Conjunctival Fibrosis Research Articles

Erosive Tarsal Conjunctival Lesions Following Immunogenic Events in Early Development of Ocular Graft-vs-Host Disease.

Ocular graft-versus-host disease (oGVHD) affects more than half of the patients following allogeneic hematopoietic stem cell transplantation (HSCT). The disease onset and the pathogenesis of oGVHD are not well understood. We hope to identify the triggers and explore the clinical signs and symptoms of oGVHD development at the early stages. The records of post-HSCT patients seen consecutively in a 1-year span in a single provider's clinic were reviewed. The history, symptoms, and clinical findings of the patients with erosive tarsal conjunctival lesions (ETCLs) were analyzed. Out of the 228 patients screened, 19 had clinically witnessed ETCL in at least one eye during the period. Twelve (63%) patients had a never-before-described nodular erosion on the subtarsal conjunctiva; seven (37%) had previously described pseudomembranous erosions. The ocular symptom onset was within 1 month after immunosuppression (IS) taper, vaccination, or donor lymphocyte infusion (DLI) in 16 of the 19 patients. While 16 (84%) patients reported painless mucous discharge, only 9 (47%) reported dryness as the initial symptom. Within 6 months, only 4 (21%) had discharge but 15 (82%) patients endorsed dryness. Subepithelial conjunctival fibrosis followed ETCL immediately in situ. Corneal punctate staining increased with time, while aqueous tear production decreased. The ETCL described is likely one of the earliest detectable findings of oGVHD and triggered by certain immunogenic events. The ocular symptoms of wet mucous discharge should be considered a warning sign for oGVHD onset, particularly when it occurs shortly after prominently immunogenic events.

Multimodal mucosal and systemic immune characterization of a non-human primate trachoma model highlights the critical role of local immunity during acute phase disease.

Trachoma is a leading cause of infection-related blindness worldwide. This disease is caused by recurrent Chlamydia trachomatis (Ct) infections of the conjunctiva and develops in two phases: i) active (acute trachoma, characterized by follicular conjunctivitis), then long-term: ii) scarring (chronic trachoma, characterized by conjunctival fibrosis, corneal opacification and eyelid malposition). Scarring trachoma is driven by the number and severity of reinfections. The immune system plays a pivotal role in trachoma including exacerbation of the disease. Hence the immune system may also be key to developing a trachoma vaccine. Therefore, we characterized clinical and local immune response kinetics in a non-human primate model of acute conjunctival Ct infection and disease. The conjunctiva of non-human primate (NHP, Cynomolgus monkeys-Macaca fascicularis-) were inoculated with Ct (B/Tunis-864 strain, B serovar). Clinical ocular monitoring was performed using a standardized photographic grading system, and local immune responses were assessed using multi-parameter flow cytometry of conjunctival cells, tear fluid cytokines, immunoglobulins, and Ct quantification. Clinical findings were similar to those observed during acute trachoma in humans, with the development of typical follicular conjunctivitis from the 4th week post-exposure to the 11th week. Immunologic analysis indicated an early phase influx of T cells in the conjunctiva and elevated interleukins 4, 8, and 5, followed by a late phase monocytic influx accompanied with a decrease in other immune cells, and tear fluid cytokines returning to initial levels. Our NHP model accurately reproduces the clinical signs of acute trachoma, allowing for an accurate assessment of the local immune responses in infected eyes. A progressive immune response occurred for weeks after exposure to Ct, which subsided into a persistent innate immune response. An understanding of these local responses is the first step towards using the model to assess new vaccine and therapeutic strategies for disease prevention.

A Novel Murine Model for Lupus-Like Ocular Chronic Graft-Versus-Host Disease.

