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Chen X, Sullivan DA, Sullivan AG, Kam WR, Liu Y.
Toxicity of cosmetic preservatives on human ocular surface and adnexal cells. Exp Eye Res 2018;
AbstractCosmetic products, such as mascara, eye shadow, eyeliner and eye makeup remover are used extensively to highlight the eyes or clean the eyelids, and typically contain preservatives to prevent microbial growth. These preservatives include benzalkonium chloride (BAK) and formaldehyde (FA)-releasing preservatives. We hypothesize that these preservatives, at concentrations (BAK = 1 mg/ml; FA = 0.74 mg/ml) approved for consumer use, are toxic to human ocular surface and adnexal cells. Accordingly, we tested the influence of BAK and FA on the morphology, survival, and proliferation and signaling ability of immortalized human meibomian gland (iHMGECs), corneal (iHCECs) and conjunctival (iHConjECs) epithelial cells. iHMGECs, iHCECs and iHConjECs were cultured with different concentrations of BAK (5 μg/ml to 0.005 μg/ml) or FA (1 mg/ml to 1 μg/ml) under basal, proliferating or differentiating conditions up to 7 days. We used low BAK levels, because we found that 0.5 mg/ml and 50 μg/ml BAK killed iHMGECs within 1 day after a 15 min exposure. Experimental procedures included analyses of cell appearance, cell number, and neutral lipid content (LipidTox), lysosome accumulation (LysoTracker) and AKT signaling in all 3 cell types. Our results demonstrate that BAK and FA cause dose-dependent changes in the morphology, survival, proliferation and AKT signaling of iHMGECs, iHCECs and iHConjECs. Many of the concentrations tested induced cell atrophy, poor adherence, decreased proliferation and death, after 5 days of exposure. Cellular signaling, as indicated by AKT phosphorylation after 15 (FA) or 30 (BAK) minutes of treatment, was also reduced in a dose-dependent fashion in all 3 cell types, irrespective of whether cells had been cultured under proliferating or differentiating conditions. Our results support our hypothesis and demonstrate that the cosmetic preservatives, BAK and FA, exert many toxic effects on cells of the ocular surface and adnexa.
Chen D, Sahin A, Kam WR, Liu Y, Rahimi Darabad R, Sullivan DA.
Influence of lipopolysaccharide on proinflammatory gene expression in human corneal, conjunctival and meibomian gland epithelial cells. Ocul Surf 2018;16(3):382-389.
AbstractPURPOSE: Lipopolysaccharide (LPS), a bacterial endotoxin, is known to stimulate leuokotriene B4 (LTB4) secretion by human corneal (HCECs), conjunctival (HConjECs) and meibomian gland (HMGECs) epithelial cells. We hypothesize that this LTB4 effect represents an overall induction of proinflammatory gene expression in these cells. Our objective was to test this hypothesis. METHODS: Immortalized HCECs, HConjECs and HMGECs were cultured in the presence or absence of LPS (15 μg/ml) and ligand binding protein (LBP; 150 ng/ml). Cells were then processed for RNA isolation and the analysis of gene expression by using Illumina BeadChips, background subtraction, cubic spline normalization and GeneSifter software. RESULTS: Our findings show that LPS induces a striking increase in proinflammatory gene expression in HCECs and HConjECs. These cellular reactions are associated with a significant up-regulation of genes associated with inflammatory and immune responses (e.g. IL-1β, IL-8, and tumor necrosis factor), including those related to chemokine and Toll-like receptor signaling pathways, cytokine-cytokine receptor interactions, and chemotaxis. In contrast, with the exception of Toll-like signaling and associated innate immunity pathways, almost no proinflammatory ontologies were upregulated by LPS in HMGECs. CONCLUSIONS: Our results support our hypothesis that LPS stimulates proinflammatory gene expression in HCECs and HConjECs. However, our findings also show that LPS does not elicit such proinflammatory responses in HMGECs.
Chen Y, Chauhan SK, Lee HS, Stevenson W, Schaumburg CS, Sadrai Z, Saban DR, Kodati S, Stern ME, Dana R.
Effect of desiccating environmental stress versus systemic muscarinic AChR blockade on dry eye immunopathogenesis. Invest Ophthalmol Vis Sci 2013;54(4):2457-64.
