Development Of Proliferative Vitreoretinopathy Research Articles

Resveratrol inhibits transforming growth factor-β2-induced epithelial-to-mesenchymal transition in human retinal pigment epithelial cells by suppressing the Smad pathway.

Proliferative vitreoretinopathy (PVR) is the main cause of failure following retinal detachment surgery. Transforming growth factor (TGF)-β2-induced epithelial-to-mesenchymal transition (EMT) plays an important role in the development of PVR, and EMT inhibition decreases collagen gel contraction and fibrotic membrane formation, resulting in prevention of PVR. Resveratrol is naturally found in red wine and has inhibitory effects on EMT. Resveratrol is widely used in cardioprotection, neuroprotection, chemotherapy, and antiaging therapy. The purpose of this study was to investigate the effects of resveratrol on TGF-β2-induced EMT in ARPE-19 cells in vitro. We found that resveratrol suppressed the decrease of zona occludens-1 (ZO-1) and caused an increase of alpha-smooth muscle actin expression in TGF-β2-treated ARPE-19 cells, assessed using Western blots; moreover, it also suppressed the decrease in ZO-1 and the increase of vimentin expression, observed using immunocytochemistry. Resveratrol attenuated TGF-β2-induced wound closure and cell migration in ARPE-19 cells in a scratch wound test and modified Boyden chamber assay, respectively. We also found that resveratrol reduced collagen gel contraction – assessed by collagen matrix contraction assay – and suppressed the phosphorylation of Smad2 and Smad3 in TGF-β2-treated ARPE-19 cells. These results suggest that resveratrol mediates anti-EMT effects, which could be used in the prevention of PVR.

A novel lipid prodrug strategy for sustained delivery of hexadecyloxypropyl 9-[2-(phosphonomethoxy)ethyl]guanine (HDP-PMEG) on unwanted ocular proliferation

Proliferative vitreoretinopathy (PVR) is a blinding eye disease and there is no effective pharmacological measure to prevent PVR development. The difficulty comes from lack of potent antiproliferative agent and lack of sustained delivery to cover high-risk time window for PVR to develop. Lipid prodrug of PMEG, hexadecyloxypropyl 9-[(2-phosphonomethoxy)ethyl]guanine (HDP-PMEG), was prepared and was evaluated as a pharmacological adjuvant to surgical management of PVR. A dose-escalation study determined that the highest nontoxic dose for intravitreal use in pigmented rabbits was 3 µg per eye. The genotoxicity of HDP-PMEG was harnessed as a perioperative preventative measure against PVR in a rabbit eye model while the sustained intravitreal pharmacological effect was evaluated on a laser-induced fibrovascular model in rat eye. After intravitreal 3 µg, HDP-PMEG particles in the rabbit vitreous was visible for at least 6 weeks. A single 50-min intravitreal infusion of HDP-PMEG demonstrated significant inhibition of PVR formation when compared with the eyes infused with only BSS (BSS vs. HDP-PMEG: estimate = 1.14, OR = 3.1, p = .027). A single intravitreal 104 ng (equivalent to 3 µg for rabbit eye) of HDP-PMEG significantly inhibit laser-induced fibrovascular proliferation in rat eye by 55% (least square mean pixel, BSS = 4763569.5 vs. HDP-PMEG = 2148129.7, p < .0001, generalized estimating equation [GEE]). Retinal fluorescein angiography showed the odds for BSS intervened eyes to have higher-rated FA leaking grades were 38.5 times compared with HDP-PMEG treated eyes (p < .0001, GEE). Our study results indicate that single intravitreal HDP-PMEG may be a promising ocular drug delivery as a perioperative intervention to prevent PVR reoccurrence following primary surgical management.

MicroRNA-182 Suppresses HGF/SF-Induced Increases in Retinal Pigment Epithelial Cell Proliferation and Migration through Targeting c-Met.

