Pathogenesis Of Posterior Capsule Opacification Research Articles

Fabrication of a 3D bioprinting model for posterior capsule opacification using GelMA and PLMA hydrogel-coated resin.

Posterior capsule opacification (PCO) remains the predominant complication following cataract surgery, significantly impairing visual function restoration. In this study, we developed a PCO model that closely mimics the anatomical structure of the crystalline lens capsule post-surgery. The model incorporated a threaded structure for accurate positioning and observation, allowing for opening and closing. Utilizing 3D printing technology, a stable external support system was created using resin material consisting of a rigid, hollow base and cover. To replicate the lens capsule structure, a thin hydrogel coating was applied to the resin scaffold. The biocompatibility and impact on cellular functionality of various hydrogel compositions were assessed through an array of staining techniques, including calcein-AM/PI staining, rhodamine staining, BODIPY-C11 staining and EdU staining in conjunction with transwell assays. Additionally, the PCO model was utilized to investigate the effects of eight drugs with anti-inflammatory and anti-proliferative properties, including 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), THZ1, sorbinil, 4-octyl itaconate (4-OI), xanthohumol, zebularine, rapamycin and caffeic acid phenethyl ester, on human lens epithelial cells (HLECs). Confocal microscopy facilitated comprehensive imaging of the PCO model. The results demonstrated that the GelMA 60 5% + PLMA 2% composite hydrogel exhibited superior biocompatibility and minimal lipid peroxidation levels among the tested hydrogels. Moreover, compared to using hydrogel as the material for 3D printing the entire model, applying surface hydrogel spin coating with parameters of 2000 rpm × 2 on the resin-based 3D printed base yielded a more uniform cell distribution and reduced apoptosis. Furthermore, rapamycin, 4-OI and AICAR demonstrated potent antiproliferative effects in the drug intervention study. Confocal microscopy imaging revealed a uniform distribution of HLECs along the anatomical structure of the crystalline lens capsule within the PCO model, showcasing robust cell viability and regular morphology. In conclusion, the PCO model provides a valuable experimental platform for studying PCO pathogenesis and exploring potential therapeutic interventions.

Complete Blood Cell Count-Derived Inflammation Biomarkers and the Need for Laser Capsulotomy Due to Posterior Capsule Opacification Following Cataract Surgery.

Inflammation plays a significant role in the proliferation, migration, and differentiation of lens epithelial cells after cataract surgery, clinically manifested as posterior capsule opacification (PCO). This condition is typically treated with neodymium: yttrium-aluminum-garnet (Nd:YAG) laser capsulotomy. Our objective is to evaluate the association between blood-derived inflammatory markers and the development of clinically significant PCO necessitating treatment with laser capsulotomy. We conducted a retrospective review of charts for all patients who underwent Nd:YAG laser capsulotomy in our department between January 2021 and December 2022. The study included 70 patients who diagnosed with clinically significant PCO requiring treatment with Nd:YAG laser capsulotomy following cataract surgery, as well as 70 pseudophakic controls with no signs of PCO. Complete blood cell count parameters were obtained from medical records and the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and monocyte-to-lymphocyte ratio (MLR) were calculated. The mean age of the Nd:YAG laser capsulotomy and control group was 71.83±8.46 and 72.27±9.98 years, respectively. The preoperative NLR scores for the Nd:YAG laser capsulotomy group (mean rank = 34.43) were statistically significantly higher than those of the control group (mean rank = 25.41) (p = 0.044). However, after adjusting for preoperative measurements, no statistically significant differences were observed between the groups for the other parameters. Preoperative NLR scores were higher in patients who developed clinically significant PCO requiring treatment with Nd:YAG laser capsulotomy. This finding suggests that patients with elevated systemic inflammation may be at an increased risk of developing PCO following cataract surgery. Further research is needed to evaluate the role of systemic inflammation in the pathogenesis of PCO.

TGF-β2-induced NEAT1 regulates lens epithelial cell proliferation, migration and EMT by the miR-26a-5p/FANCE axis.