Lupus-like chronic graft-versus-host disease (cGVHD) has been previously described, but the ocular findings have not been elucidated. Recipient mice in a lupus-like cGVHD model manifested notable and persistent ocular surface phenotypes. Herein, we further explored immunopathogenic mechanisms underlying these ocular phenotypes. A previously described lupus-like cGVHD model was established by intraperitoneal injection of splenocytes from bm12 mice into C57BL/6J mice. Systemic findings were evaluated for the presence of splenomegaly, proteinuria, and autoantibodies. Comprehensive evaluations were conducted on ocular manifestations and immunopathological features in this model. The lupus-like cGVHD model was successfully constructed 2 weeks post-transplantation. The recipient mice developed lupus-like phenotypes, including splenomegaly, proteinuria, and increased autoantibodies, and their ocular presentations included corneal epithelial defects and decreased tear secretion. Histological analysis revealed a reduction in corneal nerve fiber density and corneal endothelial cells, along with conjunctival fibrosis and loss of goblet cells. Moreover, cGVHD induced progressive aggravation of immune cell infiltration and fibrosis in the lacrimal glands. RNA-Sequencing (RNA-seq) results of the lacrimal glands demonstrated that the differentially expressed genes (DEGs) between the control and cGVHD groups were associated with GVHD pathways. Immune infiltration analysis using RNA-seq and flow cytometry confirmed that CD8+ T lymphocytes predominantly constituted the inflammatory infiltrating cells within the lacrimal glands. This lupus-like cGVHD model (bm12→C57BL/6J) exhibited persistent ocular surface manifestations, characterized by immune infiltration of CD8+ T lymphocytes in the lacrimal glands. Thus, this ocular cGVHD model may be used to explore the underlying mechanisms and discover novel therapeutic interventions.

TGFβ1-Induced Fibrotic Responses of Conjunctival Fibroblasts through the Wnt/β-Catenin/CRYAB Signaling Pathway

Conjunctival fibrosis (CF) is a common postoperative complication of glaucoma filtration surgery (GFS), resulting in uncontrolled intraocular pressure and surgery failure. Therefore, it’s urgent to understand the molecular mechanisms underlying CF and explore novel pharmacological anti-fibrosis therapies for GFS. Our 4D-DIA quantitative proteomic results, coupled with experimental data, revealed the activation of the Wnt/β-catenin pathway in TGFβ1-induced human conjunctival fibroblasts (HConFs). Treatment with ICG-001, a Wnt/β-catenin inhibitor, effectively inhibited cell proliferation and migration in TGFβ1-treated HConFs. ICG-001 treatment alleviated the increased generation of extracellular matrix (ECM) proteins induced by TGFβ1. In addition, ICG-001 reduced the expression level of alpha smooth muscle actin (α-SMA) and inhibited cell contractility in TGFβ1-treated HConFs. Proteomics data further suggested that CRYAB was a downstream target of the Wnt/β-catenin, which was upregulated by TGFβ1 and downregulated by ICG-001. Immunoblotting assay also indicated that ICG-001 reduced the expressions of ubiquitin and β-catenin in TGFβ1-treated HConFs, implying that CRYAB stabilized β-catenin by inhibiting its ubiquitination degradation. Exogenous CRYAB promoted cell viability, increased ECM proteins levels, and upregulated α-SMA expression of HConFs under TGFβ1 stimulation. Furthermore, CRYAB rescued TGFβ1-induced fibrotic responses that were suppressed by ICG-001. In conclusion, our study elucidates the regulatory mechanism of Wnt/β-catenin/CRYAB pathway in CF, offering promising therapeutic targets for mitigating bleb scarring after GFS.

Developing a model for aqueous deficient dry eye secondary to periglandular cicatrizing conjunctivitis