As increases in hepatocyte growth factor/scatter factor (HGF/SF) induce retinal pigment epithelial (RPE) migration and proliferation into the vitreous cavity and contribute to proliferative vitreoretinopathy (PVR) development, we determined if changes in miR-182 expression affect such behavioral changes. We found that miR-182 expression was less in PVR clinical samples than in primary RPE cells whereas c-Met was upregulated. Ectopic miR-182 inhibited RPE cell proliferation, cell cycle, and migration. Bioinformatic analysis identified c-Met as a miR-182 target, which was confirmed with the luciferase reporter assay. Transfection of miR-182 into RPE cells induced c-Met downregulation, which led to reduced cell proliferation and migration through declines in p-Akt formation. MiR-182 downregulation along with c-Met upregulation in PVR tissues suggest that these two opposing effects play important roles in PVR development. As ectopic miR-182 expression suppressed RPE cell proliferation and migration, strategies to selectively upregulate miR-182 expression in a clinical setting may provide a novel option to treat this disease.

Validity of aqueous flare measurement in predicting proliferative vitreoretinopathy in patients with rhegmatogenous retinal detachment.

To investigate aqueous flare as a preoperative predictor for later proliferative vitreoretinopathy (PVR) development in patients with rhegmatogenous retinal detachment (RD) and to determine the validity of this measurement in patients at low clinical risk for postoperative PVR. This study included 100 eyes of 100 patients who underwent surgery for primary RD. Aqueous flare was determined preoperatively with a laser flare-cell meter (Kowa FM-500, Kowa Company Ltd, Tokyo, Japan). Patients were followed for at least 6months postoperatively. Failures related to PVR were recorded for statistical analysis. Twenty eyes (20%) developed PVR postoperatively. Preoperative flare values in these eyes were significantly higher than in eyes with no redetachment (48.12±61.24 versus 17.74±29.63 photon counts per millisecond (pc/ms), p=0.002). The odds ratio for PVR development with flare values >15pc/ms was 12.3 (p<0.0001, 95% confidence interval, 3.54-42.59). Of 54 eyes at low clinical risk for postoperative PVR, five developed PVR postoperatively. Flare values were significantly higher in these eyes (25.30±7.10pc/ms) than in eyes with no redetachment (12.44±10.16pc/ms, p=0.008). Using logistic regression, the odds ratio of PVR redetachment risk increased by the factor 1.078 per 1pc/ms of flare value (95% CI, 1.01-1.15). Preoperative aqueous flare is a strong predictive factor for PVR redetachment. The laser flare-cell meter provides a fast and safe tool to accurately identify patients at risk for postoperative PVR, especially when clinical examination did not predict this risk.

Intravitreal methotrexate infusion for proliferative vitreoretinopathy.

PurposeThe purpose of this study was to evaluate intravitreal methotrexate infusion (IMI) during pars plana vitrectomy (PPV) for retinal detachment in patients with high risk for the development of proliferative vitreoretinopathy (PVR).MethodsPatients presenting with severe recurrent PVR with tractional retinal detachment and/or a history of severe ocular inflammation were treated with IMI. Clinical outcomes were determined from a retrospective medical chart review.ResultsTwenty-nine eyes presenting with either tractional retinal detachment and recurrent PVR (n=22) or a history of severe inflammation associated with high PVR risk (n=7) received IMI during PPV. Best-corrected visual acuity at 6 months was ≥20/200 in 19 of 29 eyes (66%) and remained stable or improved compared with initial presentation in 24 of 29 eyes (83%). At the last follow-up examination, the retinas of 26 of 29 eyes (90%) remained attached after IMI while three eyes required another reattachment procedure. Three additional eyes (10%) developed recurrent limited PVR without recurrent RD and were observed. No complications attributable to IMI occurred during a mean follow-up of 27 months.ConclusionEyes at high risk for PVR development due to a history of prior PVR or intraocular inflammation had a low incidence of PVR following IMI at the time of PPV for RD repair. No significant safety issues from IMI were observed in this series.

Histopathological and ophthalmoscopic evaluation of apocynin on experimental proliferative vitreoretinopathy in rabbit eyes.

The aim of the current study was to evaluate the effect of apocynin (APO) on the development of proliferative vitreoretinopathy (PVR). New Zealand-type male rabbits were randomly grouped into three as follows: (1) Sham group rabbits which were applied intraperitoneal (i.p.) vehicle without PVR; (2) PVR group rabbits where PVR was created and an i.p. vehicle was administered for 21 successive days; (3) PVR+APO group rabbits where PVR was created and i.p. APO was administered for 21 successive days. Fundus examination was conducted with an indirect ophthalmoscope before starting the experiments and at each visit afterwards. At the end of the work, the rabbits were sacrificed under high-dose anesthesia and then eye tissues were taken for histopathological analyses. In the PVR+APO group, histopathologic and ophthalmoscopic examination revealed significant decrease in PVR formation. As the result, it has been observed that APO at least partially inhibits PVR formation.