AbstractPURPOSE: A majority of experimental data on dry eye disease (DED) immunopathogenesis have been derived from a murine model of DED that combines desiccating environmental stress with systemic muscarinic acetylcholine receptor (mAChR) inhibition. However, to our knowledge the effects of pharmacologic mAChR blockade on the pathogenesis of experimental DED have not been evaluated systemically. The purpose of our study was to investigate the differential effects of desiccating environmental stress and mAChR inhibition on the pathogenesis of DED. METHODS: DED was induced in female C57BL/6 mice by exposure to a desiccating environment in the controlled-environment chamber or to systemic scopolamine, or by performing extraorbital lacrimal gland excision. Clinical disease was assessed using corneal fluorescein staining (CFS) and the cotton thread test (CTT). Corneal CD11b(+) and conjunctival CD3(+) T-cell infiltration were evaluated by flow cytometry. T-cells from draining cervical lymph nodes (CLN) and distant inguinal lymph nodes (ILN) were analyzed for Th1, Th2, Th17, and Treg responses by flow cytometry and ELISA. RESULTS: Desiccating environmental stress and systemic mAChR blockade induced similar clinical signs of DED. However, desiccating environmental stress imparted higher conjunctival CD3(+) T-cell infiltration, and greater Th17-cell activity and Treg dysfunction than mAChR blockade, while mAChR blockade decreased tear secretion to a greater extent than desiccating environmental stress. Systemic mAChR blockade attenuated Th17 activity and enhanced Th2 and Treg responses without affecting Th1 activity. CONCLUSIONS: In vivo inhibition of mAChRs variably affects CD4(+) T-cell subsets, and desiccating environmental stress and systemic mAChR blockade induce DED through different primary pathogenic mechanisms.
Cheng S-F, Dastjerdi MH, Ferrari G, Okanobo A, Bower KS, Ryan DS, Amparo F, Stevenson W, Hamrah P, Nallasamy N, Dana R.
Short-term topical bevacizumab in the treatment of stable corneal neovascularization. Am J Ophthalmol 2012;154(6):940-948.e1.
AbstractPURPOSE: To evaluate the safety and efficacy of topical bevacizumab in the treatment of corneal neovascularization. DESIGN: Prospective, nonrandomized, interventional case series. METHODS: setting: Institutional, multicenter clinical trial. study population: Twenty eyes from 20 patients with stable corneal neovascularization. intervention procedures: Patients were treated with topical 1.0% bevacizumab for 3 weeks and were monitored for a total of 24 weeks. main outcome measures: Primary outcome measures included: neovascular area, defined as the area of the corneal vessels themselves; vessel caliber, defined as the mean corneal vessel diameter; and invasion area, defined as the fraction of the total cornea into which the vessels extended. The occurrence of ocular and systemic adverse events was monitored closely. RESULTS: As compared with the baseline visit, patients exhibited a statistically significant improvement in neovascular area by week 6 (P = .007) and in vessel caliber by week 12 (P = .006). At the final visit, neovascular area, vessel caliber, and invasion area were reduced by 47.5%, 36.2%, and 20%, respectively. The decreases in neovascular area and vessel caliber were statistically significant (P < .001 and P = .003, respectively); however, the reduction in invasion area did not reach statistical significance (P = .06). There were no significant changes in the secondary outcomes, and there were no adverse events. CONCLUSIONS: Short-term topical bevacizumab treatment reduced the extent of stable corneal neovascularization as measured by neovascular area and vessel caliber with no associated adverse events. Interestingly, the degree of treatment efficacy was inversely proportional to the baseline invasion area.
Cheng W, Li L, Luo G, Wang Y.
Using a smartphone app in the measurement of posture-related pupil center shift on centration during corneal refractive surgery. Front Cell Dev Biol 2023;11:1174122.
