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Hopkinson A, Figueiredo FC. A Narrative Review of Amniotic Membrane Transplantation in Ocular Surface Repair: Unveiling the Immunoregulatory Pathways for Timely Intervention. Ophthalmol Ther 2025:10.1007/s40123-025-01143-w. [PMID: 40360962 DOI: 10.1007/s40123-025-01143-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2024] [Accepted: 04/04/2025] [Indexed: 05/15/2025] Open
Abstract
This narrative review explores the pathophysiology of ocular surface inflammation and highlights the therapeutic potential of patch amniotic membrane transplantation (patch-AMT) in ocular surface repair. Disruptions in ocular surface homeostasis caused by trauma, disease, or immune dysregulation trigger an inflammatory cascade that, if unresolved, can impair epithelial healing, lead to fibrosis, corneal haze, and vision loss. Patch-AMT provides a biological intervention with epitheliotropic, anti-inflammatory, anti-fibrotic, anti-angiogenic, and neuroprotective effects that support wound healing, regulate inflammation, and reduce pain. The review examines patch-AMT's role in acute conditions (chemical burns, Stevens-Johnson Syndrome) and chronic disease (persistent epithelial defects, dry eye disease), focusing on its ability to entrap immune cells, regulate cytokine signaling, and prevent fibrotic remodeling while releasing trophic proteins. Additionally, this review explores how preservation methods, application orientation, and intervention timing influences patch-AMT's efficacy. Recent advancements in non-surgical application methods have expanded accessibility, enabling earlier intervention and outpatient use. However, variability in clinical protocols emphasize the need for standardized guidelines. The review concludes by highlighting the need for further research to refine treatment timing, optimize repeat application strategies, and evaluate cost-effectiveness. While patch-AMT remains underutilized, growing evidence underscores its potential to improve clinical outcomes, particularly when applied early in disease progression.
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Affiliation(s)
- Andrew Hopkinson
- Academic Ophthalmology, Division of Clinical Neuroscience, Queen's Medical Centre (QMC), University of Nottingham, Queen's Medical Centre Campus, Nottingham, NG7 2UH, UK.
- NuVision Biotherapies, MediCity Nottingham, Nottingham, NG90 6BH, UK.
| | - Francisco C Figueiredo
- Department of Ophthalmology, Royal Victoria Infirmary, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK
- Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne, UK
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Bisen AC, Sanap SN, Agrawal S, Biswas A, Mishra A, Verma SK, Singh V, Bhatta RS. Etiopathology, Epidemiology, Diagnosis, and Treatment of Fungal Keratitis. ACS Infect Dis 2024; 10:2356-2380. [PMID: 38847789 DOI: 10.1021/acsinfecdis.4c00203] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/13/2024]
Abstract
Fungal keratitis (FK) is a severe ocular condition resulting from corneal infection that is prevalent in tropical countries, particularly in developing regions of Asia and Africa. Factors like corneal lens misuse, inappropriate steroid use, and diagnostic challenges have provoked the epidemic. FK causes significant vision impairment, scarring, and ocular deformities. Accurate pathological diagnosis is crucial for effective therapeutic intervention. Topical antifungal therapy with surface healing medications proves effective in preventing fungal-borne ulcers. Managing FK requires a comprehensive understanding of fungal pathogenesis, guiding formulation strategies and preventive measures to curb global ocular blindness. This review provides in-depth insights into FK, covering etiology, epidemiology, pathogenesis, therapeutic interventions, antifungal resistance, limitations, prevention, and future perspectives on ocular surface disease management.
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Affiliation(s)
- Amol Chhatrapati Bisen
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow 226031, India
- Academy of Scientific & Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh 201002, India
- Sophisticated Analytical Instrument Facility and Research, CSIR-Central Drug Research Institute, Lucknow 226031, India
| | - Sachin Nashik Sanap
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow 226031, India
- Academy of Scientific & Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh 201002, India
| | - Sristi Agrawal
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow 226031, India
- Academy of Scientific & Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh 201002, India
| | - Arpon Biswas
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow 226031, India
| | - Anjali Mishra
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow 226031, India
| | - Sarvesh Kumar Verma
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow 226031, India
| | - Vaishali Singh
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow 226031, India
| | - Rabi Sankar Bhatta
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow 226031, India
- Academy of Scientific & Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh 201002, India
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Liu S, Peng R, Ma J, Shen Z, Hu B, Zhao Y, Hong J. Assessment of Corneal Epithelial Changes and Related Factors in Ocular Chronic Graft-Versus-Host Disease (GVHD) by in Vivo Confocal Microscopy. Ocul Immunol Inflamm 2024; 32:454-462. [PMID: 36758227 DOI: 10.1080/09273948.2023.2173240] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Revised: 11/14/2022] [Accepted: 01/22/2023] [Indexed: 02/11/2023]
Abstract
PURPOSE To evaluate corneal epithelial changes and related factors in chronic ocular graft-versus-host disease (oGVHD) patients. METHODS 21 patients (35 eyes) with chronic oGVHD and 8 patients (12 eyes) without oGVHD after bone marrow transplantation were recruited for assessment involving in vivo confocal microscopy (IVCM) analysis, ocular surface parameter determination and tear cytokine level analysis. The IVCM corneal epithelial scoring system was used to evaluate corneal epithelial changes. RESULTS There was a significant difference in the corneal epithelial score (p = .001) between the two groups. The corneal epithelial scores were significantly correlated with the corneal fluorescein staining scores (CFS, r = 0.463, p < .001), Schirmer's test (r = -0.389, p = .009) and tear cytokine levels of EGF (r = -0.491, p < .001) and APRIL (r = -0.318, p = .030). CONCLUSIONS The depth of corneal epithelial defects can be estimated by the CFS. Corneal epithelial changes of chronic oGVHD are considered to be associated with lacrimal deficiency and a lack of EGF.
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Affiliation(s)
- Shuwan Liu
- Department of Ophthalmology, Peking University Third Hospital, Beijing, China
| | - Rongmei Peng
- Department of Ophthalmology, Peking University Third Hospital, Beijing, China
| | - Jiao Ma
- Department of Ophthalmology, Peking University Third Hospital, Beijing, China
| | - Zhan Shen
- Department of Ophthalmology, Peking University Third Hospital, Beijing, China
| | - Bohao Hu
- Department of Ophthalmology, Peking University Third Hospital, Beijing, China
| | - Yinghan Zhao
- Department of Ophthalmology, Peking University Third Hospital, Beijing, China
| | - Jing Hong
- Department of Ophthalmology, Peking University Third Hospital, Beijing, China
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Cheung AY, Holland EJ, Lee WB, Beckman KA, Tu E, Farid M, Pepose J, Gupta PK, Fram N, Mah F, Mannis MJ. Neurotrophic keratopathy: An updated understanding. Ocul Surf 2023; 30:129-138. [PMID: 37666470 DOI: 10.1016/j.jtos.2023.09.001] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2023] [Revised: 08/10/2023] [Accepted: 09/01/2023] [Indexed: 09/06/2023]
Abstract
PURPOSE To propose an updated definition and staging system for neurotrophic keratopathy (NK) and provide consensus on diagnosis and treatment. METHODS A study group was convened to review the data pertinent to NK using a modified nominal group process. They proposed an updated definition for NK and a new 6-step staging system (Neurotrophic Keratopathy Study Group [NKSG] Classification) that can be used in conjunction with the different treatment options available currently or in the future. RESULTS NK is defined as the dysfunction of corneal innervation that results in dysregulation of corneal and/or cellular function. It is characterized by loss of corneal sensation and neuronal homeostasis, leading to eventual corneal epithelial breakdown and ultimately keratolysis if untreated. The NKSG classification emphasizes verifying corneal sensation early and distinguishes different epithelial and stromal aspects of NK with the following stages: stage 1 (altered sensation without keratopathy), stage 2 (epitheliopathy/punctate epithelial keratopathy [PEK] without stromal haze), stage 3 (persistent/recurrent epithelial defects without stromal haze), stage 4 (epitheliopathy/PEK or persistent/recurrent epithelial defects with stromal haze), stage 5 (persistent/recurrent epithelial defect with corneal ulceration), and stage 6 (corneal perforation). Treatment consists of a variety of modalities (both indirect and direct). CONCLUSIONS This updated definition and staging system will provide clinicians with the necessary information to diagnose and treat NK at an early stage before it becomes a sight-threatening disorder. It also provides a framework for evaluating current and future treatment options at distinct stages of the disease.