Proliferative Vitreoretinopathy: Therapeutic Strategies

Development of proliferative vitreoretinopathy (PVR) is one of the most important complications of vitreoretinal surgery. Reaching the decision to treat and surgical treatment itself are both challenging. Our own data and a review of the literature in PubMed are summarised. Pharmacological approaches to the prevention and treatment of proliferative vitreoretinopathy have been limited to concepts that have been investigated in preclinical and a few clinical studies. Anti-inflammatory and antiproliferative substances may be mentioned in this context. Surgical techniques range from scleral buckling to the gold standard pars plana vitrectomy, preferably with silicone oil endotamponade. Applying an encircling band, retinotomy or retinectomy can be useful in reattaching the tractional shortened retina. Surgery is still the method of choice for the treatment of PVR. Pharmacological strategies to prevent or treat PVR have not been established.

Clinical and surgical risk factors in the development of proliferative vitreoretinopathy following retinal detachment surgery: a systematic review protocol.

BackgroundProliferative vitreoretinopathy (PVR) is a known complication of retinal detachment surgery. It has been postulated that the establishment of PVR involves inflammatory and ischaemic processes. Surgical and clinical risk factors contribute to making certain patients more vulnerable to developing PVR.The objective of this systematic review is to identify and appraise the evidence on clinical and surgical risk factors and their utility in predicting the occurrence or worsening of PVR post-surgery.MethodsElectronic databases and grey literature will be searched dating from 1980. Studies will be eligible if they include patients that underwent retinal reattachment surgery for rhegmatogenous retinal detachment (RRD), with and without PVR, and where risk factors were measured before or during surgery. Screening, data extraction and quality assessment will be performed independently by two reviewers using pre-defined criteria. Should any models be identified, we will liaise with the Cochrane prognostic group to help define the most appropriate quality assessment criteria based on the PROBLAST tool which is in development. All findings will be tabulated and narratively synthesised. Studies presenting models or adjusted data will likely be more informative than studies reporting unadjusted results for a single risk factor. When clinically and methodologically appropriate, random effects meta-analysis will be performed.DiscussionThis review will systematically and comprehensively retrieve evidence to evaluate the clinical and surgical risk factors associated with PVR. The identified evidence may aid standardisation of clinical practice and more effective management for improving patient outcomes following RRD surgery and will provide a clear reference point for vitreoretinal surgeons.Systematic review registrationPROSPERO CRD42016035848Electronic supplementary materialThe online version of this article (doi:10.1186/s13643-016-0284-7) contains supplementary material, which is available to authorized users.

Nonsteroidal anti-inflammatory therapy effectively prevents the development of proliferative vitreoretinopathy in the experiment

Introduction and purpose. Proliferative vitreoretinopathy (PVR) is caused by retinal damage and increased permeability of the blood-ocular barrier. Activation of inflammation, cell migration and proliferation leading to the membrane formation on the surface of the retina in the lesion area, causes blindness. After surgical removal of all membranes the frequency of PVR recurrence is 30 % on average. Therapeutic approaches are not developed. Since inflammation plays a key role in PVR formation, the aim of our study was to justify the use of non-steroidal anti-inflammatory drug lornoxicam for prevention of the development of proliferative vitreoretinopathy. Materials and methods. The work was performed on rats. PVR was modeled by intravitreal injection of dispase, 0,015 U/μl. Intravitreal administration of lornoxicam was performed 20 minutes later, 8 mg/ml. Volume of injections was 2 μl. On the second and the third day of the experiment we performed intraperitoneal injections of the drug in a dose of 230 mg/kg. Intact animals were used as a control group. Enucleation of the eyes was performed on the first, third, seventh and 42th day of the experiment. Results. Lornoxicam reduced the inflammatory response caused by the dispase introduction. It shifted the start of retinal remodeling from the first to the third day of the experiment, restrained a formation of «rosette» structures in the retina (p<0.05), decreased the rate of destruction of photoreceptors by 34 % (p<0.05) and caused twofold decrease (p<0.05) in the severity of photoreceptor changes. Throughout the experiment, the thickness of retinal and choroidal layers among the treated animals was the same as the thickness of retina and choroid of intact rats. The dispase introduction was accompanied by fibrous membrane formation during the period from 7th to 42th day after the beginning of the experiment. Lornoxicam decreased the incidence of membrane formation by 43 % (p<0.05), and the membranes were smaller and contained less fibrotic components. Conclusions. The use of lornoxicam during early period of PVR development reduced the manifestation of signs of inflammation in the eye: it controlled retinal remodeling at all stages of the disease, decreased the incidences of membrane formation by 43 % and significantly reduced the intensity of fibrotic processes in the membranes.