To explore the regulatory mechanism of nuclear paraspeckle assembly transcript 1 (NEAT1) in the pathogenesis of posterior capsule opacification (PCO). Quantitative reverse transcription polymerase chain reaction (RT-qPCR) was executed to analyze NEAT1 and microRNA (miR)-26a-5p expression in transforming growth factor-beta 2 (TGF-β2)-disposed lens epithelial cells (LECs). The proliferation, cell cycle progression, apoptosis, and migration of TGF-β2-disposed LECs were evaluated. The relationship between NEAT1 or fanconi anemia (FA) complementation group E (FANCE) and miR-26a-5p was verified by dual-luciferase reporter assay. TGF-β2 induced NEAT1 expression in LECs. NEAT1 inhibition accelerated apoptosis, cell cycle arrest, decreased proliferation, epithelial-mesenchymal transition (EMT), and migration of TGF-β2-disposed LECs. NEAT1 sponged miR-26a-5p to further regulate FANCE expression. Rescue experiments presented that miR-26a-5p downregulation overturned NEAT1 silencing-mediated impacts on TGF-β2-disposed LEC biological behaviors. Additionally, FANCE overexpression reversed miR-26a-5p mimic-mediated impacts on TGF-β2-disposed LEC biological behaviors. TGF-β2-induced NEAT1 facilitates LEC proliferation, migration, and EMT by upregulating FANCE via sequestering miR-26a-5p.

Suppression of epithelial to mesenchymal transition markers in mouse lens by a Smad7-based recombinant protein

Cataracts, a clouding of the eye lens, are a leading cause of visual impairment and are responsible for one of the most commonly performed surgical procedures worldwide. Although generally safe and effective, cataract surgery can lead to a secondary lens abnormality due to transition of lens epithelial cells to a mesenchymal phenotype (EMT) and opacification of the posterior lens capsular bag. Occurring in up to 40% of cataract cases over time, posterior capsule opacification (PCO) introduces additional treatment costs and reduced quality of life for patients. Studies have shown that PCO pathogenesis is driven in part by TGF-β, signaling through the action of the family of Smad coactivators to effect changes in gene transcription. In the present study, we evaluated the ability of Smad-7, a well characterized inhibitor of TGF-β -mediated Smad signaling, to suppress the EMT response in lens epithelial cells associated with PCO pathogenesis. Treatment of lens epithelial cells with a cell-permeable form of Smad7 variant resulted in suppressed expression of EMT markers such as alpha smooth muscle actin and fibronectin. A single application of cell-permeable Smad7 variant in the capsular bag of a mouse cataract surgery model resulted in suppression of gene transcripts encoding alpha smooth muscle actin and fibronectin. These results point to Smad7 as a promising biotherapeutic agent for prevention or substantial reduction in the incidence of PCO following cataract surgery.

Moderate oxidative stress promotes epithelial-mesenchymal transition in the lens epithelial cells via the TGF-β/Smad and Wnt/β-catenin pathways.

The epithelial-mesenchymal transition (EMT) plays a significant role in fibrosis and migration of lens epithelial cells (LECs), and eventually induces posterior capsule opacification (PCO). In the past, it was generally believed that the TGF-β/Smad pathway regulates lens EMT. A recent study found that attenuated glutathione level promotes LECs EMT via the Wnt/β-catenin pathway, which suggests a more complex pathogenesis of PCO. To test the hypothesis, we used the mouse cataract surgery PCO model and tested both canonical Wnt/β-catenin and TGF-β/Smad signaling pathways. The results showed that both TGF-β/Smad and Wnt/β-catenin pathways were activated during the lens capsule fibrosis. Compared with the freshly isolated posterior capsule, the expression level of phosphorylated Smad2 was highest at day3 and then slightly decreased, but the expression level of Wnt10a gradually increased from day0 to day7. It shows that these two pathways are involved in the lens epithelium's fibrotic process and may play different roles in different periods. Subsequently, we established oxidative stress-induced EMT model in primary porcine lens epithelial cells and found that both the TGF-β/Smad and Wnt/β-catenin pathways were activated. Further study suggests that block Wnt/β-catenin pathway using XAV939 alone or block TGF-β/Smad pathway using LY2109761 could partially block pLECs fibrosis, but blocking Wnt/β-catenin and TGF-β/Smad pathway using combined XAV939 and LY2109761 could completely block pLECs fibrosis. In conclusion, this study demonstrates that both TGF-β/Smad and canonical Wnt/β-catenin pathways play a significant role in regulating epithelial-mesenchymal transformation of lens epithelial cells but might be in a different stage.