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Effect of Polydeoxyribonucleotide (PDRN) Treatment on Corneal Wound Healing in Zebrafish ( Danio rerio). Int J Mol Sci 2022; 23:ijms232113525. [PMID: 36362312 PMCID: PMC9659220 DOI: 10.3390/ijms232113525] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 10/31/2022] [Accepted: 10/31/2022] [Indexed: 11/06/2022] Open
Abstract
This study aimed to develop a corneal epithelial injury model in zebrafish (Danio rerio) and investigate the effectiveness of polydeoxyribonucleotide (PDRN) treatment on in vivo corneal epithelial regeneration and wound healing. Chemical injury to zebrafish cornea was produced by placing a small cotton swab containing 3% acetic acid solution. PDRN treatment was performed by immersing corneal-injured zebrafish in water containing PDRN (2 mg/mL) for 10 min at 0, 24, 48, and 72 h post-injury (hpi). The level of corneal healing was evaluated by fluorescein staining, histological examination, transcriptional profiling, and immunoblotting techniques. Fluorescein staining results demonstrate that PDRN treatment significantly (p < 0.05) reduced the wounded area of the zebrafish eye at 48 and 72 hpi, suggesting that PDRN may accelerate the corneal re-epithelialization. Histopathological evaluation revealed that injured corneal epithelial cells were re-organized at 72 hpi upon PDRN treatment with increased goblet cell density and size. Moreover, transcriptional analysis results demonstrate that PDRN treatment induced the mRNA expression of adora2ab (6.3-fold), pax6a (7.8-fold), pax6b (29.3-fold), klf4 (7.3-fold), and muc2.1 (5.0-fold) after the first treatment. Besides, tnf-α (2.0-fold) and heat-shock proteins (hsp70; 2.8-fold and hsp90ab1; 1.6-fold) have modulated the gene expression following the PDRN treatment. Immunoblotting results convincingly confirmed the modulation of Mmp-9, Hsp70, and Tnf-α expression levels upon PDRN treatment. Overall, our corneal injury model in zebrafish allows for understanding the morphological and molecular events of corneal epithelial healing, and ophthalmic responses for PDRN treatment following acid injury in zebrafish.
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Jin HN, Kim J, Yoon HJ, Yoon KC. Clinical Manifestation of Infectious Keratitis in Ocular Graft Versus Host Disease. JOURNAL OF THE KOREAN OPHTHALMOLOGICAL SOCIETY 2022. [DOI: 10.3341/jkos.2022.63.7.592] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Purpose: We evaluated the clinical manifestations of, and risk factors for, infectious keratitis in patients with ocular graft-versus-host disease (GVHD).Methods: A total of 11 patients who developed infectious keratitis after a diagnosis of ocular GVHD between January 2015 and December 2020, and 36 who did not (the control group), were included in this retrospective study. We recorded sex, age, any underlying disease, any other organ affected by systemic GVHD, systemic immunosuppressant use, follow-up duration, clinical manifestations, the severity of ocular GVHD prior to infection, the size of the epithelial defect, the depth of infiltration, hypopyon status, and the results of microbiological tests. Systemic and ocular indices (including systemic GVHD status) were compared using the chi-squared test. Risk factors for infection were identified.Results: Of the corneal indices, the presence of corneal filaments, the extent of corneal neovascularization, and the number of corneal epithelial defects were significantly higher in the infected group (p = 0.023, p = 0.004, and p = 0.001, respectively). GVHD severity was also significantly higher in that group (p < 0.001). The presence of corneal filaments, corneal neovascularization, and corneal epithelial defects prior to infection correlated significantly with the risk of infection (p = 0.046, p = 0.010, and p = 0.003, respectively). Multivariate analysis identified corneal epithelial defects as a significant risk factor for infection (p = 0.029).Conclusions: In patients with ocular GVHD, corneal epithelial defects, corneal neovascularization, and corneal filaments prior to infection were associated with the development of infection. In particular, corneal epithelial defects before infection was a significant risk factor for infection.
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Prevalence of neurotrophic keratopathy in patients with chronic ocular graft-versus-host disease. Ocul Surf 2022; 26:13-18. [PMID: 35843560 DOI: 10.1016/j.jtos.2022.07.001] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2022] [Revised: 07/08/2022] [Accepted: 07/09/2022] [Indexed: 11/22/2022]
Abstract
PURPOSE To determine the prevalence, clinical characteristics, and risk factors associated with neurotrophic keratopathy (NK) in patients with chronic ocular graft-versus-host disease (oGVHD). DESIGN Retrospective cohort study. METHODS We performed a chart review of patients diagnosed with chronic oGVHD between January 2015 and December 2018 at a single academic institution and recorded demographic data, systemic and ocular comorbidities, history of hematologic malignancy, transplant characteristics, oGVHD severity scores, and adnexal and ocular examination findings. We determined the prevalence of NK and clinical characteristics associated with NK in these patients. A multivariate logistic regression analysis was performed to determine the risk factors associated with NK in these patients. MAIN OUTCOME MEASURE Prevalence of NK in chronic oGVHD. RESULTS We identified 213 patients diagnosed with chronic oGVHD following hematopoietic stem cell or bone marrow transplantation from our electronic patient database, and the prevalence of NK was 14%. The mean age of oGVHD patients with NK was 62.6 ± 12.9 years; 48% were women, 19 had unilateral NK, and ten had bilateral NK. In the cohort, 56%, 20%, and 24% eyes of the patients had grades 1, 2, and 3 of NK, respectively. The mean time to diagnose NK after transplantation was 52.9 ± 45.4 months. oGVHD patients diagnosed with NK had a significantly higher NIH oGVHD severity score (p = 0.04) and a lower corneal sensation score (p = 0.0001) than those without NK. Our analyses showed a significantly higher CFS score (p = 0.01) and a trend toward lower Schirmer test scores (p = 0.16) and tear break-up times (p = 0.08) in oGVHD patients with NK. Additionally, we observed a significantly higher prevalence of persistent epithelial defect (p = 0.0001), corneal ulceration (p = 0.0001), and corneal perforation (p = 0.005) in oGVHD patients diagnosed with NK. A logistic regression analysis to determine factors associated with NK showed that a higher NIH oGVHD score (odds ratio [OR] = 2.03, p = 0.026) and history of cataract surgery (odds ratio [OR] = 5.03, p = 0.001) are significant risk factors for NK in oGVHD patients. CONCLUSIONS The prevalence of NK in chronic oGVHD patients was 14% during the study period. Our analysis shows that oGVHD patients with a higher NIH oGVHD severity score and previous history of cataract surgery are at a higher risk of developing NK and may develop severe sequelae such as persistent epithelial defect or corneal ulceration.
