in the Retinal Pigment Epithelium (RPE)  [PDF]
Xiaorong Gu, Nikolas J. Neric, John S. Crabb, John W. Crabb, Sanjoy K. Bhattacharya, Mary E. Rayborn, Joe G. Hollyfield, Vera L. Bonilha
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0038673
Abstract: Background Age-related changes in the retina are often accompanied by visual impairment but their mechanistic details remain poorly understood. Methodology Proteomic studies were pursued toward a better molecular understanding of retinal pigment epithelium (RPE) aging mechanisms. RPE cells were isolated from young adults (3–4 month-old) and old (24–25 month-old) F344BN rats, and separated into subcellular fractions containing apical microvilli (MV) and RPE cell bodies (CB) lacking their apical microvilli. Proteins were extracted in detergent, separated by SDS-PAGE, digested in situ with trypsin and analyzed by LC MS/MS. Select proteins detected in young and old rat RPE were further studied using immunofluorescence and Western blot analysis. Principal Findings A total of 356 proteins were identified in RPE MV from young and 378 in RPE MV from old rats, 48% of which were common to each age group. A total of 897 proteins were identified in RPE CB from young rats and 675 in old CB, 56% of which were common to each age group. Several of the identified proteins, including proteins involved in response to oxidative stress, displayed both quantitative and qualitative changes in overall abundance during RPE aging. Numerous proteins were identified for the first time in the RPE. One such protein, collectrin, was localized to the apical membrane of apical brush border of proximal tubules where it likely regulates several amino acid transporters. Elsewhere, collectrin is involved in pancreatic β cell proliferation and insulin secretion. In the RPE, collectrin expression was significantly modulated during RPE aging. Another age-regulated, newly described protein was DJ-1, a protein extensively studied in brain where oxidative stress-related functions have been described. Conclusions/Significance The data presented here reveals specific changes in the RPE during aging, providing the first protein database of RPE aging, which will facilitate future studies of age-related retinal diseases.
Chronic Cigarette Smoke Causes Oxidative Damage and Apoptosis to Retinal Pigmented Epithelial Cells in Mice  [PDF]
Masashi Fujihara, Norihiro Nagai, Thomas E. Sussan, Shyam Biswal, James T. Handa
PLOS ONE , 2008, DOI: 10.1371/journal.pone.0003119
Abstract: The purpose of this study was to determine whether mice exposed to chronic cigarette smoke develop features of early age-related macular degeneration (AMD). Two month old C57Bl6 mice were exposed to either filtered air or cigarette smoke in a smoking chamber for 5 h/day, 5 days/week for 6 months. Eyes were fixed in 2.5% glutaraldehyde/2% paraformaldehyde and examined for ultrastructural changes by transmission electron microscopy. The contralateral eye was fixed in 2% paraformaldehyde and examined for oxidative injury to the retinal pigmented epithelium (RPE) by 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-OHdG) immunolabeling and apoptosis by TUNEL labeling. Mice exposed to cigarette smoke had immunolabeling for 8-OHdG in 85±3.7% of RPE cells counted compared to 9.5±3.9% in controls (p<0.00001). Bruch membrane was thicker in mice exposed to smoke (1086±332 nm) than those raised in air (543±132 nm; p = 0.0069). The two most pronounced ultrastructural changes (severity grading scale from 0–3) seen were a loss of basal infoldings (mean difference in grade = 1.98; p<0.0001), and an increase in intracellular vacuoles (mean difference in grade = 1.7; p<0.0001). Ultrastructural changes to Bruch membrane in cigarette-smoke exposed mice were smaller in magnitude but consistently demonstrated significantly higher grade injury in cigarette-exposed mice, including basal laminar deposits (mean difference in grade = 0.54; p<0.0001), increased outer collagenous layer deposits (mean difference in grade = 0.59; p = 0.002), and increased basal laminar deposit continuity (mean difference in grade = 0.4; p<0.0001). TUNEL assay showed a higher percentage of apoptotic RPE from mice exposed to cigarette smoke (average 8.0±1.1%) than room air (average 0±0%; p = 0.043). Mice exposed to chronic cigarette smoke develop evidence of oxidative damage with ultrastructural degeneration to the RPE and Bruch membrane, and RPE cell apoptosis. This model could be useful for studying the mechanism of smoke induced changes during early AMD.