An in vitro system to investigate IOL: Lens capsule interaction

Posterior capsule opacification (PCO) is the most common complication associated with intraocular lens (IOL) implantation. Unfortunately, current in vitro models cannot be used to assess the potential of PCO due to their failure to simulate the posterior curvature of the lens capsule (LC) and IOL, a factor known to affect PCO pathogenesis in clinic. To overcome such a challenge, a new system to study IOL: LC interaction and potentially predict PCO was developed in this effort. It is believed that the interactions between an IOL and the lens capsule may influence the extent of PCO formation. Specifically, strong adhesion force between an IOL and the LC may impede lens epithelial cell migration and proliferation and thus reduce PCO formation. To assess the adhesion force between an IOL and LC, a new in vitro model was established with simulated LC and a custom-designed micro-force tester. A method to fabricate simulated LCs was developed by imprinting IOLs onto molten gelatin to create simulated three dimensional (3D) LCs with curvature resembling the bag-like structure that collapses on the IOL post implantation. By pushing the LC mold vertically downward, while measuring the change in position of the bending bar with respect to its start position, the adhesion force between the IOLs and LCs was measured.An in vitro system that can measure the adhesion force reproducibly between an IOL and LC with a resolution of ~1 μN was established in this study. During system optimization, the 10% high molecular weight gelatin produced the best LC with the highest IOL: LC adhesion force with all test lenses that were fabricated from acrylic foldable, polymethylmethacrylate (PMMA) and silicone materials. Test IOLs exerted different adhesion force with the 3D simulated LCs in the following sequence: acrylic foldable IOL > silicone IOL > PMMA IOL. These results are in good agreement with the clinical observations associated with PCO performance of IOLs made of the same materials. This novel in vitro system can provide valuable insight on the IOL: LC interplay and its relationship to clinical PCO outcomes.

TGF-β regulation of microRNA miR-497-5p and ocular lens epithelial cell mesenchymal transition.

The purpose of this study was to investigate the role of a human lens microRNA (miR-497-5p) in regulating epithelialmesenchymal transition (EMT) under the control of transforming growth factor beta (TGF-β). A microRNA array was used to evaluate the microRNA profiles of untreated and TGF-β-treated human lens epithelial cells in culture. This showed that TGF-β treatment led to the upregulation of 96 microRNAs and downregulation of 39 microRNAs. Thirteen microRNAs were predicted to be involved in the pathogenesis of posterior capsule opacification (PCO). Meanwhile, overexpression of miR-497-5p suppressed cell proliferation and EMT 48 h post-transfection, and inhibition of miR-497-5p accelerated cell proliferation and EMT. Treatment with TGF-β inhibited the expression of miR-497-5p, but not cell proliferation. miR-497-5p was also found to regulate the level of CCNE1 and FGF7, which are reported to be actively involved in EMT. CCNE1 and FGF7 were bona fide targets of miR-497-5p. The results suggest that miR-497-5p participates in the direct regulation of lens epithelial cell EMT and is regulated by TGF-β. miR-497-5p may be a novel target for PCO therapy.

Let-7a-5p represses proliferation, migration, invasion and epithelial-mesenchymal transition by targeting Smad2 in TGF-β2-induced human lens epithelial cells