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Gardnerella vaginalis induces matrix metalloproteinases in the cervicovaginal epithelium through TLR-2 activation. J Reprod Immunol 2022; 152:103648. [PMID: 35679790 PMCID: PMC9313515 DOI: 10.1016/j.jri.2022.103648] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Revised: 05/07/2022] [Accepted: 05/20/2022] [Indexed: 11/21/2022]
Abstract
Lactobacillus-deficient cervicovaginal microbiota, including Gardnerella vaginalis, are implicated in cervical remodeling and preterm birth. Mechanisms by which microbes drives outcomes are not fully elucidated. We hypothesize that Gardnerella vaginalis induces matrix metalloproteinases through TLR-2, leading to epithelial barrier dysfunction and premature cervical remodeling. Cervicovaginal cells were treated with live Gardnerella vaginalis or Lactobacillus crispatus or their bacteria-free supernatants for 24 h. For TLR-2 experiments, cells were pretreated with TLR-2 blocking antibody. A Luminex panel was run on cell media. For human data, we conducted a case-control study from a prospective pregnancy cohort of Black individuals with spontaneous preterm (sPTB) (n = 40) or term (n = 40) births whose vaginal microbiota had already been characterized. Cervicovaginal fluid was obtained between 20 and 24 weeks' gestation. Short cervix was defined as < 25 mm by second trimester transvaginal ultrasound. MMP-9 was quantified by ELISA. Standard analytical approaches were used to determine differences across in vitro conditions, as well as MMP-9 and associations with clinical outcomes. Gardnerella vaginalis induced MMP-1 in cervical cells (p = 0.01) and MMP-9 in cervical and vaginal (VK2) cells (p ≤ 0.001 for all). TLR-2 blockade mitigated MMP-9 induction by Gardnerella vaginalis. MMP-9 in cervicovaginal fluid is higher among pregnant individuals with preterm birth, short cervix, and Lactobacillus-deficient microbiota (p < 0.05 for all). MMP-9 is increased in the cervicovaginal fluid of pregnant individuals with subsequent sPTB. Our in vitro work ascribes a potential mechanism by which a cervicovaginal microbe, commonly associated with adverse pregnancy outcomes, may disrupt the cervicovaginal epithelial barrier and promote premature cervical remodeling in spontaneous preterm birth.
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Yildizhan E, Ulger BV, Akkus M, Akinci D, Basol O. Comparison of topical sucralfate with dexpanthenol in rat wound model. Int J Exp Pathol 2022; 103:164-170. [PMID: 35441448 PMCID: PMC9264344 DOI: 10.1111/iep.12441] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Revised: 02/28/2022] [Accepted: 03/21/2022] [Indexed: 11/30/2022] Open
Abstract
Wound healing is a dynamic process initiated in response to injury. There are many factors that have detrimental effects on the wound healing process. Numerous studies have been conducted for improving wound healing processes. Dexpanthenol is widely used to accelerate wound healing. Sucralfate is used for the treatment of peptic ulcers. We aimed to compare the efficacy of topical Dexpanthenol and Sucralfate in an experimental wound model in rats via histopathological examinations and immune histochemical determinations, as well, to evaluate their effects on EGF levels. Three different groups were formed: the Control Group, the Dexpanthenol Group and the Sucralfate Group. Full-thickness skin wounds were created on the back of each rat and isotonic saline was applied to the wounds of the rats in the control group, Bepanthol® cream was applied in Dexpanthenol Group and 10% Sucralfate cream was applied in Sucralfate Group, once a day. On the 7th, 14th and 21st days the wounds were measured and seven rats from each group were sacrificed and the wounds were excised for histopathological examination. Sucralfate increased wound healing rates by increasing neovascularization, fibroblast activation, reepithelialization and collagen density, as well as dexpanthenol. Our study revealed that the dexpanthenol and sucralfate groups were better than the control group in terms of their effects on wound healing, however there was no statistically significant difference among these two groups. Sucralfate improves EGF expression in skin wounds and has positive results on skin wound healing comparable to dexpanthenol.
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Affiliation(s)
- Eda Yildizhan
- Department of Histology and Embryology, Faculty of Medicine, Dicle University, Diyarbakır, Turkey
| | - Burak Veli Ulger
- Department of General Surgery, Faculty of Medicine, Dicle University, Diyarbakır, Turkey
| | - Murat Akkus
- Department of Histology and Embryology, Faculty of Medicine, Dicle University, Diyarbakır, Turkey
| | - Dilara Akinci
- Department of Histology and Embryology, Faculty of Medicine, Dicle University, Diyarbakır, Turkey
| | - Omer Basol
- Department of General Surgery, Gazi Yasargil E.A.H., Diyarbakır, Turkey
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Marchegiani A, Gialletti R, Cassarani MP, Cerquetella M, Attili AR, Lombardo G, Lombardo M, Spaterna A, Arcelli R. Riboflavin/UV-A corneal phototherapy as stand-alone management of ulcerative keratitis in dogs. VET MED-CZECH 2022; 67:190-198. [PMID: 39170804 PMCID: PMC11334441 DOI: 10.17221/46/2021-vetmed] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Accepted: 12/13/2021] [Indexed: 08/23/2024] Open
Abstract
Corneal ulcers are one of the most common ocular disorders in veterinary ophthalmology and several factors can negatively influence the efficacy of the currently available therapeutic options, leading to a loss of corneal transparency and, thus, vision. Twenty-five dogs with clinical signs of corneal ulcers were randomised to receive either corneal phototherapy (16 dogs; study group) or topical standard medical therapy (9 dogs; control group). The riboflavin/UV-A corneal phototherapy (PACK-CXL) consisted in the application of a riboflavin ophthalmic solution (Visioflavin®; Vision Engineering Italy srl, Rome, Italy) onto the cornea for 20 min followed by 30 mW/cm2 UV-A irradiance for 3 min using a point-of-care UV-A device (Vetuvir®; Vision Engineering Italy srl, Rome, Italy). The complete healing of the ulcerative lesion was defined as the complete restoration of the corneal epithelial integrity with negative fluorescein staining. The corneal phototherapy achieved complete corneal healing in all the dogs by 20.5 ± 7.8 days. In the control group, only two dogs achieved complete healing by 21.5 ± 15.6 days. This intervention may represent a valid option to hasten corneal wound healing and a clinical resolution of ulcerative keratitis in dogs.