AbstractPurpose: Pupil center is an important anchor point in corneal refractive surgery, which may affect by body position. This study investigated the feasibility of using a smartphone application in measurement of posture-related pupil center shifts. Methods: Images of undilated eyes were captured for 25 participants (age: 18-38 years) at a distance of 40 cm in four body positions (seated, supine, right lateral, and left lateral) under controlled lighting conditions. During taking images, a smartphone application was used to guide positioning without head rotation and tilt. From the images, the location of the pupil center and pupil diameter with respect to the limbus boundary were measured. Results: According to the data obtained by the smartphone application, pupil center was located slightly nasal and superior to the limbus center in the seated position, and it shifted more nasally and superiorly (p < 0.001, OD 0.54 ± 0.11 mm, OS 0.57 ± 0.14 mm) in the supine position. When body position switched between left and right lateral positions, the pupil centers of both eyes shifted along the direction of gravity (p < 0.05), and no significant shift occurred along the longitudinal axis. Moreover, pupil constriction was observed when the body position changed from seated to supine position (p < 0.001, OD 0.64 ± 0.57 mm, OS 0.63 ± 0.58 mm). Conclusion: Posture-related pupil center shift may be larger than the error tolerance of centration in corneal refractive surgery, which might be difficult to measure by the existing instruments. An accessible application is necessary for evaluating the shift of pupil center and guiding centration during the surgery.
Cherfan DG, Melki SA.
Corneal perforation by an astigmatic keratotomy performed with an optical coherence tomography-guided femtosecond laser. J Cataract Refract Surg 2014;40(7):1224-7.
AbstractUNLABELLED: We present a case of corneal perforation secondary to an intrastromal astigmatic keratotomy performed with an optical coherence tomography-guided femtosecond laser. The keratotomy was concomitant with cataract surgery and resulted in a flat anterior chamber prior to the start of lens extraction. Interrupted nylon sutures were placed to seal the keratotomy prior to phacoemulsification. Escape of cavitation bubbles into the anterior chamber or the liquid interface can alert the surgeon to the possibility of unintended perforation of the endothelium or the epithelium, respectively. FINANCIAL DISCLOSURE: Neither author has a financial or proprietary interest in any material or method mentioned.
Chirapapaisan C, Abbouda A, Jamali A, Müller RT, Cavalcanti BM, Colon C, Witkin D, Sahin A, Dana R, Cruzat A, Hamrah P.
In Vivo Confocal Microscopy Demonstrates Increased Immune Cell Densities in Corneal Graft Rejection Correlating With Signs and Symptoms. Am J Ophthalmol 2019;203:26-36.
AbstractPURPOSE: Diagnosis of graft rejection is based on patient symptoms and on clinical signs detected by slit-lamp biomicroscopy. This study investigated whether laser in vivo confocal microscopy (IVCM) can aid in the diagnosis of corneal graft rejection by detecting cellular corneal changes that take place after transplantation. DESIGN: Prospective case-control study. SUBJECTS: Thirty-eight eyes of 38 patients with penetrating keratoplasty (15 eyes with corneal graft rejection, 23 eyes without rejection) and 9 age-matched normal controls. METHODS: Laser IVCM was performed in the corneal grafts centrally. The density of immune cells (IC) was assessed for epithelial, sub-epithelial, stromal, and endothelial layers by 2 masked observers. IC density was compared among different groups and correlated to clinical signs and symptoms of corneal graft rejection. MAIN OUTCOME MEASUREMENTS: Outcome measurement was the IC density in the corneal layers and its associations with the presence of clinical signs and symptoms of corneal graft rejection. RESULTS: The IC density was significantly different between rejected and non-rejected grafts (P = 0.004) and different from that of normal controls (P = 0.001). Among corneal layers, IC density was significantly higher in rejected grafts than in non-rejected grafts in only the sub-basal (611.54 ± 573.74 vs. 340.61 ± 268.60 cells/mm, respectively; P = 0.049) and endothelial layers (250.62 ± 267.13 vs. 103.47 ± 81.91 cells/mm, respectively; P = 0.001). Patients with decreased best corrected visual acuity, Khodadoust line, and anterior chamber cells demonstrated a significant increase in total IC density (P < 0.05), whereas patients with symptoms of irritation, light sensitivity, and pain revealed a specific increase in IC density in the sub-basal layer (P < 0.05). Patients with ocular pain had higher IC density in the epithelial layer than those without pain (P = 0.03). CONCLUSIONS: Patients with corneal graft rejection demonstrate a significant increase in corneal immune cells, particularly, in the sub-basal and endothelial layers compared to patients with non-rejected grafts and controls. Although symptoms associated with endothelial rejection demonstrate a general increase in IC, pain, irritation, and light sensitivity are associated with increased IC in the sub-basal layer. Assessment of patients with corneal graft rejection by IVCM may serve as an adjunctive tool in the diagnosis and management of corneal graft rejection.
Chirapapaisan C, Muller RT, Sahin A, Cruzat A, Cavalcanti BM, Jamali A, Pavan-Langston D, Hamrah P.