Wnt5a Is Associated with Cigarette Smoke-Related Lung Carcinogenesis via Protein Kinase C  [PDF]
Young Mi Whang, Ukhyun Jo, Jae Sook Sung, Hyun Jung Ju, Hyun Kyung Kim, Kyong Hwa Park, Jong Won Lee, In Song Koh, Yeul Hong Kim
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0053012
Abstract: Wnt5a is overexpressed during the progression of human non-small cell lung cancer. However, the roles of Wnt5a during smoking-related lung carcinogenesis have not been clearly elucidated. We investigated the associations between Wnt5a and the early development of cigarette smoke related lung cancer using human bronchial epithelial (HBE) cells (NHBE, BEAS-2B, 1799, 1198 and 1170I) at different malignant stages established by exposure to cigarette smoke condensate (CSC). Abnormal up-regulation of Wnt5a mRNA and proteins was detected in CSC-exposed transformed 1198 and tumorigenic 1170I cells as compared with other non-CSC exposed HBE cells. Tumor tissues obtained from smokers showed higher Wnt5a expressions than matched normal tissues. In non-CSC exposed 1799 cells, treatment of recombinant Wnt5a caused the activations of PKC and Akt, and the blockage of Wnt5a and PKC significantly decreased the viabilities of CSC-transformed 1198 cells expressing high levels of Wnt5a. This reduced cell survival rate was associated with increased apoptosis via the down-regulation of Bcl2 and the induction of cleaved poly ADP-ribose polymerase. Moreover, CSC-treated 1799 cells showed induction of Wnt5a expression and enhanced colony-forming capacity. The CSC-induced colony forming efficiency was suppressed by the co-incubation with a PKC inhibitor. In conclusion, these results suggest that cigarette smoke induces Wnt5a-coupled PKC activity during lung carcinogenesis, which causes Akt activity and anti-apoptosis in lung cancer. Therefore, current study provides novel clues for the crucial role of Wnt5a in the smoking-related lung carcinogenesis.
The Aged Retinal Pigment Epithelium/Choroid: A Potential Substratum for the Pathogenesis of Age-Related Macular Degeneration  [PDF]
Huiyi Chen, Bin Liu, Thomas J. Lukas, Arthur H. Neufeld
PLOS ONE , 2008, DOI: 10.1371/journal.pone.0002339
Abstract: Background Although the statement that age is the greatest risk factor for Age-related macular degeneration (AMD) is widely accepted, the cellular and molecular explanations for that clinical statement are not generally known. A major focus of AMD research is the retinal pigment epithelium (RPE)/choroid. The purpose of this study was to characterize the changes in the RPE/choroid with age that may provide a background for the development of AMD. Methodology/Principal Findings We compared the transcriptional profiles, key protein levels and histology of the RPE/choroid from young and old mice. Using three statistical methods, microarray data demonstrated marked changes in the old mouse. There were 315 genes differentially expressed with age; most of these genes were related to immune responses and inflammatory activity. Canonical pathways having significant numbers of upregulated genes in aged RPE/choroid included leukocyte extravasation, complement cascades, natural killer cell signaling and IL-10 signaling. By contrast, the adjacent neural retina showed completely different age-related changes. The levels of proteins that participate in leukocyte extravasation and complement pathways were consistently increased in the normal, aged RPE/choroid. Furthermore, there was increased gene expression and protein levels of leukocyte attracting signal, chemokine ligand 2 (Ccl2) in aged RPE/choroid. In old animals, there was marked extravasation and accumulation of leukocytes from the choroidal circulation onto Bruch's membrane and into the RPE. Conclusions/Significance These phenotypic changes indicate that the RPE/choroid in the normal, old mouse has become an immunologically active tissue. There are signals from the normal, aged RPE/choroid which recruit leukocytes from the circulation and activate the complement cascade. These age-related changes that occur in the RPE/choroid with age, to the extent that they occur in the human retina, may provide the background for an error in regulation of immunological activity to cause AMD to appear in an elderly individual.