Transforming growth factor β2 (TGF-β2)/Smad signaling is widely accepted as a key inducer of proliferation and epithelial-mesenchymal transition (EMT) of human lens epithelial cells (LECs), contributing to the development of posterior capsule opacification (PCO). Increasing evidence shows that microRNAs (miRNAs) play important roles in PCO pathogenesis. Herein, we aimed to explore the role and molecular mechanism of let-7a-5p on TGF-β2-induced proliferation and EMT in LECs. qRT-PCR was performed to detect the expression of let-7a-5p and Smad2 mRNA. Western blot was used to determine the Smad2 level and the induction of EMT. The targeted correlation between let-7a-5p and Smad2 was confirmed using dual-luciferase reporter and RNA immunoprecipitation assays. CCK-8 assay was employed to determine cell proliferation, and transwell assays were performed to assess cell migration and invasion. We found that TGF-β2 induced EMT of LECs, and TGF-β2 upregulated Smad2 expression and reduced let-7a-5p expression in LECs. Smad2 was a direct target of let-7a-5p. Moreover, let-7a-5p upregulation repressed proliferation, migration, invasion and EMT in TGF-β2-induced LECs. But, Smad2 expression restoration abrogated the inhibitory effect of let-7a-5p upregulation. In conclusion, our data indicated that let-7a-5p upregulation repressed TGF-β2-induced proliferation, migration, invasion and EMT at least partly by targeting Smad2 in LECs, highlighting that let-7a-5p might act as a promising therapeutic target to intervene to the progression of PCO.

EGF-Mediated Overexpression of Myc Attenuates miR-26b by Recruiting HDAC3 to Induce Epithelial-Mesenchymal Transition of Lens Epithelial Cells.

The previous study has demonstrated that epidermal growth factor (EGF) and EGF receptor (EGFR) signaling plays a critical role in the development of posterior capsule opacification (PCO) through regulating lens epithelial cells (LECs) proliferation. Recent studies have suggested that the residual LECs undergo proliferation and migration, and epithelial-mesenchymal transition (EMT) is the important cause of PCO formation after cataract surgery. EMT of LECs is considered to be playing a central role in the pathogenesis of PCO. In the present study, we investigated whether and how EGF may regulate EMT of LECs. First, we demonstrated that EGF and EGFR signaling induces Myc overexpression in primary human lens epithelial cells (HLECs). In turn, Myc overexpression could inhibit miR-26b by recruitment of HDAC3. Consequently, the downregulated expression of miR-26b increased the expression of EZH2 in primary HLECs. Mechanistically, miR-26b directly controls EZH2 expression by targeting its 3′-UTR in HLECs by luciferase reporter assays. Finally, we demonstrated that EGF induces the expression of EMT markers in primary HLECs via a miR-26b-dependent mechanism. In summary, EGF activated Myc and Myc overexpression inhibited miR-26b by recruitment of HDAC3, which in turn induced the expression of EZH2 and promoted the progression of EMT in HLECs.

Influence of aldose reductase on epithelial-to-mesenchymal transition signaling in lens epithelial cells

Cataract is the most frequent cause of blindness worldwide and is treated by surgical removal of the opaque lens to restore the light path to the retina. While cataract surgery is a safe procedure, some patients develop a complication of the surgery involving opacification and wrinkling of the posterior lens capsule. This process, called posterior capsule opacification (PCO), requires a second clinical treatment that can in turn lead to additional complications. Prevention of PCO is a current unmet need in the vision care enterprise. The pathogenesis of PCO involves the transition of lens epithelial cells to a mesenchymal phenotype, designated epithelial-to-mesenchymal transition (EMT). Our previous studies showed that transgenic mice designed for overexpression of human aldose reductase developed lens defects reminiscent of PCO. In the current study, we evaluated the impact of aldose reductase (AR) on expression of expression of EMT markers in the lens. Primary lens epithelial cells from AR-transgenic mice showed downregulated expression of Foxe3 and Pax6 and increased expression of α-SMA, fibronectin and snail, a pattern of gene expression typical of cells undergoing EMT. A role for AR in these changes was further confirmed when we observed that they could be normalized by treatment of cells with Sorbinil, an AR inhibitor. Smad-dependent and Smad-independent pathways are known to contribute to EMT. Interestingly, AR overexpression induced ERK but not Smad-2 activation. These results suggest that elevation of AR may lead to activation of ERK signaling and thus play a role in TGF-β/Smad independent induction of EMT in lens epithelial cells.