Effect of herpes simplex keratitis scar location on bilateral corneal nerve alterations: an in vivo confocal microscopy study. Br J Ophthalmol 2022;106(3):319-325.
AbstractAIMS: To evaluate the impact of herpes simplex virus (HSV)-induced scar location on bilateral corneal nerve alterations using laser in vivo confocal microscopy (IVCM). METHODS: Central and peripheral corneal subbasal nerve density (CSND) were assessed bilaterally in 39 patients with unilateral HSV-induced corneal scars (21 central scars (CS), 18 peripheral scars (PS)) using IVCM. Results were compared between patients and 24 age-matched controls. CSND was correlated to corneal sensation for all locations. RESULTS: Overall patients revealed significant decrease of CSND in the central and peripheral cornea (9.13±0.98 and 6.26±0.53 mm/mm2, p<0.001), compared with controls (22.60±0.77 and 9.88±0.49 mm/mm2). CS group showed a decrease in central (8.09±1.30 mm/mm2) and total peripheral nerves (5.15±0.62 mm/mm2) of the affected eyes, whereas PS group demonstrated a decrease in central (10.34±1.48 mm/mm2) and localised peripheral nerves only in the scar area (4.22±0.77 mm/mm2) (all p<0.001). In contralateral eyes, CSND decreased in the central cornea of the CS group (16.88±1.27, p=0.004), and in the peripheral area, mirroring the scar area in the affected eyes of the PS group (7.20±0.87, p=0.032). Corneal sensation significantly decreased in the whole cornea of the affected, but not in contralateral eyes (p<0.001). A positive correlation between CSND and corneal sensation was found in all locations (p<0.001). CONCLUSIONS: Patients with HSV scar demonstrate bilateral CSND decrease as shown by IVCM. CSND and corneal sensation decrease in both central and peripheral cornea in affected eyes, although only in the scar area in PS group. Interestingly, diminishment of CSND was found locally in the contralateral eyes, corresponding and mirroring the scar location in the affected eyes.
Chodosh J, Ung L.
Adoption of Innovation in Herpes Simplex Virus Keratitis. Cornea 2020;39 Suppl 1:S7-S18.
AbstractHerpes simplex keratitis, caused primarily by human herpes simplex virus type 1 (HSV-1), remains the most common infectious cause of unilateral blindness and vision impairment in the industrialized world. Major advances in the care of HSV keratitis have been driven in large part by the landmark Herpetic Eye Disease Study randomized clinical trials, which were among the first in ophthalmology to reflect emerging trial conventions, including multicenter subject enrollment, double-masking, placebo controls, and a priori sample size determinations. The results of these trials now form much of the evidence basis for the management of this disease. However, management patterns in clinical practice often deviate from evidence-based care. These perceived quality gaps have given rise to the evolving field of implementation science, which is concerned with the methods of promoting the application of evidence-based medicine within routine care. To overcome variations in the quality and consistency of care for HSV keratitis, a range of clinical- and technology-based innovations are proposed. The most pressing needs include the following: a rational and tractable disease classification scheme that provides an immediate link between the anatomical localization of disease (corneal epithelial, stromal, or endothelial) and the appropriate treatment, and the actualization of an electronic medical record system capable of providing evidence-based treatment algorithms at relevant points of care. The latter would also input data to population-wide disease registries to identify implementation-rich targets for quality improvement, education, and research. These innovations may allow us to reduce the human and economic burdens of this highly morbid, and often blinding, disease.
Choi CJ, Peggy Chang H-Y, Lee NG.
An Unusual Corneal Degeneration. JAMA Ophthalmol 2017;135(6):667-668.
Choi W, Byun YJ, Jung E, Noh H, Hajrasouliha AR, Sadrai Z, Chang EJ, Lee JH, Lee HK.
Chemokine decoy receptor D6 mimicking trap (D6MT) prevents allosensitization and immune rejection in murine corneal allograft model. J Leukoc Biol 2015;97(2):413-24.