PurposeThe current study used various techniques to develop a rabbit animal model of lacrimal gland damage caused by scarring conjunctivitis in the periglandular area. MethodsLeft eyes of New Zealand white rabbits were injected with 0.1 ml of 1M NaOH subconjunctivally around superior and inferior lacrimal gland orifices (Group 1, n = 4), touched with 1M NaOH for 100 s to the superior and inferior fornices with conjunctival denuding (Group 2; n = 4), and electrocauterization to the ductal opening area (Group 3; n = 4). The ocular surface staining, Schirmer I, lacrimal gland, and conjunctival changes were observed at baseline,1, 4, 8, and 12 weeks. The degree of glandular inflammation, conjunctival fibrosis (Masson Trichrome), and goblet cell density (PAS) were also assessed. ResultsAt 12 weeks, the lacrimal glands of group 1 rabbits with periglandular injection showed severe inflammation with mean four foci/10HPF and a significant mean reduction in the Schirmer values by 7.6 mm (P = 0.007). Lacrimal glands had diffuse acinar atrophy, loss of myoepithelial cells, and ductular dilatation. The overlying conjunctiva showed fibrosis, goblet cell loss, and corneal vascularization in the inferotemporal quadrant. No lacrimal gland or ocular surface changes were observed in groups 2 and 3 at 12 weeks, except for localized subconjunctival fibrosis. ConclusionPeriglandular injection of 0.1 ml of 1M NaOH induced extensive lacrimal gland damage with reduced secretion and scarring in the subconjunctival plane compared to direct cauterization or direct NaOH contact to the ductal orifices of the rabbit lacrimal gland.

Pharmacological Stimulation of Soluble Guanylate Cyclase Counteracts the Profibrotic Activation of Human Conjunctival Fibroblasts.

Conjunctival fibrosis is a serious clinical concern implicated in a wide spectrum of eye diseases, including outcomes of surgery for pterygium and glaucoma. It is mainly driven by chronic inflammation that stimulates conjunctival fibroblasts to differentiate into myofibroblasts over time, leading to abnormal wound healing and scar formation. Soluble guanylate cyclase (sGC) stimulation was found to suppress transforming growth factor β (TGFβ)-induced myofibroblastic differentiation in various stromal cells such as skin and pulmonary fibroblasts, as well as corneal keratocytes. Here, we evaluated the in vitro effects of stimulation of the sGC enzyme with the cell-permeable pyrazolopyridinylpyrimidine compound BAY 41-2272 in modulating the TGFβ1-mediated profibrotic activation of human conjunctival fibroblasts. Cells were pretreated with the sGC stimulator before challenging with recombinant human TGFβ1, and subsequently assayed for viability, proliferation, migration, invasiveness, myofibroblast marker expression, and contractile properties. Stimulation of sGC significantly counteracted TGFβ1-induced cell proliferation, migration, invasiveness, and acquisition of a myofibroblast-like phenotype, as shown by a significant downregulation of FAP, ACTA2, COL1A1, COL1A2, FN1, MMP2, TIMP1, and TIMP2 mRNA levels, as well as by a significant reduction in α-smooth muscle actin, N-cadherin, COL1A1, and FN-EDA protein expression. In addition, pretreatment with the sGC stimulator was capable of significantly dampening TGFβ1-induced acquisition of a contractile phenotype by conjunctival fibroblasts, as well as phosphorylation of Smad3 and release of the proinflammatory cytokines IL-1β and IL-6. Taken together, our findings are the first to demonstrate the effectiveness of pharmacological sGC stimulation in counteracting conjunctival fibroblast-to-myofibroblast transition, thus providing a promising scientific background to further explore the feasibility of sGC stimulators as potential new adjuvant therapeutic compounds to treat conjunctival fibrotic conditions.

Vernal keratoconjunctivitis in adults: a narrative review of prevalence, pathogenesis, and management.

Vernal keratoconjunctivitis (VKC) is a chronic, progressive, allergic ocular surface disorder that can lead to sight-threatening complications. VKC occurs primarily in children and generally resolves about the time of puberty; however, case series and retrospective analyses indicate that approximately 10% of patients with VKC are adults, and that a subset of adult cases develop after puberty. Consequently, two age-related variants of VKC have recently been described: early-onset VKC-which manifests during childhood and persists into adult life-and late-onset disease, which emerges de novo after puberty. Although the signs and symptoms of adult and childhood VKC are similar, adult VKC is a long-lasting disease characterized by severe inflammation and increased risk of conjunctival fibrosis, which may place adult patients at higher risk for sight-threatening complications and adverse impacts on daily life. This review discusses the epidemiology, signs, symptoms, immunopathogenesis of adult VKC variants, and highlights current gaps in research and management of patients with this condition.