Bit1—a potential positive regulator of epithelial–mesenchymal transition in lens epithelial cells

Posterior capsule opacification (PCO) is a common postoperative complication of cataract surgery. Epithelial-mesenchymal transition (EMT) of lens epithelial cells (LECs) is an important initial step of PCO pathogenesis. We have previously shown that Bit1 expresses in rat LECs. In this study, we aim to investigate the role of Bit1 in the EMT of human LECs. The expression of Bit1 was firstly detected in human PCO-attached LECs and human lens cell line SRA01/04 by real-time PCR and immunofluorescence staining. The proliferation and migration of Bit1 knockdown SRA01/04 cells were evaluated by cell counting, wound-healing assay, and transwell migration assay. The EMT of LECs was triggered by TGF-β2, and then the effect of Bit1 on EMT with a key biomarker of α-smooth muscle actin (α-SMA) was analyzed by siRNA knockdown assay, and the reversal of EMT was validated by real-time PCR and western blot. Bit1 was obviously augmented in LECs derived from PCO tissues and Bit1 expressed with high levels in the cytoplasm of cultured SRA01/04 cells. Cell proliferation, invasion, and migration, as well as α-SMA expression, were significantly decreased in Bit1 knockdown SRA01/04 cells. While TGF-β2 elevated Bit1 and α-SMA expression levels in a dose-dependent manner, with peak levels at 10ng/ml of TGF-β2 treatment, suppression of Bit1 in SRA01/04 cells reversed the EMT process. TGF-β2 induced elevation of α-SMA expression level, as well as migration, and invasion abilities were all suppressed by Bit1 deficiency. These findings reveal that Bit1 promotes TGF-β2 induced α-SMA expression and acts as an positive regulator of EMT. Suppressing Bit1 inhibits the proliferation, migration, and EMT of LECs. Bit1 may be a potential novel therapeutic target for the prevention and treatment of PCO.

Inhibition of Rho-kinase inhibitor fasudil on the growth and migration of human LECs and extracellular matrix synthesis

Background Biological behavior changes of human lens epithelial cells (LECs) and extracellular matrix (ECM) synthesis are major events in the pathogenesis of posterior capsule opacification (PCO). Rho-kinase inhibitor fasudil can inhibit the cytoskeleton remodeling, migration and fibrosis, however, the mechanism of its effect in LECs is below understood. Objective This study was to investigate the role of Rho-kinase inhibitor fasudil in proliferation, migration of human LECs and ECM synthesis in vitro. Methods Human LECs line HLEB-3 cells were regularly cultured and assigned to the control group and the drug treatment groups. Different doses of fasudil were added into the medium to make the final concentrations 10, 20, 40 and 60 μmol/L, respectively. Cell proliferation was assessed by cell counting kit-8 (CCK-8) assay in 12, 24 and 48 hours after addition of drug to calculate the growth inhibitory rate. Transwell test was employed to detect the migrating number of the cells in 12, 24, 36 and 48 hours after action of drug. The concentrations of collagen type Ⅰ (COL-Ⅰ), fibronectin (FN) in cell supernatant and α-smooth muscle actin (α-SMA) content in the cells were measured by ELISA. Results The cell growth inhibitory rates in different doses of fasudil groups were higher than that in the control group. The cell growth inhibitory rates were gradually elevated as the increases of fasudil concentrations and prolong of action time (Fconcentration=966.727, P=0.000; Ftime=280.428, P=0.000). Transwell migration assay showed that the number of migration cells across polycarbonate membrane was 29.20±1.28 in the control group after 48 hours of incubation, which was much more than 24.40±1.33, 17.00±1.10, 14.60±0.68, 6.60±1.29 in the 10, 20, 40 and 60 μmol/L fasudil groups, respectively, with a significant difference among the five groups (F=57.34, P<0.05). COL-Ⅰ and FN protein contents in supernatant were gradually declined with the increase of drug concentrations and lapse of time (COL-Ⅰ: F concentration=143.992, P=0.000; Ftime=113.745, P=0.000.FN: Fconcentration=81.761, P=0.000; Ftime=69.602, P=0.000), and the α-SMA levels in the cells were significantly reduced with the increase of drug concentrations and lapse of time (Fconcentration=78.156, P=0.000; Ftime=65.162, P=0.000). Conclusions Fasudil can inhibit the proliferation, migration and ECM synthesis of human LECs in vitro in a dose- and time-dependent manner. Key words: Rho-associated kinases/antagonists and inhibitors; Epithelial cells, lens/drug effect; Humans; Cell migration; Cell proliferation; Collagen type I; Fibronectins; Extracellular matrix; Fasudil /pharmacology