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Affiliation(s)
- Andrea Marchegiani
- School of Biosciences and Veterinary Medicine, University of Camerino, Matelica (Macerata), Italy
| | - Rodolfo Gialletti
- Department of Veterinary Medicine, University of Perugia, Perugia, Italy
| | - Maria Paola Cassarani
- School of Biosciences and Veterinary Medicine, University of Camerino, Matelica (Macerata), Italy
| | - Matteo Cerquetella
- School of Biosciences and Veterinary Medicine, University of Camerino, Matelica (Macerata), Italy
| | - Anna Rita Attili
- School of Biosciences and Veterinary Medicine, University of Camerino, Matelica (Macerata), Italy
| | - Giuseppe Lombardo
- CNR-IPCF, Istituto per i Processi Chimico-Fisici, Messina, Italy
- Vision Engineering Italy srl, Rome, Italy
| | - Marco Lombardo
- Vision Engineering Italy srl, Rome, Italy
- Studio Italiano di Oftalmologia, Rome, Italy
| | - Andrea Spaterna
- School of Biosciences and Veterinary Medicine, University of Camerino, Matelica (Macerata), Italy
| | - Rolando Arcelli
- Department of Veterinary Medicine, University of Perugia, Perugia, Italy
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Yeu E, Hashem O, Sheha H. Treatment of Epithelial Basement Membrane Dystrophy to Optimize the Ocular Surface Prior to Cataract Surgery. Clin Ophthalmol 2022; 16:785-795. [PMID: 35321046 PMCID: PMC8935016 DOI: 10.2147/opth.s356421] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Accepted: 02/23/2022] [Indexed: 11/23/2022] Open
Abstract
Purpose To assess the effectiveness of cryopreserved amniotic membrane (CAM) after debridement in treating epithelial basement membrane dystrophy (EBMD) prior to cataract surgery. Methods This pilot study included 2 treatment groups: a prospective study group of 9 subjects with significant EBMD who received debridement followed by self-retained CAM, and a retrospective, control group of 10 consecutive subjects who received debridement followed by a bandage contact lens (BCL). Slit-lamp photography after fluorescein staining were used to monitor healing. Corneal topography and IOL calculation were compared at baseline and 1 month after the procedure. Refraction and ocular surface stability were also compared after cataract surgery. Results Corneal reepithelialization after debridement occurred in 4.6 ± 0.8 days in the study group and 6.8 ± 0.6 days in the control (p < 0.05). Corneal topography showed changes in curvature from 43.5 ± 1.2D at baseline to 44.6 ± 1.2D at 1 month in the study group and from 45.0 ± 0.6D to 45.7 ± 0.8D in the control (p = 0.38). Average change in IOL calculation was 1.56 D in the study group, compared to 0.95 D in control (p = 0.29). Post-cataract refraction in both groups was within ±0.5 Diopter of the anticipated, and corneal surface remained stable without EBMD recurrence. Conclusion Management of ocular surface disorders prior to cataract surgery stabilizes IOL calculation and reduces postoperative refractive surprises. CAM relatively accelerated healing after debridement; however, it was not better than BCL in stabilizing the ocular surface and improving visual outcome. The use of CAM in cases of EBMD remains speculative.
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Affiliation(s)
- Elizabeth Yeu
- Virginia Eye Consultants, Norfolk, VA, USA
- Eastern Virginia Medical School, Norfolk, VA, USA
| | - Omar Hashem
- Research Institute of Ophthalmology, Cairo, Egypt
| | - Hosam Sheha
- Research Institute of Ophthalmology, Cairo, Egypt
- Florida International University Herbert Wertheim College of Medicine, & Glaucoma Research Organization, Miami, FL, USA
- Manhattan Eye, Ear and Throat Hospital, Hofstra Northwell School of Medicine, New York, NY, USA
- Correspondence: Hosam Sheha, Department of Ophthalmology, Manhattan Eye, Ear and Throat Hospital, 210 E 64 Street, New York, NY, 10065, USA, Tel +1 917-810-9555, Email
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Brzheskiy VV, Popov VY, Efimova EL, Golubev SY. [Modern capabilities in diagnosis and treatment of neurotrophic keratopathy]. Vestn Oftalmol 2022; 138:123-132. [PMID: 36573956 DOI: 10.17116/oftalma2022138061123] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
In recent years, the problem of diagnosing and treating neurotrophic keratopathy (NK) has become relevant in view of its prevalence reaching 1.6-11.0 per 10000 people. While previously it was associated only with neuroparalytic keratitis, at present the violation of sensitive and trophic innervation of the cornea with the development of characteristic keratopathy is observed in many diseases and injuries of the organ of vision. Diagnosis of NK is based on anamnestic information and assessment of clinical and functional parameters: determination of the stability of the tear film, tear production and assessment of staining of the ocular surface with vital dyes. The main role in the diagnosis of NK belongs to corneal sensitivity determined with the Cochet-Bonnet esthesiometer. Treatment of NK is designed to restore or increase corneal sensitivity and involves tear replacement therapy, instillations of preparations derived from patient's own blood, anti-inflammatory, metabolic and antibacterial therapy. However, instillations of human erve growth factor (NGF) - the drug Cenegermin (registered in Europe in 2017 at a dose of 20 μg/ml under the name Oxervate), a recombinant form of human rhNGF from Escherichia coli bacteria - exhibit the highest pathogenetic orientation. Its «target» is the affected nerve fibers (specific receptors for their growth factor), which makes it possible to eliminate the violation of reparative processes in neural and epithelial cells. A high and long-term clinical efficacy of a course of six (with an interval of 2 hours) instillations of the drug for 8 weeks in the treatment of children and adults with NK has been established. Among the pathogenetically justified methods of surgical treatment, there is the so-called surgical neurotization of the cornea involving the contralateral supraorbital, supratrochlear, great auricular and other nerves, which has a long-term clinical effect.
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Affiliation(s)
- V V Brzheskiy
- Saint Petersburg State Pediatric Medical University, Saint Petersburg, Russia
| | - V Yu Popov
- Saint Petersburg State Pediatric Medical University, Saint Petersburg, Russia
| | - E L Efimova
- Saint Petersburg State Pediatric Medical University, Saint Petersburg, Russia
| | - S Yu Golubev
- Institute of Biomedical Problems, Moscow, Russia
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Kesim E, Pirhan D, Yardimoglu Yilmaz M, Yuksel N, Yazir Y, Bicaklioglu G, Furat Rencber S. Comparative Analysis of Matrix-Regenerating Agent and Corneal Cross-Linking in an Experimental Alkali Burn Rabbit Model. Curr Eye Res 2021; 47:187-195. [PMID: 34435926 DOI: 10.1080/02713683.2021.1971722] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
PURPOSE This study aimed to investigate the clinical and histopathological effects of corneal cross-linking (CXL) and matrix-regenerating agent (RGTA) treatments after corneal alkali burn. MATERIALS AND METHODS Twenty-four alkali-burned corneas from 24 rabbits were divided into three groups: control, CXL, and RGTA. All animals were investigated for epithelial healing, opacification, ulceration, and neovascularization at days 1, 7, 14, and 21 after the alkali burn. Corneas were excised and sent for histological examination on day 21. RESULTS One animal each from the CXL and control groups exhibited moderate ulceration, while no ulceration was observed in the RGTA group. No significant difference was observed among the groups in corneal thickness or corneal opacity measurements at the final visit (p = .058 and p = .544, respectively). Both RGTA and CXL treatments were effective in terms of epithelial healing and neovascularization (p = .023 and p = .03, respectively). On histological examination, the CXL and RGTA groups were more effective in treating epithelial loss, stromal edema, corneal vascularization, and leukocytic infiltration than the control group (p < .05). The immunohistochemical staining scores of the CXL and RGTA groups for caspase-3, vascular endothelial growth factor, and matrix metalloproteinase-9 in the epithelium and stroma were significantly lower than those in the control group (p < .05). In the immunohistochemical examination for inducible nitric oxide synthase, epithelial staining scores were similar among the groups (p > .05). In contrast, the stromal staining scores of the CXL and RGTA groups were lower than those of the control group (p < .05). CONCLUSION Both CXL and RGTA therapies were effective in reducing anatomical and histopathological complications after corneal alkali burn. Further investigation is needed to determine the optimal timing, duration, and dosage of these treatments.