Short-term exposure of mice to cigarette smoke and/or residual oil fly ash produces proximal airspace enlargements and airway epithelium remodeling
Biselli, P.J.C.;Lopes, F.D.T.Q.S.;Moriya, H.T.;Rivero, D.H.R.F.;Toledo, A.C.;Saldiva, P.H.N.;Mauad, T.;Martins, M.A.;
Brazilian Journal of Medical and Biological Research , 2011, DOI: 10.1590/S0100-879X2011007500040
Abstract: chronic obstructive pulmonary disease (copd) is associated with inflammatory cell reactions, tissue destruction and lung remodeling. many signaling pathways for these phenomena are still to be identified. we developed a mouse model of copd to evaluate some pathophysiological mechanisms acting during the initial stage of the disease. forty-seven 6- to 8-week-old female c57/bl6 mice (approximately 22 g) were exposed for 2 months to cigarette smoke and/or residual oil fly ash (rofa), a concentrate of air pollution. we measured lung mechanics, airspace enlargement, airway wall thickness, epithelial cell profile, elastic and collagen fiber deposition, and by immunohistochemistry transforming growth factor-β1 (tgf-β1), macrophage elastase (mmp12), neutrophils and macrophages. we observed regional airspace enlargements near terminal bronchioles associated with the exposure to smoke or rofa. there were also increases in airway resistance and thickening of airway walls in animals exposed to smoke. in the epithelium, we noted a decrease in the ciliated cell area of animals exposed to smoke and an increase in the total cell area associated with exposure to both smoke and rofa. there was also an increase in the expression of tgf-β1 both in the airways and parenchyma of animals exposed to smoke. however, we could not detect inflammatory cell recruitment, increases in mmp12 or elastic and collagen fiber deposition. after 2 months of exposure to cigarette smoke and/or rofa, mice developed regional airspace enlargements and airway epithelium remodeling, although no inflammation or increases in fiber deposition were detected. some of these phenomena may have been mediated by tgf-β1.
Conditional Ablation of the Choroideremia Gene Causes Age-Related Changes in Mouse Retinal Pigment Epithelium  [PDF]
Silène T. Wavre-Shapton, Tanya Tolmachova, Mafalda Lopes da Silva, Clare E. Futter, Miguel C. Seabra
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0057769
Abstract: The retinal pigment epithelium (RPE) is a pigmented monolayer of cells lying between the photoreceptors and a layer of fenestrated capillaries, the choriocapillaris. Choroideremia (CHM) is an X-linked progressive degeneration of these three layers caused by the loss of function of Rab Escort protein-1 (REP1). REP1 is involved in the prenylation of Rab proteins, key regulators of membrane trafficking. To study the pathological consequences of chronic disruption of membrane traffic in the RPE we used a cell type-specific knock-out mouse model of the disease, where the Chm/Rep1 gene is deleted only in pigmented cells (ChmFlox, Tyr-Cre+). Transmission electron microscopy (TEM) was used to quantitate the melanosome distribution in the RPE and immunofluorescent staining of rhodopsin was used to quantitate phagocytosed rod outer segments in retinal sections. The ultrastructure of the RPE and Bruch’s membrane at different ages was characterised by TEM to analyse age-related changes occurring as a result of defects in membrane traffic pathways. Chm/Rep1 gene knockout in RPE cells resulted in reduced numbers of melanosomes in the apical processes and delayed phagosome degradation. In addition, the RPE accumulated pathological changes at 5–6 months of age similar to those observed in 2-year old controls. These included the intracellular accumulation of lipofuscin-containing deposits, disorganised basal infoldings and the extracellular accumulation of basal laminar and basal linear deposits. The phenotype of the ChmFlox, Tyr-Cre+ mice suggests that loss of the Chm/Rep1 gene causes premature accumulation of features of aging in the RPE. Furthermore, the striking similarities between the present observations and some of the phenotypes reported in age-related macular degeneration (AMD) suggest that membrane traffic defects may contribute to the pathogenesis of AMD.
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