EGFR-Blockade With Erlotinib Reduces EGF and TGF-β2 Expression and the Actin-Cytoskeleton Which Influences Different Aspects of Cellular Migration in Lens Epithelial cells

Introduction: After cataract surgery, residual lens epithelial cells migrate and proliferate within the capsular bag resulting in posterior capsule opacification (PCO). The up-regulation of TGF-β2, EGF and FGF-2 has been identified as a key factor in PCO pathogenesis leading to actin fiber assembly and alterations in the migration pattern. In this in vitro study, the influence of Erlotinib as a selective EGFR inhibitor is investigated on the cellular features indicated, which might promote a future clinical application.Methods: Expression of EGF, FGF-2 and TGF-β2 was measured using RT-PCR and ELISA in human lens epithelial cells (HLEC). Computational data of an in vitro time lapse microscopy assay were used for statistical analysis of single cell migration with a particular focus on cell–cell interaction; cell velocity distribution; and displacement before, during and after mitosis. The effect of Erlotinib on the actin-cytoskeleton was evaluated using Alexa Fluor 488 Phalloidin and epifluorescence microscopy.Results: EGF and TGF-β2 mRNA expression and protein levels are reduced by Erlotinib, while FGF-2 expression remained stable. Overall fluidity of cell–cell interaction is less in the presence of Erlotinib compared to the control and the velocity distribution across all cells becomes less uniform within the cell cluster. After mitosis, HLEC move significantly faster without EGFR inhibition, which can be completely blocked by Erlotinib. Furthermore, Erlotinib diminishes the amount of actin stress fibers and the stress fiber diameter.Conclusion: As a novel effect of Erlotinib on HLEC, we describe the down-regulation of EGF and TGF-β2 expression, both are crucial factors for PCO development. Cellular movement displays complex alterations under EGFR inhibition, which is partly explained by actin fiber depletion. These findings further underline the role of Erlotinib in pharmacologic PCO prophylaxis.

Attenuation of human lens epithelial cell spreading, migration and contraction via downregulation of the PI3K/Akt pathway

Posterior capsule opacification (PCO) represents a major challenge in the postoperative management of cataract patients. Spreading, migration and contraction of residual human lens epithelial cells play a pivotal role in the pathogenesis of PCO. Therefore, we analyzed the effect of the alkylphosphocholine (APC) erufosine on these cellular features as well as on PI3K/Akt, a crucial pathway in PCO pathogenesis. Human lens epithelial cells were cultured under standard cell culture conditions. Cell spreading was analyzed on fibronectin-coated wells and chemokinetic migration was assessed by time-lapse microscopy. For evaluation of cell-mediated collagen matrix contraction, the cells were seeded into collagen gels and incubated with an APC in different non-toxic concentrations before the surface area was measured on day 6. The activity of PI3K/Akt was assessed by an ELISA kit after incubation of the cells with different APC concentrations. Human lens epithelial cell spreading and migration were attenuated by APCs as follows: 7% spreading, 48% migration (0.1μM APC), and 32% spreading, 68% migration (1.0μM APC). APC concentrations of 0.1μM reduced collagen gel diameter by 5%, and 1.0μM by less than 1%, compared to untreated, cell-populated gels that resulted in a cell diameter contraction of 36%. PI3K was downregulated in a concentration-dependent manner. The crucial cellular features of PCO pathogenesis are attenuated by the APC erufosine via downregulation of the PI3K pathway. Thus, erufosine might become a valuable tool for pharmacologic PCO prophylaxis in the future.