Alterations in clinical parameters in cicatrising conjunctivitis secondary to GvHD

Cicatricial conjunctivitis is part of a well‐known complication of graft versus host disease (GVHD) resulting from the tissue fibrosis that affects different body organs. It results from inflammatory reactions determined by recognition of recipient antigens as foreign by donor cells. The main target tissues in ocular GVHD are the conjunctiva and the lacrimal gland, and conjunctival involvement is usually associated with more severe systemic disease. Clinical manifestations of cicatricial conjunctivitis includes conjunctival fibrosis, conjunctival shortening, conjunctival scarring and keratinization, and symblepharon and/or ankyloblepharon. Such scarring may even lead to cicatricial lagophthalmos, ectropion, entropion, and stenosis or closure of the lacrimal puncta. In fact, the degree of palpebral conjunctival changes has been used as a criterion to classify conjunctival involvement in chronic GVHD.Conjunctival epithelial cells and myofibroblasts may have donor origin, though with a very small proportion. These donor‐derived fibroblasts may play a role in the pathogenesis of conjunctival fibrosis. In addition, it has been shown that the ocular surface of patients with chronic GVHD may show epithelial‐mesenchymal transition, in which the epithelium may gain the mesenchymal phenotype and the ability to migrate into the subepithelial stroma, resulting in conjunctival fibrosis.Our group showed that a significant proportion of patients with ocular GHVD had subtarsal fibrosis, that was non evident in non‐GHVD dry eye disease (DED) patients, even with the same degree of clinical severity. Extent of involvement varied from one eye to another; on average, more than a quarter of the visible tarsal area was affected by the fibrosis. Such fibrosis was significantly associated with ocular surface epitheliopathy and conjunctival staining. In contrast, densities of epithelial and stromal immune cells in the conjunctiva were comparable between GVHD and non GVHD DED patients after adjustment for severity of DED. We also showed that spontaneous extrusion of punctal plugs occurs in a majority of ocular GVHD‐associated DED patients within 90 days of plug placement, and this lower retention rate of punctal plugs has been attributed to punctal subepithelial fibrosis.In all patients with ocular GVHD, the eye care provider should evaluate the presence of conjunctival fibrosis and associated ocular surface complications. If present, the therapeutic strategy should attempt to address this scarring process.

Viral ocular surface inflammation

Viral infections of the ocular surface (OS) may cause chronic, and/or recurrent inflammation that disrupt OS homeostasis, impact quality of life, and potentially impair vision through loss of corneal transparency and/or regularity. In this presentation, we'll review basic and clinical findings underlying OS inflammation in the context of the 3 most common viral pathogens affecting the OS, i.e. Adenovirus, Herpes Simplex virus type 1 and Varicella Zoster Virus.During its acute replicative phase, adenoviral keratoconjunctivitis may trigger severe acute conjunctival inflammation, leading to transmucosal exudation and fibrinous pseudo‐membrane formation. If left untreated, the latter induce conjunctival fibrosis with extensive loss of goblet cells. In a second phase of the disease, antigen‐driven immune‐mediated mechanisms may cause chronic corneal subepithelial infiltration.In the context of HSV and VZV keratitis, OS inflammation is caused by a combination of specific immune response to viral replication, causing stromal infiltration, and neovascularisation and ii) non‐specific inflammatory processes caused by corneal innervation alterations that impact tear secretion and osmolarity. While clinical disease is most often unilateral, unaffected side may display subclinical alterations, including decrease in corneal sensitivity and corneal nerve density, and decrease in endothelial cell density.Management of viral ocular surface inflammation involves a combination of strategies aiming at controlling viral replication, decrease associated inflammatory/immune response and restore OS homeostasia.