Epithelial-to-Mesenchymal Transition of RPE Cells In Vitro Confers Increased β1,6-N-Glycosylation and Increased Susceptibility to Galectin-3 Binding.

Epithelial-to-mesenchymal transition (EMT) of retinal pigment epithelial cells is a crucial event in the onset of proliferative vitreoretinopathy (PVR), the most common reason for treatment failure in retinal detachment surgery. We studied alterations in the cell surface glycan expression profile upon EMT of RPE cells and focused on its relevance for the interaction with galectin-3 (Gal-3), a carbohydrate binding protein, which can inhibit attachment and spreading of human RPE cells in a dose- and carbohydrate-dependent manner, and thus bares the potential to counteract PVR-associated cellular events. Lectin blot analysis revealed that EMT of RPE cells in vitro confers a glycomic shift towards an abundance of Thomsen-Friedenreich antigen, poly-N-acetyllactosamine chains, and complex-type branched N-glycans. Using inhibitors of glycosylation we found that both, binding of Gal-3 to the RPE cell surface and Gal-3-mediated inhibition of RPE attachment and spreading, strongly depend on the interaction of Gal-3 with tri- or tetra-antennary complex type N-glycans and sialylation of glycans but not on complex-type O-glycans. Importantly, we found that β1,6 N-acetylglucosaminyltransferase V (Mgat5), the key enzyme catalyzing the synthesis of tetra- or tri-antennary complex type N-glycans, is increased upon EMT of RPE cells. Silencing of Mgat5 by siRNA and CRISPR-Cas9 genome editing resulted in reduced Gal-3 binding. We conclude from these data that binding of recombinant Gal-3 to the RPE cell surface and inhibitory effects on RPE attachment and spreading largely dependent on interaction with Mgat5 modified N-glycans, which are more abundant on dedifferentiated than on the healthy, native RPE cells. Based on these findings we hypothesize that EMT of RPE cells in vitro confers glycomic changes, which account for high affinity binding of recombinant Gal-3, particularly to the cell surface of myofibroblastic RPE. From a future perspective recombinant Gal-3 may disclose a therapeutic option allowing for selectively targeting RPE cells with pathogenic relevance for development of PVR.

Resveratrol inhibits epithelial-mesenchymal transition of retinal pigment epithelium and development of proliferative vitreoretinopathy.

Proliferative vitreoretinopathy (PVR) is a serious complication of retinal detachment and ocular trauma, and its recurrence may lead to irreversible vision loss. Epithelial to mesenchymal transition (EMT) of retinal pigment epithelial (RPE) cells is a critical step in the pathogenesis of PVR, which is characterized by fibrotic membrane formation and traction retinal detachment. In this study, we investigated the potential impact of resveratrol (RESV) on EMT and the fibrotic process in cultured RPE cells and further examined the preventive effect of RESV on PVR development using a rabbit model of PVR. We found that RESV induces mesenchymal to epithelial transition (MET) and inhibits transforming growth factor-β2(TGF-β2)-induced EMT of RPE cells by deacetylating SMAD4. The effect of RESV on MET was dependent on sirtuin1 activation. RESV suppressed proliferation, migration and fibronectin synthesis induced by platelet-derived growth factor-BB or TGF-β2. In vivo, RESV inhibited the progression of experimental PVR in rabbit eyes. Histological findings showed that RESV reduced fibrotic membrane formation and decreased α-SMA expression in the epiretinal membranes. These results suggest the potential use of RESV as a therapeutic agent to prevent the development of PVR by targeting EMT of RPE.

Intravitreal Steroids for the Prevention of PVR After Surgery for Retinal Detachment.