Posterior capsule opacification after lens implantation: incidence, risk factors and management

Postoperative capsular opacification is a multifactorial physiological consequence of cataract surgery. Opacification involving the central posterior capsule has a significant impact on high- and low-contrast acuity and low-contrast sensitivity. The proliferation, migration and abnormal differentiation of residual lens epithelial cells and fibers in the capsular bag have been implicated in the pathogenesis of posterior capsule opacification (PCO). The incidence and severity of PCO correlates to the use of surgical techniques, intraocular lens optic edge designs and intraocular lens materials. This article summarizes the clinical studies with recommendations for retarding the development of central PCO. These studies will remain critical for future endeavors undertaken for the eradication of PCO.

Interleukin-6 in the pathogenesis of posterior capsule opacification and the potential role for interleukin-6 inhibition in the future of cataract surgery

Posterior capsule opacification (PCO) is a debilitating and relatively common complication of cataract surgery despite modern medical and surgical advances. The pathophysiology of this condition has largely been attributed to peptide mediators, such as transforming growth factor-beta (TGFβ), epidermal growth factor (EGF) and matrix metalloproteinases (MMPs), with the inhibition of these and other related molecules showing promising results. Studies have also shown that the levels of interleukin-6 are elevated in the eyes following cataract surgery and in various ocular inflammatory disorders that predispose to PCO development. This review proposes, utilizing ocular and extra-ocular disease models, several potential pathways through which IL-6 may modulate the activity of TGFβ, EGF, MMP-2/-9 and immune cells to promote PCO. Among the IL-6-mediated pathways discussed are the transactivation of EGF receptor, the up-regulation of TGFβ and MMP-2/-9, and the loss of ocular immune privilege through trans-signaling, down-regulation of T-regulatory cells (Tregs) and up-regulation of Th17 cells. After establishing both the potential role of ocular IL-6 in the development of PCO and the apparent upstream activity of IL-6 in relation to the known mediators of PCO, the author hypothesizes that intraoperative anti-IL-6 therapy may be of great benefit in reducing all parameters of PCO pathogenesis. This review also provides a strong basis for carrying out multiple experimental studies with IL-6 inhibitors to further elucidate the specific pathways by which IL-6 may promote PCO as well as to better determine what role inflammation may play in this disease process.

Post-operative Capsular Opacification: A review

Post-operative capsular opacification is a multifactorial physiological consequence of cataract surgery. Opacification involving the central posterior capsule has a significant impact on high and low contrast acuity and low contrast sensitivity. The assessment of Posterior Capsule Opacification (PCO) on cadaver eyes, experimental studies, culture models and in clinical studies has provided an understanding of its pathogenesis. The proliferation, migration and abnormal differentiation of residual lens epithelial cells and fibers in the capsular bag have been implicated in the pathogenesis of PCO. The incidence and severity of PCO correlates to the meticulous use of surgical techniques, IOL optic edge designs and IOL materials. This article summarizes the clinical studies with recommendations for retarding the development of central PCO. It discusses experiments with pharmacological agents broadly categorized as anti-inflammatory, immuno-modulating, antiproliferative, antiadhering, antitransdifferentiating agents for the prevention of PCO. These studies will remain critical for future endeavors undertaken for eradication of PCO.

Influence of intraocular lens material and design on postoperative intracapsular cellular reactivity