AbstractAlthough corneal allotransplantation is performed in the immune-privileged cornea, many grafts are still rejected after transplantation. This study examined the role of chemokine receptor D6 expression in a corneal allograft rejection, investigated the modulation of D6 expression in cells, and determined the effect of D6 on graft survival. Interestingly, D6 was highly expressed in CD45 -: cells and the corneal epithelium of accepted corneal allografts. From the mouse corneal allograft model, TGF-β was found to play a key role in D6 up-regulation, leading to reduced CCL2, CCL5, and CCL3. To modulate D6 chemokine binding, a D6MT was developed and showed effective chemokine trapping through SPR and FACS assays. By treating corneal allografts with D6MT, the allograft survival rate was improved, and (lymph) angiogenesis was reduced. Direct allosensitization and DC LN homing was drastically reduced in the mouse corneal allograft model. These findings suggest that TGF-β is a positive regulator of D6 expression, and it is a potential therapeutic target to enhance the survival of corneal allografts.
Christen WG, Cook NR, Manson JAE, Buring JE, Lee I-M, Bubes V, Friedenberg G, Dushkes R, Smith D, Schaumberg DA, Schaumberg DA.
Efficacy of Marine ω-3 Fatty Acid Supplementation vs Placebo in Reducing Incidence of Dry Eye Disease in Healthy US Adults: A Randomized Clinical Trial. JAMA Ophthalmol 2022;140(7):707-714.
AbstractImportance: Results of several small randomized clinical trials have suggested that supplements of marine ω-3 fatty acids may be beneficial in treating signs and symptoms of dry eye disease (DED). However, randomized clinical trial data to examine whether ω-3 fatty acid supplements can prevent DED are lacking. Objective: To evaluate whether long-term daily supplementation with marine ω-3 fatty acids prevents the development of DED. Design, Setting, and Participants: This was a prespecified ancillary study of the Vitamin D and Omega-3 Trial (VITAL), a nationwide randomized double-blind placebo-controlled 2 × 2 factorial trial of vitamin D and marine ω-3 fatty acids in the primary prevention of cancer and cardiovascular disease. Participants in this ancillary study were 23 523 US adults (men 50 years and older and women 55 years and older) who at study entry were free of a previous diagnosis of DED and were not experiencing severe dry eye symptoms. Participants were enrolled from November 2011 to March 2014, and treatment and follow-up ended on December 31, 2017. Data were analyzed from January 2020 to August 2021. Interventions: Marine ω-3 fatty acids, 1 g per day. Main Outcomes and Measures: The primary end point was incident clinically diagnosed DED confirmed by review of the medical records. The secondary end point was a composite of all confirmed incident clinically diagnosed DED cases plus all incident reports of severe DED symptoms. Results: The mean (SD) age of the 23 523 participants included in the analysis was 67.0 (7.0) years, and 11 349 participants (48.3%) were women. The cohort included 4610 participants (20.0%) who self-identified as Black, 16 481 (71.6%) who self-identified as non-Hispanic White, and 1927 (8.4%) of other racial or ethnic groups or who declined to respond, consolidated owing to small numbers, including American Indian or Alaska Native, Asian, Hispanic or Latino, and Native Hawaiian or Other Pacific Islander. During a median (range) 5.3 (3.8-6.1) years of treatment and follow-up, 472 of 23 523 participants (2.0%) experienced a medical record-confirmed diagnosis of DED. There was no difference in diagnosed DED by randomized ω-3 fatty acid assignment (232 of 11 757 participants [2.0%] with end points in the treated group vs 240 of 11 766 [2.0%] with end points in the placebo group; hazard ratio, 0.97; 95% CI, 0.81-1.16). Similarly, there was no difference between groups for the secondary end point of diagnosed DED plus incident severe DED symptoms (1044 participants [8.9%] with end points in the treated group vs 1074 [9.1%] with end points in the placebo group; hazard ratio, 0.97; 95% CI, 0.89-1.06). Conclusions and Relevance: In this randomized clinical trial, long-term supplementation with 1 g per day of marine ω-3 fatty acids for a median (range) of 5.3 (3.8-6.1) years did not reduce the incidence of diagnosed DED or a combined end point of diagnosed DED or incident severe DED symptoms. These results do not support recommending marine ω-3 fatty acid supplementation to reduce the incidence of DED. Trial Registration: ClinicalTrials.gov Identifier: NCT01880463.
Chu D, Zhao M, Rong SS, Jhe W, Cai X, Xiao Y, Zhang W, Geng X, Li Z, Zhang X, Li J.
Dual-Atom Nanozyme Eye Drops Attenuate Inflammation and Break the Vicious Cycle in Dry Eye Disease. Nanomicro Lett 2024;16(1):120.