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Affiliation(s)
- Enes Kesim
- Department of Ophthalmology, Tuzla State Hospital, Istanbul, Turkey
| | - Dilara Pirhan
- Department of Ophthalmology, Kocaeli University Faculty of Medicine, Kocaeli, Turkey
| | - Melda Yardimoglu Yilmaz
- Department of Histology and Embryology, Kocaeli University Faculty of Medicine, Kocaeli, Turkey
| | - Nursen Yuksel
- Department of Ophthalmology, Kocaeli University Faculty of Medicine, Kocaeli, Turkey
| | - Yusufhan Yazir
- Department of Histology and Embryology, Kocaeli University Faculty of Medicine, Kocaeli, Turkey
| | | | - Selenay Furat Rencber
- Department of Histology and Embryology, Kocaeli University Faculty of Medicine, Kocaeli, Turkey
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14
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Nishida T, Sugioka K, Fukuda K, Murakami J. Pivotal Role of Corneal Fibroblasts in Progression to Corneal Ulcer in Bacterial Keratitis. Int J Mol Sci 2021; 22:ijms22168979. [PMID: 34445684 PMCID: PMC8396668 DOI: 10.3390/ijms22168979] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2021] [Revised: 08/12/2021] [Accepted: 08/17/2021] [Indexed: 01/05/2023] Open
Abstract
The shape and transparency of the cornea are essential for clear vision. However, its location at the ocular surface renders the cornea vulnerable to pathogenic microorganisms in the external environment. Pseudomonas aeruginosa and Staphylococcus aureus are two such microorganisms and are responsible for most cases of bacterial keratitis. The development of antimicrobial agents has allowed the successful treatment of bacterial keratitis if the infection is diagnosed promptly. However, no effective medical treatment is available after progression to corneal ulcer, which is characterized by excessive degradation of collagen in the corneal stroma and can lead to corneal perforation and corneal blindness. This collagen degradation is mediated by both infecting bacteria and corneal fibroblasts themselves, with a urokinase-type plasminogen activator (uPA)-plasmin-matrix metalloproteinase (MMP) cascade playing a central role in collagen destruction by the host cells. Bacterial factors stimulate the production by corneal fibroblasts of both uPA and pro-MMPs, released uPA mediates the conversion of plasminogen in the extracellular environment to plasmin, and plasmin mediates the conversion of secreted pro-MMPs to the active form of these enzymes, which then degrade stromal collagen. Bacterial factors also stimulate expression by corneal fibroblasts of the chemokine interleukin-8 and the adhesion molecule ICAM-1, both of which contribute to recruitment and activation of polymorphonuclear neutrophils, and these cells then further stimulate corneal fibroblasts via the secretion of interleukin-1. At this stage of the disease, bacteria are no longer necessary for collagen degradation. In this review, we discuss the pivotal role of corneal fibroblasts in corneal ulcer associated with infection by P. aeruginosa or S. aureus as well as the development of potential new modes of treatment for this condition.
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Affiliation(s)
- Teruo Nishida
- Department of Ophthalmology, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi 755-8505, Japan;
- Division of Cornea and Ocular Surface, Ohshima Eye Hospital, Fukuoka 812-0036, Japan
| | - Koji Sugioka
- Department of Ophthalmology, Kindai University Nara Hospital, Ikoma, Nara 630-0293, Japan;
| | - Ken Fukuda
- Department of Ophthalmology and Visual Science, Kochi Medical School, Kochi University, Nankoku, Kochi 783-8505, Japan
- Correspondence:
| | - Junko Murakami
- Division of Ophthalmology, Sakibana Hospital, Izumi, Osaka 594-1105, Japan;
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15
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Capistrano da Silva E, Carossino M, Smith-Fleming KM, Langohr IM, Martins BDC. Determining the efficacy of the bovine amniotic membrane homogenate during the healing process in rabbits' ex vivo corneas. Vet Ophthalmol 2021; 24:380-390. [PMID: 34402564 DOI: 10.1111/vop.12917] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Revised: 06/06/2021] [Accepted: 06/18/2021] [Indexed: 11/28/2022]
Abstract
OBJECTIVE To evaluate the efficacy of bovine amniotic membrane homogenate (BAMH) on wounded ex vivo rabbit corneas. PROCEDURE Eighteen corneas obtained from normal rabbit eyes were wounded equally using a 6 mm trephine and cultured into an air-liquid interface model. Corneas were treated with phosphate-buffered saline (PBS) (n = 6, control group), 0.2% ethylenediaminetetraacetic acid (EDTA; n = 6), or BAMH (n = 6). All treatments were applied topically 6 times/day. Each cornea was macrophotographed daily with and without fluorescein stain to assess epithelialization and haziness. After 7 days, corneal transparency was evaluated, and the tissues prepared for histologic analysis of viability, and total and epithelial thickness. RESULTS The mean epithelialization time was 6.2 ± 0.82 days for the control group, 6.2 ± 0.75 days for the EDTA-treated group, and 5.1 ± 0.40 days for the BAMH-treated group, demonstrating a significant difference between the BAMH and the other groups. The corneas that received EDTA had better transparency compared with the other groups. Histologically, all corneas had adequate morphology and architecture after healing. Analysis of corneal and epithelial thickness revealed no significant difference among groups. CONCLUSION Bovine amniotic membrane homogenate is an effective and promising treatment for stromal and epithelial ulcers.
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Affiliation(s)
- Erotides Capistrano da Silva
- Department of Comparative Biosciences, College of Veterinary Medicine, University of Illinois Urbana-Champaign, Urbana, IL, USA
| | - Mariano Carossino
- Louisiana Animal Disease Diagnostic Laboratory, Louisiana State University, Baton Rouge, LA, USA
| | - Kathryn M Smith-Fleming
- Department of Veterinary Clinical Medicine, College of Veterinary Medicine, University of Illinois Urbana-Champaign, Urbana, IL, USA
| | - Ingeborg M Langohr
- Department of Pathobiological Sciences, Louisiana State University, Baton Rouge, LA, USA
| | - Bianca da C Martins
- Department of Comparative Biosciences, College of Veterinary Medicine, University of Illinois Urbana-Champaign, Urbana, IL, USA.,Department of Veterinary Clinical Medicine, College of Veterinary Medicine, University of Illinois Urbana-Champaign, Urbana, IL, USA
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16
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Donovan C, Koudouna E, Margo CE, Avila MY, Espana EM. Genipin Delays Corneal Stromal Enzymatic Digestion. Transl Vis Sci Technol 2021; 10:25. [PMID: 34424287 PMCID: PMC8394563 DOI: 10.1167/tvst.10.9.25] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Purpose To evaluate the use of genipin in delaying enzymatic digestion of corneal stroma. Methods Human corneal stromal tissue was treated with genipin, a known chemical crosslinker, and then along with control tissue was subjected to enzymatic digestion with collagenase. The effects of genipin treatment in retarding stromal digestion were analyzed with phase contrast microscopy, a protein quantification assay, second harmonic generation imaging, and transmission electron microscopy. Results Genipin increased stromal resistance to enzymatic digestion when compared with untreated stroma. A morphologic analysis and protein quantification showed increased stromal resistance to enzymatic digestion once stromal tissue was treated with genipin. Second harmonic generation imaging revealed persistent fibrillar collagen signaling in genipin-treated tissue in contrast with untreated tissue suggesting that genipin retards collagenolysis. Conclusions Genipin increases stromal resistance to enzymatic digestion in controlled experiments as demonstrated by protein quantification studies and through morphologic imaging. Translational Relevance This study explores the novel use of genipin in delaying enzymatic stromal digestion. Delaying stromal melting in the setting of corneal infectious or autoimmune keratitis can potentially decrease clinical morbidity.