Bilateral Glaucoma Drainage Device (GDD) Implantation in Steroid Induced Glaucoma

Objective: This study aims to report a case of Bilateral Glaucoma Drainage Device (GDD) implantation surgery in a patient with Steroid Induced Glaucoma. Case Presentation: A 18-year-old male patient with steroid-induced glaucoma and allergic conjunctivitis. The patient also complained about red eyes and itchy in both eyes and had been using steroid eye drops for 5 years. The patient also complained about headaches and blurry vision. The patient had undergone trabeculectomy surgery 5 months ago on the left eye. The visual acuity was 6/6 on the right eye and 6/7.5 on the left eye. His intraocular pressure (IOP) on the right eye was 24 mmHg, and his left eye was 23 mmHg with conjunctival left eye bleb, flat, and fibrosis. The patient then underwent a non-valve Virna’s GDD implant surgery on the right eye. On day two post-GDD, the IOP was 4 mmHg, and the COA was shallow, so reform the COA. At the first month follow-up, the patient's right eye pressure was still in normal condition with no complications, and then the plan was for left eye Virna’s GDD implantation surgery. At the first month follow-up after left eye GDD implantation, the visual acuity was 6/9 on the right eye and 6/24 on the left eye, with IOP RE 11mmHg and LE 16mmHg, from anterior segment deep anterior chamber, no plate exposed, no leakage, and tube not attached to the corneal endothelium. The patient's intraocular pressure was still in normal condition in both eyes, and no complications was found, although the patient was still using low-dose topical steroid eye drops. Conclusion: In steroid-induced glaucoma, after trabeculectomy failure, the implantation of GDD is the most effective option in controlling high IOP and slowing down glaucoma progressivity.

Ocular Gene Therapy: Literature Review

This literature offers complete information about the advances in gene treatment in the of the eye, inclusive of cornea, conjunctiva, lacrimal gland, and trabecular meshwork. We talked about gene transport systems, collectively with viral and non-viral vectors as exact as gene modifying techniques, generally CRISPR-Cas9, and epigenetic treatments, consisting of antisense and siRNA therapeutics. We moreover furnish a specific assessment of gene treatment has been examined with corresponding outcomes. Disease stipulations embody corneal and conjunctival fibrosis and scarring, corneal epithelial wound healing, corneal graft survival, corneal neovascularization, genetic corneal dystrophies, herpetic keratitis, glaucoma, dry eye disease, and specific ocular surface diseases. Although most of the analyzed consequences on the use and validity of gene treatment at the ocular surface have been offered in vitro or the utilization of animal models, we moreover talked about the on hand human studies. Gene treatment methods are nowadays viewed very promising as rising future remedies of a variety of diseases, and this area is unexpectedly expanding.

Differential Gene and Protein Expression of Conjunctival Bleb Hyperfibrosis in Early Failure of Glaucoma Surgery.

The early failure of glaucoma surgery is mainly caused by over-fibrosis at the subconjunctival space, causing obliteration of the filtration bleb. Because fibrosis has a suspected basis of genetic predisposition, we have undertaken a prospective study to identify upregulated profibrotic genes in a population of glaucoma patients with signs of conjunctival fibrosis and early postoperative surgical failure. Clinical data of re-operated fibrosis patients, hyperfibrosis patients who re-operated more than once in a short time, and control patients with no fibrosis were recorded and analyzed at each follow-up visit. Conjunctival-Tenon surgical specimens were obtained intraoperatively to evaluate the local expression of a panel of genes potentially associated with fibrosis. In order to correlate gene expression signatures with protein levels, we quantified secreted proteins in primary cultures of fibroblasts from patients. Expression of VEGFA, CXCL8, MYC, and CDKN1A was induced in the conjunctiva of hyperfibrosis patients. VEGFA and IL8 protein levels were also increased in fibroblast supernatants. We propose that an increase in these proteins could be useful in detecting conjunctival fibrosis in glaucoma patients undergoing filtering surgery. Molecular markers could be crucial for early detection of patients at high risk of failure of filtration surgery, leading to more optimal and personalized treatments.

Novel Therapies for the Prevention of Fibrosis in Glaucoma Filtration Surgery

Conjunctival fibrosis remains the major impediment to the success of glaucoma filtration surgery. Anti-metabolites remain the gold standard for mitigating post-surgical fibrosis, but they are associated with high complication rates and surgical failure rates. Establishing a more targeted approach to attenuate conjunctival fibrosis may revolutionize the surgical approach to glaucoma. A new strategy is needed to prevent progressive tissue remodeling and formation of a fibrotic scar, subsequently increasing surgical success and reducing the prevalence of glaucoma-related vision loss. Advancements in our understanding of molecular signaling and biomechanical cues in the conjunctival tissue architecture are broadening the horizon for new therapies and biomaterials for the mitigation of fibrosis. This review aims to highlight the strategies and current state of promising future approaches for targeting fibrosis in glaucoma filtration surgery.