AbstractDry eye disease (DED) is a major ocular pathology worldwide, causing serious ocular discomfort and even visual impairment. The incidence of DED is gradually increasing with the high-frequency use of electronic products. Although inflammation is core cause of the DED vicious cycle, reactive oxygen species (ROS) play a pivotal role in the vicious cycle by regulating inflammation from upstream. Therefore, current therapies merely targeting inflammation show the failure of DED treatment. Here, a novel dual-atom nanozymes (DAN)-based eye drops are developed. The antioxidative DAN is successfully prepared by embedding Fe and Mn bimetallic single-atoms in N-doped carbon material and modifying it with a hydrophilic polymer. The in vitro and in vivo results demonstrate the DAN is endowed with superior biological activity in scavenging excessive ROS, inhibiting NLRP3 inflammasome activation, decreasing proinflammatory cytokines expression, and suppressing cell apoptosis. Consequently, the DAN effectively alleviate ocular inflammation, promote corneal epithelial repair, recover goblet cell density and tear secretion, thus breaking the DED vicious cycle. Our findings open an avenue to make the DAN as an intervention form to DED and ROS-mediated inflammatory diseases.
Ciolino JB, Belin MW, Todani A, Al-Arfaj K, Rudnisky CJ, Group BKTS1.
Retention of the Boston keratoprosthesis type 1: multicenter study results. Ophthalmology 2013;120(6):1195-200.
AbstractOBJECTIVE: To report the retention rate of the Boston keratoprosthesis type 1 and to identify risk factors for keratoprosthesis loss. DESIGN: Cohort study. PARTICIPANTS: A total of 300 eyes of 300 patients who underwent implantation of the Boston keratoprosthesis type I device between January 2003 and July 2008 by 19 surgeons at 18 medical centers. METHODS: Forms reporting preoperative, intraoperative, and postoperative parameters were prospectively collected and subsequently analyzed at a central data collection site. MAIN OUTCOME MEASURES: Keratoprosthesis retention. RESULTS: A total cumulative number of 422 life-years of device implantation are included in this analysis. The average duration of follow-up was 17.1 ± 14.8 months, with a range of 1 week to >6.1 years. Ninety-three percent of the 300 Boston keratoprosthesis implants were retained at their last follow-up, corresponding to a retention time of 396 patient-years or 1.42 years/keratoprosthesis. The probability of retention after 1 year and 2 years was 94% and 89%, respectively. During the study period, 21 (7%) eyes failed to retain the device; the reasons for keratoprosthesis loss include sterile keratolysis (9), fungal infections (8), dense retroprosthetic membranes (3), and bacterial endophthalmitis (1). Multivariate analysis demonstrated 3 independent risk factors for keratoprosthesis loss: autoimmune cause (hazard ratio [HR], 11.94; 95% confidence interval [CI], 3.31-43.11), ocular surface exposure requiring a concomitant tarsorrhaphy (HR, 3.43; 95% CI, 1.05-11.22), and number of prior failed penetrating keratoplasties (HR, 1.64; 95% CI, 1.18-2.28). CONCLUSIONS: The Boston keratoprosthesis type 1 seems to be a viable option for eyes that are not candidates for penetrating keratoplasty (PK). Ocular surface disease due to an autoimmune cause demonstrated the lowest retention rate. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.
Coco G, Amparo F, Patel SP, Foulsham W, Carreno-Galeano JT, Stockslager SG, Ciolino JB, Yin J, Dana R.
Oral guaifenesin for treatment of filamentary keratitis: A pilot study. Ocul Surf 2019;
AbstractPURPOSE: Pilot study to evaluate the safety and efficacy of oral guaifenesin in reducing the signs and symptoms of filamentary keratitis. METHODS: Prospective, uncontrolled open-label pilot study. Twelve patients with non-Sjögren dry eye disease (DED) and secondary filamentary keratitis received treatment with oral guaifenesin 600 mg twice a day (total dose of 1.2 g/day) for 4 weeks. Adverse events, change in the number of corneal filaments, corneal fluorescein staining (CFS; NEI grading system), and symptoms (Ocular Surface Disease Index) were assessed. RESULTS: Before starting oral guaifenesin, all patients were on topical medical therapy for their condition. At baseline, the mean number of filaments was 5.8 ± 2.9, CFS score 7.3 ± 3.2, and OSDI score 55.6 ± 25. After 4 weeks of treatment, the number of filaments was 2.1 ± 2.2 (p = 0.04 vs. baseline), CFS score 6.5 ± 3.1 (p = 0.5), and OSDI score 46.1 ± 30.9 (p = 0.2). One patient discontinued the medication due to gastrointestinal side effects. CONCLUSIONS: Oral guaifenesin was safe and generally well tolerated, and demonstrated modest efficacy in reducing the severity of filamentary keratitis. These results should be considered preliminary; however, placebo-controlled investigations would be justified to evaluate the therapeutic efficacy of oral guaifenesin as a mucolytic in treatment of filamentary keratitis.