Proliferative vitreoretinopathy (PVR) can occur in eyes with rhegmatogenous retinal detachment (RRD) or after RRD surgery, and it is the most common cause of failure of this surgery, accounting for about 75% of all primary failures. Complex biological pathways induce PVR development, with growth factors and cytokines from the vitreous and from the serum (as a result of the breakdown of the blood-retinal barrier) stimulating RPE and Muller cells transformation and proliferation, and membrane formation and contraction. Identification of pre-operative risk factors, recognition of the early signs of PVR, use of adequate surgical techniques and of pharmacological therapy can reduce the PRV incidence. Steroids can influence the inflammatory and proliferative components of PVR, by reducing the breakdown of the blood-retinal barrier, and the proliferation of Müller cell and of RPE cells. Some new formulation of intravitreal steroids are promising tool for the prevention of the PVR formation in eyes treated by vitreoretinal surgery.

Retinal Detachment and Proliferative Vitreoretinopathy.

In normal eyes, retinal detachment (RD) occurs at a rate of approximately 5 per 100,000 people per year and the frequency of proliferative vitreoretinopathy (PVR) remains largely unchanged in primary RD, with the incidence ranging from 5.1 to 11.7%. PVR is the most common cause of failed repair of rhegmatogenous RD, and risk factors for PVR are related to several well-known pre-, intra-, and postoperative clinical situations. Current methods of surgical management of RD and PVR are pneumatic retinopexy, scleral buckling, and pars plana vitrectomy (PPV). Surgical success rates for PVR have improved as techniques and instruments of vitrectomy evolved. However, despite these advances, more than one fourth of initially successful cases results in redetachment due to recurrent vitreoretinal traction. Retinal pigment epithelial cells are the key factor in triggering PVR development. In addition, soluble mediators and the extracellular matrix components play a critical role in cellular events, including proliferation and tissue contraction which occur in PVR. Although PPV remains a critical component of the treatment in RD and PVR, ongoing efforts seek to identify adjuvant therapies that might inhibit PVR development. Recent studies have therefore been directed toward pharmacologic inhibition of cellular proliferation and membrane contraction with drugs such as daunorubicin, 5-fluorouracil, and heparin. More detailed understanding of the pathophysiology underlying PVR may lead to the development of effective prophylactic and/or adjunctive therapies. Further work is necessary to identify optimal adjunctive therapies for the management of RD and PVR.

Notch signaling regulates M2 type macrophage polarization during the development of proliferative vitreoretinopathy

Macrophages play an important role in the pathogenesis of proliferative vitreoretinopathy (PVR). M2 macrophages can promote tissue remodeling and repair. In this study, CD206 positive M2 type macrophages were found in preretinal fibrous membranes of the mouse model of PVR induced by the intravitreal injection of retinal pigment epithelial (RPE) cells. Notch signaling determines M2 macrophage polarization. The specific inhibition of Notch signaling pathway by the intravitreal injection of γ-secretase inhibitor DAPT attenuated RPE cells-induced PVR formation as demonstrated by the decreased expression of α-SMA, and inhibited M2 type macrophage infiltation as demonstrated by the decreased expression of Arg-1. Notch signaling may modulate PVR formation by regulating M2 type macrophage polarization.

Artificial vitreous body: Strategies for vitreous body substitutes

Although numerous advances have been made in technology and techniques of pars plana vitrectomy and tamponades, there are still unsolved issues, such as proliferative vitreoretinopathy (PVR), multiple retinal breaks and persistent hypotonia. All available internal tamponades (e.g, gases, oils and fluorocarbons) are hydrophobic, so they approximate the neurosensory retina to the retinal pigment epithelium due to buoyant force and surface tension. Even though these tamponade materials exhibit various beneficial attributes in the clinical application, the hydrophobic nature has clear disadvantages and compartmentalization and significant incidence of PVR development still occur. An ideal vitreous body substitute should mimic the native human vitreous body, in both form and function. Vitreous body substitutes, such as hydrogels fulfill the biophysical needs in a similar manner to the natural vitreous body by providing an internal tamponade effect through swelling pressure and viscosity. New approaches range from cross-linked semisynthetic to synthetic polymers. These hydrogels have a good biocompatibility, optical clarity, a refractive index and rheological properties that are similar to the natural human vitreous body and are able to act as anti-adhesive and anti-migrative agents and can therefore reduce PVR. Furthermore, hydrogels could also serve as controlled-release drug-delivery systems for anti-proliferative, neuroprotective or nutritive drugs.