Impairment of autophagy promotes human conjunctival fibrosis and pterygium occurrence via enhancing the SQSTM1-NF-κB signaling pathway.

Pterygium is a common ocular disease with a high recurrence rate, characterized by hyperplasia of subconjunctival fibrovascular tissue. Autophagy, an important process to maintain cellular homeostasis, participates in the pathogenic fibrosis of different organs. However, the exact role of autophagy in pterygium pathogenesis remains unknown. Here, we found that autophagic activity was decreased in human pterygium tissues compared with adjacent normal conjunctival tissues. The in vitro model of fibrosis was successfully established using human primary conjunctival fibroblasts (ConFB) treated with transforming growth factor-β1 (TGF-β1), evidenced by increased fibrotic level and strong proliferative and invasive capabilities. The autophagic activity was suppressed during TGF-β1- or ultraviolet-induced fibrosis of ConFB. Activating autophagy dramatically retarded the fibrotic progress of ConFB, while blocking autophagy exacerbated this process. Furthermore, SQSTM1, the main cargo receptor of selective autophagy, was found to significantly promote the fibrosis of ConFB through activating the PKCι-NF-κB signaling pathway. Knockdown of SQSTM1, PKCι, or p65 in ConFB delayed TGF-β1-induced fibrosis. Overexpression of SQSTM1 drastically abrogated the inhibitory effect of rapamycin or serum starvation on TGF-β1-induced fibrosis. Collectively, our data suggested that autophagy impairment of human ConFB facilitates fibrosis via activating the SQSTM1-PKCι-NF-κB signaling cascades. This work was contributory to elucidating the mechanism of autophagy underlying pterygium occurrence.

3D-printed long-acting 5-fluorouracil implant to prevent conjunctival fibrosis in glaucoma.

To develop a sustained release 5-fluorouracil (5-FU) implant by three-dimensional (3D) printing to effectively prevent conjunctival fibrosis after glaucoma surgery. 3D-printed implants composed of polycaprolactone (PCL) and chitosan (CS) were fabricated by heat extrusion technology and loaded with 1% 5-FU. Light microscopy and scanning electron microscopy were used to study the surface morphology. The 5-FU concentration released over 8 weeks was measured by ultraviolet visible spectroscopy. The effects on cell viability, fibroblast contractility and the expression of key fibrotic genes were assessed in human conjunctival fibroblasts. The PCL-CS-5-FU implant sustainably released 5-FU over 8 weeks and the peak concentration was over 6.1 μg/ml during weeks 1 and 2. The implant had a smooth surface and its total weight decreased by 3.5% after 8 weeks. The PCL-CS-5-FU implant did not affect cell viability in conjunctival fibroblasts and sustainably suppressed fibroblast contractility and key fibrotic genes for 8 weeks. The PCL-CS-5-FU implant was biocompatible and degradable with a significant effect in suppressing fibroblast contractility. The PCL-CS-5-FU implant could be used as a sustained release drug implant, replacing the need for repeated 5-FU injections in clinic, to prevent conjunctival fibrosis after glaucoma surgery.

Ocular Rosacae Complicated By Bilateral Ectropion: A Case Report

The most common ocular manifestations of rosacea include chronic blepharitis, conjunctival fibrosis, punctate keratitis, corneal ulceration, peripheral neovascularization. Cicatricial ectropion is rarely reported as a complication of this pathology, physiopathologie seems to be related to a type IV hypersensitivity reaction in the conjunctival tissue. We report the case of a patient with bilateral ectropion, secondary to ocular rosacea, with alteration of the break-up time (5 seconds), an eversion of lacrimal punctum which is fibrotic and a crust on the free margin of the eyelid, we also found conjunctival fibrosis, punctate epithelial keratitis.