Coco G, Foulsham W, Nakao T, Yin J, Amouzegar A, Taketani Y, Chauhan SK, Dana R.
Regulatory T cells promote corneal endothelial cell survival following transplantation via interleukin-10. Am J Transplant 2020;20(2):389-398.
AbstractThe functional competence of corneal endothelial cells (CEnCs) is critical for survival of corneal allografts, but these cells are often targets of the immune response mediated by graft-attacking effector T cells. Although regulatory T cells (Tregs) have been studied for their role in regulating the host's alloimmune response towards the graft, the cytoprotective function of these cells on CEnCs has not been investigated. The aim of this study was to determine whether Tregs suppress effector T cell-mediated and inflammatory cytokine-induced CEnC death, and to elucidate the mechanism by which this cytoprotection occurs. Using 2 well-established models of corneal transplantation (low-risk and high-risk models), we show that Tregs derived from low-risk graft recipients have a superior capacity in protecting CEnCs against effector T cell-mediated and interferon-γ and tumor necrosis factor-α-induced cell death compared to Tregs derived from high-risk hosts. We further demonstrate that the cytoprotective function of Tregs derived from low-risk hosts occurs independently of direct cell-cell contact and is mediated by the immunoregulatory cytokine IL-10. Our study is the first to report that Tregs provide cytoprotection for CEnCs through secretion of IL-10, indicating potentially novel therapeutic targets for enhancing CEnC survival following corneal transplantation.
Coco G, Kheirkhah A, Foulsham W, Dana R, Ciolino JB.
Keratoconus progression associated with hormone replacement therapy. Am J Ophthalmol Case Rep 2019;15:100519.
AbstractPurpose: To report a postmenopausal patient with keratoconus who experienced significant progression after using hormone replacement therapy. Observations: A 51-year-old woman with previously stable keratoconus presented with acute disease progression following hormone replacement therapy in the context of prophylactic hysterectomy and bilateral ovariosalpingectomy. Over a 14-month period after starting hormone therapy, the steepest K increased from 63.7D to 71.5D in the right eye and from 65.8D to 78.1D in the left eye. Conclusions: Hormone replacement therapy may amplify progression of keratoconus.
Contreras-Ruiz L, Ryan DS, Sia RK, Bower KS, Dartt DA, Masli S.
Polymorphism in THBS1 gene is associated with post-refractive surgery chronic ocular surface inflammation. Ophthalmology 2014;121(7):1389-97.
AbstractPURPOSE: To determine the association of single nucleotide polymorphisms (SNPs) of the thrombospondin 1 (THBS1) gene with development of chronic ocular surface inflammation (keratoconjunctivitis) after refractive surgery. DESIGN: Retrospective cohort study. PARTICIPANTS: Active duty U.S. Army soldiers (n = 143) who opted for refractive surgery. METHODS: Conjunctival impression cytology samples collected from participants before the surgery were used to harvest DNA for genotyping 5 THBS1 SNPs (rs1478604, rs2228262, rs2292305, rs2228262, and rs3743125) using the Sequenom iPLEX Gold platform (Sequenom, San Diego, CA). Samples collected after surgery were used to harvest RNA for gene expression analysis by real-time polymerase chain reaction (PCR). Participants were followed for 1 year after surgery to monitor the status of keratoconjunctivitis. MAIN OUTCOME MEASURES: Genetic basis of the development of chronic keratoconjunctivitis after refractive surgery. RESULTS: Carriers of minor alleles of 3 SNPs each were found to be more susceptible to developing chronic keratoconjunctivitis (rs1478604: odds ratio [OR], 2.5; 95% confidence interval [CI], 1.41-4.47; P = 2.5 × 10(-3); rs2228262 and rs2292305: OR, 1.9; 95% CI, 1.05-3.51; P = 4.8 × 10(-2)). Carriers of the rs1478604 minor allele expressed significantly reduced levels of thrombospondin 1 (TSP1) (P = 0.042) and increased levels of an inflammatory cytokine associated with keratoconjunctivitis, interleukin-1β (P = 0.025), in their ocular surface epithelial cells compared with homozygous major allele controls. CONCLUSIONS: Genetic variation in the THBS1 gene that results in decreased expression of the encoded glycoprotein TSP1 in ocular surface epithelial cells significantly increases the susceptibility to develop chronic ocular surface inflammation after refractive surgery. Further investigation of THBS1 SNPs in a larger sample size is warranted.