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Affiliation(s)
- Christopher Donovan
- Department of Ophthalmology, Morsani College of Medicine, University of South Florida, Tampa, FL, USA
| | - Elena Koudouna
- Department of Ophthalmology, School of Medicine, Universidad Nacional de Colombia, Hospital Universitario Nacional, Bogota, Colombia.,Structural Biophysics Group, School of Optometry and Vision Sciences, Cardiff University, Cardiff, UK
| | - Curtis E Margo
- Department of Pathology and Cell Biology, Morsani College of Medicine, University of South Florida, Tampa, FL, USA.,Department of Ophthalmology, Morsani College of Medicine, University of South Florida, Tampa, FL, USA
| | - Marcel Y Avila
- Department of Ophthalmology, School of Medicine, Universidad Nacional de Colombia, Hospital Universitario Nacional, Bogota, Colombia
| | - Edgar M Espana
- Department of Ophthalmology, Morsani College of Medicine, University of South Florida, Tampa, FL, USA.,Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL, USA
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17
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Abstract
PURPOSE OF REVIEW The management of neurotrophic keratitis (NK) has evolved in the last decade. The present article reviews updated management guidelines of this entity, as well as future innovations in the field. RECENT FINDINGS The advent of confocal microscopy has allowed for the first time to image corneal nerves. In addition, multiple novel topical treatments such as nerve growth factor have improved the prognosis of this disease, with many other in the pipeline. Finally, corneal nerve restoration is now possible with corneal neurotization procedures. SUMMARY Many novel treatments based on agents that stimulate nerve regrowth are now available to treat NK. Improvement in neurotization procedures could also address advanced stages of this disease with surgery.
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18
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Ozyol P, Ozyol E, Yildirim FE. Remodeling of Cornea With Isotretinoin Treatment. Eye Contact Lens 2021; 47:366-371. [PMID: 33323877 DOI: 10.1097/icl.0000000000000769] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/30/2020] [Indexed: 11/25/2022]
Abstract
OBJECTIVES To evaluate the change of corneal epithelial thickness (ET) in subjects using isotretinoin with spectral-domain optical coherence tomography and further to explore reflection of changes on corneal topography. METHODS Forty eyes of 40 subjects with acne vulgaris scheduled for oral isotretinoin were included in this prospective study. Subjects were examined with RTVue-XR and Pentacam at baseline, 1th, 3rd, and 6th months of treatment, and 3rd month of isotretinoin cessation. RESULTS A statistically significant increase was detected in each sector of ET map except inferonasal 7 to 9 mm between baseline and following visits (P<0.05, for all visits). The increase in superior (2-7 mm), inferior (2-7 mm), and maximum values in epithelium statistics and the decrease in superior (2-7 mm), inferior (2-7 mm), minimum, and maximum values in stroma statistics at follow-up visits were significant (P<0.05, for all visits). Central corneal thickness, maximum Ambrosio-relational thickness, average pachymetric-progression index at 1th, 3rd, and 6th months, and thinnest pachymetry, index of surface variance (ISV) at 3rd, and 6th months differed significantly (P<0.05, for specified visits). The regression in parameters was observed at 3rd month of isotretinoin cessation. CONCLUSIONS Isotretinoin treatment induces epithelial thickening and stromal thinning. Remodeling of corneal layers causes statistical differences in ISV and pachymetry-related parameters of Pentacam. The pachymetry changes in cornea return to baseline at the 3rd month of discontinuation of treatment.
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Affiliation(s)
- Pelin Ozyol
- Department of Ophthalmology (P.O., E.O.), and Dermatology (F.E.Y.), SANKO University School of Medicine, Gaziantep, Turkey
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19
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Chen Y, Miao X, Gao M, Song L. Comparison of modified corneal cross-linking with intrastromal voriconazole for the treatment of fungal corneal ulcer. Exp Ther Med 2021; 22:786. [PMID: 34055085 PMCID: PMC8145909 DOI: 10.3892/etm.2021.10218] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Accepted: 03/01/2021] [Indexed: 01/14/2023] Open
Abstract
The present study aimed to evaluate the efficacy of modified corneal cross-linking (CXL) for the treatment of fungal corneal ulcers compared with that following intrastromal voriconazole injection. In total, 31 patients with fungal corneal ulcers treated at The General Hospital of Northern Theater Command between October 2017 and October 2019 were enrolled. Among them, 10 eyes were treated with ultraviolet A (UV-A)/riboflavin CXL (CXL group), whilst 21 eyes were treated with debridement combined with intrastromal voriconazole (stromal injection group). Preoperative microbiological examination was performed in both groups, and evaluated using Fisher's exact test. Postoperatively, infection control and total efficacy rates, localized lesion, ulcer healing rate 1 week after surgery, visual acuity and complications were evaluated using Fisher's exact test, however visual acuity was analyzed by mixed-model ANOVA. The results showed that the pre-operative species distribution between the CXL and stromal injection groups did not significantly differ. The infection control rate in the CXL group was notably higher compared with that in the stromal injection group (P=0.04). Furthermore, the total efficacy rate in the CXL group was also markedly higher compared with that in the stromal injection group, though no statistically significant differences were observed. Localized lesions were observed in nine eyes (90.0%) in the CXL group and nine eyes (42.9%) in the stromal injection group (P=0.02). However, the rate of ulcer healing at 1 week postoperatively and the logarithm of the minimum angle of resolution (logMAR) of visual acuity were not found to be significantly different between the two groups. In terms of complications, with the exception of one patient in the CXL group exhibiting loss of corneal transparency and one patient in the stromal injection group presenting with partial corneal thinning, no other forms of complications were observed. In conclusion, the present study suggested that CXL could have a beneficial impact for treating fungal corneal ulcers in the aspects of infection control, localized lesions and accelerated epithelialization. In addition, except the loss of corneal transparency, this treatment approach could be applied with reduced risks of adverse events.