The effect of preserved glaucoma eye drops exposure on glaucoma surgery prevalence and surgical failure in a French nationwide study between 2009 and 2017

AbstractPurpose: Preservatives induce trabecula toxicity and conjunctival fibrosis. This may negatively affect the management of glaucoma by inducing uncontrolled intraocular pressure or excessive healing after surgery.Methods: To evaluate the association between preserved glaucoma eye drops exposure and the occurrence of glaucoma surgery as well as surgical failure. A retrospective analysis of French National database was conducted between January 1st 2009 and December 31st 2017 and followed until December 31st 2018. Patients were categorized as 0% preservative exposure, 100% preservative exposure and mixed exposure. The occurrence of glaucoma surgery was the main outcome and surgical failure the secondary outcome.Results: A total of 664 494 patients (57% women; median age, 66 years [interquartile range, IQR, 18.0 years]) with first glaucoma eye drops claim were included. Among them, 8467 (1.3%) individuals had glaucoma surgery with a median delay of 2 years (IQR, 3.3 years). The occurrence of glaucoma surgery was respectively 1.8 times higher (hazard ratio [HR], 1.8 [95% CI, 1.73–1.97], p = <0.001) for 100% preserved group, 2.7 times higher (HR, 2.7; [95% CI, 2.46–2.89]; p = <0.001) for mixed exposure compared to 0% preservatives group. Among patients with glaucoma surgery, 2671 (31.5%) individuals had surgical failure with a median delay of 6 months (IQR, 14.0 months). The risk of surgical failure increased by 1.5‐fold for 100% preserved group and low mixed group (HR = 1.5; [95% CI, 1.1–2.1]; HR = 1.5; [95% CI, 1.0–2.1], respectively) and by 1.7‐fold for high mixed group (HR = 1.7; [95% CI, 1.2–2.5]), compared to 0% preservatives group.Conclusions: An increased risk of glaucoma surgery and its failure was observed in patients treated with preserved glaucoma eye drops. This suggests the interest to initiate glaucoma treatment with preservative‐free eye drops to decrease trabecular toxicity and conjunctival fibrosis.

All Trans-Retinoic Acids Facilitate the Remodeling of 2D and 3D Cultured Human Conjunctival Fibroblasts.

Vitamin A derivative, all-trans-retinoic acid (ATRA), is known to be a potent regulator of the growth and differentiation of various types of cells. In the present study, the unidentified effects of ATRA on superficial and vertical spreading conjunctival scarring were examined. The study involved the use of two-dimensional (2D) and three-dimensional (3D) cultures of human conjunctival fibroblast (HconF) cells in the presence or absence of TGF-β2. The effects of ATRA (1 μM) on superficial or vertical spreading conjunctival scarring were evaluated by the barrier function by trans-endothelial electrical resistance (TEER) and FITC dextran permeability measurements and real-time metabolic analysis, as well as the physical properties, namely, the size and stiffness, of 3D spheroids, respectively. In addition, the expressions of several related molecules, including extracellular matrix (ECM) molecules, ECM modulators including a tissue inhibitor of metalloproteinases (TIMPs), matrix metalloproteinases (MMPs), and ER stress-related factors, were examined. ATRA significantly induced (1) an increase in TEER values and a decrease in FITC dextran permeability, respectively, in the 2D monolayers, and (2) relatively and substantially increased the size and stiffness, respectively, of the 3D spheroids. These ATRA-induced effects were further enhanced in the TGF-β2-treated cells, whereas the TGF-β2-induced enhancement in glycolytic capacity was canceled by the presence of ATRA. Consistent with these physical and morphological effects, the mRNA expressions of several molecules were significantly but differently induced between 2D and 3D cultures by ATRA, although the presence of TGF-β2 did not substantially affect these gene expression levels. The findings reported in this study indicate that ATRA may exacerbate both superficial and vertical conjunctival fibrosis spreading independently of TGF-β2-induced changes.

Ocular surface disease index questionnaire as a sensitive test for primary screening of chronic ocular graft-versus-host disease.