BAX and BCL-2 polymorphisms, as predictors of proliferative vitreoretinopathy development in patients suffering retinal detachment: the Retina 4 project.

To compare the distribution of BCL-2 -938C>A (rs2279115) and BAX -248G>A (rs4645878) genotypes among European subjects undergoing rhegmatogenous retinal detachment (RRD) surgery in relation to the further development of proliferative vitreoretinopathy (PVR). A case-control gene association study, as a part of Retina 4 project, was designed. rs2279115 and rs4645878 polymorphisms were analysed in 555 samples from patients with RRD (134 with PVR secondary to surgery). Proportions of genotypes and AA homozygous groups of BCL-2 and BAX polymorphisms between subsamples were analysed in two phases. Genotypic and allelic frequencies were compared in global sample and in subsamples. BAX: Differences were observed in the genotype frequencies and in AA carriers between controls and cases in the global series. The odds ratio (OR) of A carriers in the global sample was 1.7 (95% CI: 1.23-2.51). Proportions of genotypes in Spain + Portugal were significant different. The OR of A carriers from Spain and Portugal was 1.8 (95% CI: 1.11-2.95). BCL-2: No significant differences were observed in genotype frequencies. However, proportions of genotypes in Spain + Portugal were significant. A protective effect (OR: 0.6 95% CI: 0.43-0.96) was found in A carriers from Spain and Portugal. Results suggest that A allele of rs4645878 could be a biomarker of high risk of developing PVR in patients undergoing RD surgery. The possible role of BCL-2 (inhibitor of necroptosis pathway) as a possible new target in PVR prophylaxis should be investigated.

Merlin Regulates Epithelial-to-Mesenchymal Transition of ARPE-19 Cells via TAK1-p38MAPK-Mediated Activation.

The purpose of this study was to investigate the function of merlin, which is a binding partner of the hyaluronan receptor CD44, during the epithelial-to-mesenchymal transition (EMT) of human retinal pigment epithelium (ARPE-19) cells. Human retinal pigment epithelium cells were stimulated with TNF-α and treated using epithelial-to-mesenchymal-transition inhibitors (a dynamin inhibitor or transforming growth factor-β-activated kinase 1 [TAK1] inhibitor). Levels of protein expression were assessed by immunoblot analysis, and localization of the relevant proteins was determined by immunofluorescence microscopy. Cell proliferation was evaluated by bromodeoxyuridine (BrdU) incorporation assays. All experiments were performed in serum-free medium. Tumor necrosis factor-α treatments downregulated the expression of merlin and led to the dissociation of CD44 and merlin. The ezrin-radixin-moesin (ERM) proteins were phosphorylated, and hyaluronan endocytosis was accelerated in merlin small interfering RNA (siMerlin)-transfected cells. Treatment with the endocytosis inhibitor dynasore blocked hyaluronan endocytosis, whereas treatment with TNF-α induced mesenchymal phenotypes and downregulation of merlin. Additionally, siMerlin transfection promoted p38MAPK phosphorylation, which was inhibited not only by TAK1 inhibitor treatment but also by TAK1 small interfering RNA (siRNA, siTAK1) transfection. The increased level of BrdU incorporation in siMerlin cells was reduced by additional siTAK1 transfection. Furthermore, TNF-α-induced mesenchymal differentiation and high motility were also inhibited by TAK1 inhibitor treatment and by siTAK1 transfection. Our findings demonstrated that merlin exerts inhibitory effects on TNF-α-induced EMT by regulating hyaluronan endocytosis and the TAK1-p38MAPK signaling pathway. The proliferative and mesenchymal characteristics of RPE cells play important roles in the development of intraocular fibrotic disorders, such as proliferative vitreoretinopathy (PVR), and our findings provide new therapeutic strategies to prevent the development of PVR.

Clinical management of proliferative vitreoretinopathy: an update.