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Affiliation(s)
- Yingxin Chen
- Department of Ophthalmology, General Hospital of Northern Theater Command, Shenyang, Liaoning 110016, P.R. China
| | - Xingya Miao
- Department of Ophthalmology, General Hospital of Northern Theater Command, Shenyang, Liaoning 110016, P.R. China
| | - Minghong Gao
- Department of Ophthalmology, General Hospital of Northern Theater Command, Shenyang, Liaoning 110016, P.R. China
| | - Lixin Song
- Department of Dermatology, General Hospital of Northern Theater Command, Shenyang, Liaoning 110016, P.R. China
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20
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Dalmaso B, da Silva-Junior IA, Fragel-Madeira L, Jancar S, Del Debbio CB. Platelet activating factor in the eye: Physiological roles, diseases and future perspectives. Prostaglandins Other Lipid Mediat 2021; 153:106522. [PMID: 33358892 DOI: 10.1016/j.prostaglandins.2020.106522] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Revised: 12/03/2020] [Accepted: 12/18/2020] [Indexed: 01/09/2023]
Abstract
Platelet Activating Factor (PAF) is a known phospholipid mediator of inflammation. Since its first description in 1972, it has emerged as a key regulator of vital cellular signaling functions, as proliferation, cell adhesion, and apoptosis. Evidence suggests that interactions between PAF and its receptor (PAFR) play a critical role in nervous system tissues, including the retina. The retina is a very important constituent of the visual system, along with the cornea, sclera, choroid, iris, and ciliary body, that acts synergistically to provide vision and to maintain optical homeostasis. There is evidence that PAF may regulate a wide range of physiological functions in the visual system tissues, such as eye development, inflammation, epithelial wound healing, and synapsis. Due to their multiple functions, PAF and PAFR also have important pathological and clinical implications in ocular disorders such as Choroidal Neovascularization (CNV), Age Macular Degeneration, (AMD), Diabetic Retinopathy (DR), transplant responses, and pharmacological interactions. Studies with PAFR antagonists have shown promising results such as inhibition of neovascularization and chloroquine-induced retinopathies, as well as reducing inflammation and retinal cell death. Due to the importance of PAFR signaling in the visual system and ophthalmology research, this review aims to provide a general overview of current and future perspectives about PAF in eye biology.
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Affiliation(s)
- Barbara Dalmaso
- Department of Cell and Developmental Biology, Biomedical Sciences Institute, University of Sao Paulo, São Paulo, Brazil
| | | | - Lucianne Fragel-Madeira
- Department of Neurobiology, Institute of Biology, Fluminense Federal University, Rio de Janeiro, Brazil
| | - Sonia Jancar
- Department of Immunology, Biomedical Sciences Institute, University of Sao Paulo, São Paulo, Brazil
| | - Carolina Beltrame Del Debbio
- Department of Cell and Developmental Biology, Biomedical Sciences Institute, University of Sao Paulo, São Paulo, Brazil.
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21
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Bargagna‐Mohan P, Schultz G, Rheaume B, Trakhtenberg EF, Robson P, Pal‐Ghosh S, Stepp MA, Given KS, Macklin WB, Mohan R. Corneal nonmyelinating Schwann cells illuminated by single-cell transcriptomics and visualized by protein biomarkers. J Neurosci Res 2021; 99:731-749. [PMID: 33197966 PMCID: PMC7894186 DOI: 10.1002/jnr.24757] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Revised: 10/05/2020] [Accepted: 10/25/2020] [Indexed: 12/23/2022]
Abstract
The cornea is the most innervated tissue in the human body. Myelinated axons upon inserting into the peripheral corneal stroma lose their myelin sheaths and continue into the central cornea wrapped by only nonmyelinating corneal Schwann cells (nm-cSCs). This anatomical organization is believed to be important for central vision. Here we employed single-cell RNA sequencing (scRNA-seq), microscopy, and transgenics to characterize these nm-cSCs of the central cornea. Using principal component analysis, uniform manifold approximation and projection, and unsupervised hierarchal cell clustering of scRNA-seq data derived from central corneal cells of male rabbits, we successfully identified several clusters representing different corneal cell types, including a unique cell cluster representing nm-cSCs. To confirm protein expression of cSC genes, we performed cross-species validation, employing corneal whole-mount immunostaining with confocal microscopy in mouse corneas. The expression of several representative proteins of nm-cSCs were validated. As the proteolipid protein 1 (PLP1) gene was also expressed in nm-cSCs, we explored the Plp1-eGFP transgenic reporter mouse line to visualize cSCs. Specific and efficient eGFP expression was observed in cSCs in adult mice of different ages. Of several putative cornea-specific SC genes identified, Dickkopf-related protein 1 was shown to be present in nm-cSCs. Taken together, our findings, for the first time, identify important insights and tools toward the study nm-cSCs in isolated tissue and adult animals. We expect that our results will advance the future study of nm-cSCs in applications of nerve repair, and provide a resource for the study of corneal sensory function.
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Affiliation(s)
- Paola Bargagna‐Mohan
- Department of NeuroscienceUniversity of Connecticut Health CenterFarmingtonCTUSA
| | - Gwendolyn Schultz
- Department of NeuroscienceUniversity of Connecticut Health CenterFarmingtonCTUSA
| | - Bruce Rheaume
- Department of NeuroscienceUniversity of Connecticut Health CenterFarmingtonCTUSA
| | | | - Paul Robson
- Department of Genetics & Genome SciencesUniversity of Connecticut Health CenterFarmingtonCTUSA
- The Jackson Laboratory for Genomic MedicineFarmingtonCTUSA
| | - Sonali Pal‐Ghosh
- Department of Anatomy and Regenerative BiologyGeorge Washington University Medical SchoolWashingtonDCUSA
| | - Mary Ann Stepp
- Department of Anatomy and Regenerative BiologyGeorge Washington University Medical SchoolWashingtonDCUSA
| | - Katherine S. Given
- Department of Cell and Developmental BiologyUniversity of Colorado School of MedicineAuroraCOUSA
| | - Wendy B. Macklin
- Department of Cell and Developmental BiologyUniversity of Colorado School of MedicineAuroraCOUSA
| | - Royce Mohan
- Department of NeuroscienceUniversity of Connecticut Health CenterFarmingtonCTUSA
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22
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Sugioka K, Fukuda K, Nishida T, Kusaka S. The fibrinolytic system in the cornea: A key regulator of corneal wound healing and biological defense. Exp Eye Res 2021; 204:108459. [PMID: 33493476 DOI: 10.1016/j.exer.2021.108459] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2020] [Revised: 01/05/2021] [Accepted: 01/18/2021] [Indexed: 12/16/2022]
Abstract
The cornea is a relatively unique tissue in the body in that it possesses specific features such as a lack of blood vessels that contribute to its transparency. The cornea is supplied with soluble blood components such as albumin, globulin, and fibrinogen as well as with nutrients, oxygen, and bioactive substances by diffusion from aqueous humor and limbal vessels as well as a result of its exposure to tear fluid. The healthy cornea is largely devoid of cellular components of blood such as polymorphonuclear leukocytes, monocytes-macrophages, and platelets. The location of the cornea at the ocular surface renders it susceptible to external insults, and its avascular nature necessitates the operation of healing and defense mechanisms in a manner independent of a direct blood supply. The fibrinolytic system, which was first recognized for its role in the degradation of fibrin clots in the vasculature, has also been found to contribute to various biological processes outside of blood vessels. Fibrinolytic factors thus play an important role in biological defense of the cornea. In this review, we address the function of the fibrinolytic system in corneal defense including wound healing and the inflammatory response.