To evaluate the influence of intraocular lens (IOL) material and design on the outcome of postoperative lens epithelial cell proliferation within the capsular bag after cataract surgery.A total of 5,079 human globes containing rigid and foldable posterior chamber IOL styles commonly implanted in the United States (n = 8) were analyzed in this study. Each globe, fixated in 10% formalin, was sectioned at the equator and analyzed using the Miyake-Apple posterior technique. The study consisted of 3 parts: First, to evaluate posterior capsule opacification (PCO); the Nd:YAG laser posterior capsulotomy rate (%) was documented and plotted on a monthly basis, creating a computerized trend line for each IOL style. Second, to evaluate anterior capsule opacification (ACO); 460 globes were processed for histologic examination. Anterior capsule fibrosis was scored from 0 to III, according to the thickness of proliferative tissue/cells on the inner surface of the anterior capsule at the capsulorhexis margin. Third, interlenticular opacification (ILO) was studied by analysis of 3 pairs of acrylic piggyback lenses that had been explanted because of opacification between their optics. Each IOL pair was processed for histologic examination, and scanning electron microscopy was performed on 1 of the lenses.In the first study, relatively higher Nd:YAG laser posterior capsulotomy rates (19.1% to 32.8%) were noted with the 4 oldest IOL designs in this study (2 foldable lenses, 1 3-piece polymethyl methacrylate [PMMA] design, and 1 single-piece all-PMMA design). Four modern lenses, 1 acrylic lens, and 3 silicone foldable IOL designs had Nd:YAG rates ranging from 1.3% to 14.6% (P < .0001). In the second study, mean ACO scores were highest with silicone-plate lenses (1.77 +/- 0.86 and 1.28 +/- 0.77). The lowest mean score was observed with the acrylic lens (0.51 +/- 0.52; P < .0001). In study 3, the analyses of the 3 pairs of explanted acrylic piggyback lenses showed that the opacification between them (ILO) may have different forms.Control of postoperative intracapsular cellular proliferation is important in avoiding 3 significant clinical complications. Postoperative lens epithelial cell proliferation is involved in the pathogenesis of PCO, ACO, and ILO, the latter being a newly described form of opacification within the capsular bag related to piggyback IOL implantation. IOL material and design are important factors influencing the outcome of these complications.

Posterior capsule opacification and anterior capsule opacification.

Posterior capsule opacification (PCO) is still the most frequent complication of cataract surgery. A variety of studies has led to a better understanding of the pathogenesis of PCO, and strategies of molecular biology have produced new therapeutic options, such as immunological techniques or gene therapeutic approaches. Surgical strategies and intra-ocular lens-dependent factors also are capable to reduce the rate of PCO. In-the-bag implantation of intra-ocular lenses with a sharp optic edge seems to be effective in inhibiting equatorial lens epithelial cell migration to the center of the posterior capsule. Several PCO documentation systems have been developed that will lead to more exact and better comparable recording of PCO rates. In the year 2000, PCO or secondary cataract is still the most frequent complication after extracapsular cataract surgery. In a 1998 meta-analysis, PCO rates of 11.8% 1 year after extracapsular cataract surgery with intraocular lens implantation, 20.7% after 3 years, and 28.4 % after 5 years have been reported. For the United States, it has been estimated that the overall expenses for treatment of PCO are only exceeded by the costs for cataract treatment itself. In the past decade, a lot of experimental and clinical studies have been performed on this topic. They have led to 1) to a better understanding of the pathogenesis of the development of anterior and posterior capsule opacification; 2) more objective and better comparable systems of documentation and analysis of PCO; and a number of 3) surgical and 4) pharmaceutical strategies to prevent PCO.

Adhesion mechanisms of human lens epithelial cells on 4 intraocular lens materials

Purpose: To evaluate lens epithelial cell (LEC) adhesion on different intraocular lens (IOL) materials with particular attention to the distribution of proteins located in the focal contacts. Setting: Center of Biotechnological and Clinical Research in Ophthalmology, University of Bologna, Italy. Methods: The IOL materials tested were poly(methyl methacrylate) (PMMA), heparin surface-modified PMMA (HSM PMMA, polyHEMA, and silicone. Primary cultures of human LECs were established from human anterior capsules obtained during cataract surgery. The mean number of cells attached per square millimeter was calculated for each material after 24 and 72 hours. Transmission electron microscopy and immunocytochemical analysis were performed to detect the proteins actin, vinculin, and talin. Results: Mean adhesiveness of human LECs increased over time with PMMA and decreased with the other materials. At 72 hours, mean LECs ranged from 54.8 cells/mm 2 ± 12.8 (SD) on PMMA to 2.1 ± 0.7 cells/mm 2 on silicone. The means for HSM PMMA and polyHEMA fell in between. The cytoskeletal proteins were arranged to produce focal contacts in only the LECs cultured on PMMA. The LECs cultured on polyHEMA, HSM PMMA, and silicone attached but failed to develop focal contacts or stress fibers. Conclusion: This study confirms the multifactorial pathogenesis of posterior capsule opacification and suggests its incidence will be reduced by improving surgical techniques and using IOL surfaces that discourage cell adhesion.