Proliferative vitreoretinopathy (PVR) remains the most significant obstacle to successful retinal reattachment surgery. Preclinical studies continue to add insights into the complex molecular events leading to PVR development, helping to identify new targets for potential prophylactic or therapeutic agents. This article reviews the recent evidence supporting surgical and medical treatments for PVR. PUBMED was used for literature search. Clinical studies regarding surgical management of PVR from January 1, 2000 to August 1, 2014 were included. Clinical studies regarding medical management of PVR from January 1, 2000 to August 1, 2014 were included if the design of study was a randomized controlled trial. Many recent studies have evaluated surgical and medical strategies for the treatment and prevention of PVR. Newer vitreoretinal surgery technology (23- and 25-gauge vitrectomy) and tamponade agents (heavy silicone oils) have been studied. Medical therapies evaluated include antiinflammatory agents, low molecular weight heparin, 5-fluorouracil, 13-cis-retinoic acid, and daunorubicin, amongst others. Surgical management with pars plana vitrectomy, with or without scleral buckle or inferior retinectomy, remains an effective treatment for PVR-related detachments. Consensus regarding a preferred surgical strategy remains controversial. Many medical therapies have been studied but fail to demonstrate a statistically significant benefit in clinical trials. Further studies to clarify the efficacy of available and novel treatment options are warranted.

Role of Systemic Anti-Tumor Necrosis Factor Alpha Treatment in the Reduction of Proliferative Vitreoretinopathy

Objective: Proliferative vitreoretinopathy (PVR) is still one of the most serious complications of rhegmatogenous retinal detachment (RRD) because there is no effective treatment or prophylaxis. Tumor necrosis factor α (TNFα) has been implicated in the development of PVR. Thus, the blockade of this factor could reduce or prevent the onset of PVR. However, systemic treatment with anti-TNFα has some risks and side effects, and the use of these drugs in this situation is not yet justified. Therefore we sought an indirect approach to determine if systemic anti-TNFα provided any protection against the development of PVR after RRD surgery. We attempted to estimate the rate of RRD and PVR in patients who were treated systemically with anti-TNFα drugs because of autoimmune diseases and who also had surgically-treated RRD. Methods: Nine centers participated in this retrospective, observational study of cases and controls. Two different approaches were used to find cases and controls. The records at five clinical centers of patients who were under anti-TNFα treatment for chronic inflammatory systemic diseases between January 2004 and 2014 were reviewed to determine how many developed RRD. Additionally, the records in eight clinical centers of patients who underwent RRD surgery during this same period were reviewed to determine the numbers who were simultaneously receiving anti-TNFα treatment. Cases included patients treated with anti-TNFα treatment whereas controls were those who were not under anti-TNFα treatment. Both patients and controls had systemic inflammatory disease. The main outcome measure was development of PVR after RRD surgery at three months follow-up. Results: A total of 8,017 medical records from nine different centers were reviewed. Among the 1,884 patients with anti-TNFα treatment and 6,133 patients operated for primary RRD, only 3 controls and 1 case were identified. Conclusions: An insufficient number of patients were identified to allow any valid conclusion regarding our hypothesis that systemic anti-TNFα therapy could reduce the onset of PVR after RRD surgery. Nevertheless, this indirect approach could be useful for future research in PVR prevention.

Role of Chlamydia trachomatis intraocular infection in the development of proliferative vitreoretinopathy (experimental study)

To study the influence of C. trachomatis infection on proliferative vitreoretinopathy (PVR) stimulation and development in an experimental model. Intravitreal C. trachomatis injection was performed in 17 rabbits (right eyes) out of which 8 developed minimal chlamydial damage (1 was further subjected to histopathological examination with pathogen detection in ocular structures and other 7 were included in the study group). The control group consisted of 7 rabbits with no laboratory evidence of chlamydial infection. PVR was induced by 4 peripheral retinal punctures with a 19 G needle. Follow-up methods included ophthalmoscopy, ultrasonography, and PVR grading according to the Fastenberg classification. Histopathological examination, supplemented with pathogen detection by direct immunofluorescence in the study group, was performed at weeks 7 and 20. PVR rate and severity were higher in the study group as compared with the controls (5 out of 7 rabbits, grade 2-4 vs. 2 out of 7 rabbits, grade 0-1, p<0.01). In the study group, histopathological examination performed before and after the induction of PVR revealed a pronounced lymphocyte and macrophage infiltration, characteristic of infectious inflammation. Similarly, extra- and intracellular chlamydial inclusions could be found in the retina and/or zones of proliferation throughout the whole study period. Inflammation signs (including those of proliferation) were reliably less significant in the controls. C. trachomatis infection of the posterior segment contributes to PVR development due to associated chronic inflammation.