BackgroundAfter allogeneic hematopoietic stem cell transplantation (allo-HSCT), patients are followed up by transplant clinicians. Finding an effective primary screening method that transplant clinicians or patients can master is essential in the early referral of suspected chronic ocular graft-versus-host disease (coGVHD) to an ophthalmologist. This study investigated if the ocular surface disease index (OSDI) questionnaire could be used for coGVHD primary screening.MethodsThis case-controlled, cross-sectional study enrolled 161 allo-HSCT patients. All participants completed an OSDI questionnaire and underwent a silt-lamp examination. Bulbar conjunctival injection (BCI) was assessed using torchlight, while tear volume was measured via the Schirmer test (ST). The receiver operating characteristic curve was used to evaluate the sensitivity, specificity, and cutoff values of OSDI, ST, and BCI grading. Performance comparisons of the 3 tests applied in isolation, parallel, and series were made.ResultsThere were 84 patients with and 77 patients without coGVHD. Compared to those without coGVHD, patients with coGVHD had significantly higher median values of OSDI, corneal fluorescein staining, conjunctival injection, conjunctival fibrosis, and meibum quality, but lower ST scores (All P values <0.001). The cutoff values for OSDI, ST, and BCI grade in the diagnosis of coGVHD were 19.4 points, 7 mm, and grade 0, respectively. The sensitivity and specificity of the tests based on the cutoff values were, respectively, 89.3% and 89.6% for OSDI, 91.7% and 59.7% for ST, and 78.6% and 70.1% for BCI. The area under the curve (AUC) value of OSDI was significantly higher than that of ST (0.931 vs. 0.826; P=0.010) and BCI grade (0.931 vs. 0.781; P<0.001). The AUC values of the combinations were lower than that of OSDI alone.ConclusionsThe OSDI questionnaire can be used as a simple screening test for coGVHD as demonstrated by its high sensitivity and specificity in the transplant clinic and patients’ self-monitoring. An OSDI greater than 19.4 could be considered an ophthalmology referral criterion.

PNP Hydrogel Prevents Formation of Symblephara in Mice After Ocular Alkali Injury.

PurposeTo create an alkali injury symblephara mouse model to study conjunctival fibrosis pathophysiology and test polymer nanoparticle (PNP) hydrogel as a preventative therapeutic.MethodsMice were injured using NaOH-soaked filter paper to determine the optimal NaOH concentration to induce the formation of symblephara. Injured mice were observed for 7 days to detect the formation of symblephara. Forniceal shortening observed on hematoxylin and eosin (H&E)-stained tissue sections was used as a symblephara marker. Alpha-smooth muscle actin (α-SMA) expression, Masson's trichrome assay, and periodic acid–Schiff (PAS) staining were used to determine myofibroblast expression, collagen deposition, and goblet cell integrity. PNP hydrogel, with multivalent, noncovalent interactions between modified biopolymers and nanoparticles, was applied immediately after alkali injury to determine its ability to prevent the formation of symblephara.ResultsForniceal shortening was observed in H&E images with 1N NaOH for 2 minutes after 7 days without globe destruction. PNP hydrogel prevented forniceal shortening after alkali injury as observed by H&E histology. α-SMA expression and collagen deposition in eye tissue sections were increased in the fornix after injury with 1N NaOH compared with uninjured controls. PNP hydrogel treatment immediately after injury reduced α-SMA expression and collagen deposition in the forniceal region. Mucin-secreting goblet cells stained with PAS were significantly lower in alkali-injured and PNP hydrogel–treated conjunctivas than in uninjured control conjunctivas.ConclusionsWe observed that 1N NaOH for 2 minutes induced maximal forniceal shortening and symblephara in mice. PNP hydrogel prevented forniceal shortening and conjunctival fibrosis after injury. This first murine model for symblephara will be useful to study fibrosis pathophysiology after conjunctival injury and to determine therapeutic targets for cicatrizing diseases.Translational RelevanceThis mouse model of symblephara can be useful for studying conjunctival scarring disease pathophysiology and preventative therapeutics. We tested PNP hydrogel, which prevented the formation of symblephara after injury.