Contreras-Ruiz L, Ghosh-Mitra A, Shatos MA, Dartt DA, Masli S.
Modulation of conjunctival goblet cell function by inflammatory cytokines. Mediators Inflamm 2013;2013:636812.
AbstractOcular surface inflammation associated with Sjögren's syndrome is characterized by a loss of secretory function and alteration in numbers of mucin secreting goblet cells. Such changes are a prominent feature of ocular surface inflammatory diseases and are attributed to inflammation; however, the exact effect of the inflammatory cytokines on conjunctival goblet cell function remains largely unknown. In this study, we developed a primary culture of mouse goblet cells from conjunctival tissue and evaluated the effects on their function by inflammatory cytokines detected in the conjunctiva of mouse model of Sjögren's syndrome (Thrombospondin-1 deficient mice). We found that apoptosis of goblet cells was primarily induced by TNF-α and IFN-γ. These two cytokines also inhibited mucin secretion by goblet cells in response to cholinergic stimulation, whereas IL-6 enhanced such secretion. No changes in secretory response were detected in the presence of IL-13 or IL-17. Goblet cells proliferated to varying degrees in response to all the tested cytokines with the greatest response to IL-13 followed by IL-6. Our results therefore reveal that inflammatory cytokines expressed in the conjunctiva during an ocular surface disease directly disrupt conjunctival goblet cell functions, compromising the protective function of tears, thereby contributing to ocular surface damage.
Contreras-Ruiz L, Mir FA, Turpie B, Krauss AH, Masli S.
Sjögren's syndrome associated dry eye in a mouse model is ameliorated by topical application of integrin α4 antagonist GW559090. Exp Eye Res 2016;143:1-8.
AbstractSjögren's syndrome is an autoimmune disease associated with inflammation of exocrine glands with clinical manifestations of dry eye and dry mouth. Dry eye in this disease involves inflammation of the ocular surface tissues - cornea and conjunctiva. While systemic blockade of adhesion molecules has been used to treat autoimmune diseases, the purpose of this study was to determine the therapeutic efficacy of topical application of an integrin α4 adhesion molecule antagonist in a mouse model of dry eye associated with Sjögren's syndrome. To assess this spontaneously developed ocular surface inflammation related to Sjögren's syndrome in TSP-1null mice (12 wks) was evaluated. Mice were treated with topical formulations containing 0.1% dexamethasone or 30 mg/ml GW559090 or vehicle control. Corneal fluorescein staining and conjunctival goblet cell density were assessed. Real-time PCR analysis was performed to assess expression of the inflammatory marker IL-1β in the cornea and Tbet and RORγt in the draining lymph nodes. Ocular surface inflammation was detectable in TSP-1null mice (≥12 wk old), which resulted in increased corneal fluorescein staining indicative of corneal barrier disruption and reduced conjunctival goblet cell density. These changes were accompanied by increased corneal expression of IL-1β as compared to WT controls and an altered balance of Th1 (Tbet) and Th17 (RORγt) markers in the draining lymph nodes. Topically applied dexamethasone and GW559090 significantly reduced corneal fluorescein staining compared to vehicle treatment (p = 0.023 and p < 0.001, respectively). This improved corneal barrier integrity upon adhesion molecule blockade was consistent with significantly reduced corneal expression of pro-inflammatory IL-1β compared to vehicle treated groups (p < 0.05 for both treatments). Significant improvement in goblet cell density was also noted in mice treated with 0.1% dexamethasone and GW559090 (p < 0.05 for both). We conclude that similar to topical dexamethasone, topically administered GW559090 successfully improved corneal barrier integrity and inflammation in an established ocular surface disease associated with Sjögren's syndrome.