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Affiliation(s)
- Koji Sugioka
- Department of Ophthalmology, Kindai University Nara Hospital, 1248-1 Otodacho, Ikoma City, Nara, 630-0293, Japan; Department of Ophthalmology, Kindai University Faculty of Medicine, 377-2 Ohno-higashi, Osakasayama City, Osaka, 589-8511, Japan.
| | - Ken Fukuda
- Department of Ophthalmology and Visual Science, Kochi Medical School, Kochi University, Nankoku City, Kochi, 783-8505, Japan
| | - Teruo Nishida
- Department of Ophthalmology, Kindai University Nara Hospital, 1248-1 Otodacho, Ikoma City, Nara, 630-0293, Japan; Department of Ophthalmology, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube City, Yamaguchi, 755-8505, Japan; Division of Cornea and Ocular Surface, Ohshima Eye Hospital, 11-8 Kamigofukumachi, Hakata-ku, Fukuoka City, Fukuoka, 812-0036, Japan
| | - Shunji Kusaka
- Department of Ophthalmology, Kindai University Faculty of Medicine, 377-2 Ohno-higashi, Osakasayama City, Osaka, 589-8511, Japan
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Sinha S, Singh RB, Dohlman TH, Wang M, Taketani Y, Yin J, Dana R. Prevalence of Persistent Corneal Epithelial Defects in Chronic Ocular Graft-Versus-Host Disease. Am J Ophthalmol 2020; 218:296-303. [PMID: 32717268 DOI: 10.1016/j.ajo.2020.05.035] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Revised: 05/22/2020] [Accepted: 05/25/2020] [Indexed: 12/15/2022]
Abstract
PURPOSE To establish the prevalence, clinical characteristics, and risk factors for persistent corneal epithelial defects (PED) in patients with chronic ocular graft-versus-host disease (oGVHD) and to determine visual outcomes after healing. DESIGN Retrospective cohort study. METHODS A chart review was conducted of patients in whom chronic oGVHD was diagnosed between January 2011 and December 2018 and their demographic and clinical characteristics were collected. Data were analyzed to determine prevalence of PED, and multivariate logistic regression was performed to determine the risk factors associated with it. RESULTS A total of 405 patients at a mean age of 60 ± 13 years in whom chronic oGVHD was diagnosed; 58% were men. The prevalence of PED was 8.1%. The median time for PED development after hematopoietic stem cell transplantation was approximately 24 months. Median time to PED resolution was 4.5 weeks after starting therapy. The mean best-corrected visual acuity declined by 2 lines post-PED resolution. The prevalence rates of corneal ulcer and perforation were 6.2% and 4.0%, respectively, over 8 years. Logistic regression analysis, used to determine factors associated with PED, showed diabetes (P = .006), limbal stem cell deficiency (LSCD) (P = .02), filamentary keratitis (P = .02), subconjunctival fibrosis (P = .02), and a higher National Institutes of Health (NIH) oGVHD score (P = .01) were significant risk factors for PED development. CONCLUSIONS The study found the prevalence rate of PED, corneal ulceration, and corneal perforation in chronic oGVHD to be 8.1%, 6.2%, and 4%, respectively. Analysis showed that oGVHD patients with diabetes, LSCD, filamentary keratitis, subconjunctival fibrosis, and a high NIH score were at higher risk of developing severe corneal disease.
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24
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Fukuda K. Corneal fibroblasts: Function and markers. Exp Eye Res 2020; 200:108229. [PMID: 32919991 DOI: 10.1016/j.exer.2020.108229] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Revised: 09/01/2020] [Accepted: 09/03/2020] [Indexed: 02/06/2023]
Abstract
Corneal stromal keratocytes contribute to the maintenance of corneal transparency and shape by synthesizing and degrading extracellular matrix. They are quiescent in the healthy cornea, but they become activated in response to insults from the external environment that breach the corneal epithelium, with such activation being associated with phenotypic transformation into fibroblasts. Corneal fibroblasts (activated keratocytes) act as sentinel cells to sense various external stimuli-including damage-associated molecular patterns derived from injured cells, pathogen-associated molecular patterns of infectious microorganisms, and inflammatory mediators such as cytokines-under pathological conditions such as trauma, infection, and allergy. The expression of various chemokines and adhesion molecules by corneal fibroblasts determines the selective recruitment and activation of inflammatory cells in a manner dependent on the type of insult. In infectious keratitis, the interaction of corneal fibroblasts with various components of microbes and with cytokines derived from infiltrated inflammatory cells results in excessive degradation of stromal collagen and consequent corneal ulceration. Corneal fibroblasts distinguish between type 1 and type 2 inflammation through recognition of corresponding cytokines, with their activation by type 2 cytokines contributing to the pathogenesis of corneal lesions in severe ocular allergic diseases. Pharmacological targeting of corneal fibroblast function is thus a potential novel therapeutic approach to prevention of excessive corneal stromal inflammation, damage, and scarring.
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Affiliation(s)
- Ken Fukuda
- Department of Ophthalmology and Visual Science, Kochi Medical School, Kochi University, Oko-cho, Nankoku City, Kochi, 783-8505, Japan.
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25
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Park GW, Heo J, Kang JY, Yang JW, Kim JS, Kwon KD, Yu BC, Lee SJ. Topical cell-free conditioned media harvested from adipose tissue-derived stem cells promote recovery from corneal epithelial defects caused by chemical burns. Sci Rep 2020; 10:12448. [PMID: 32709896 PMCID: PMC7381646 DOI: 10.1038/s41598-020-69020-z] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2019] [Accepted: 06/29/2020] [Indexed: 02/07/2023] Open
Abstract
Corneal chemical burns can lead to blindness following serious complications. As most of these complications are caused by failure of reepithelization during the acute phase, treatment at this stage is critical. Although there have been some studies on corneal injury recovery using adipose tissue-derived stem cells (ADSCs), none has reported the effect of topical cell-free conditioned culture media (CM) derived from ADSCs on corneal epithelial regeneration. Here, the best conditions for CM were selected and used for in vitro and in vivo experiments. Corneal burn in rats was induced using 100% alcohol. The chosen CM was administered to corneal burn rats (CM-treated [CT] group) four times a day for three days and this group was compared with the normal control and corneal burn (CB) groups. Biomicroscopic fluorescence images and the actual physical corneas were taken over time and used for analysis. mRNA levels of hepatocyte growth factor and epidermal growth factor (EGF) were significantly increased, whereas those of vascular endothelial growth factor, interleukin (IL)-1β, IL-6, IL-10, and matrix metalloproteinase-9 were significantly decreased in the CT group compared with those in the CB group. The numbers of proliferating cell nuclear antigen- and zonular occludens-1-positive cells in the CT group were significantly higher than those in the CB group. The macrophage-infiltrating corneas in the CT group expressed significantly more of the M2 marker arginase than corneas in the CB group. Optimal CM (× 0.5 concentration) treatment significantly accelerated the migration of corneal epithelial cells and induced upregulation of the expression of IL-6, EGF, and C-X-C chemokine receptor type 4 mRNAs. Overall, in this study, topical administration of cell-free CM promoted regeneration of the corneal epithelium after induction of chemical burns.
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Affiliation(s)
| | - Jeonghoon Heo
- Department of Molecular Biology and Immunology, College of Medicine, Kosin University, Busan, Korea
| | | | - Ji Won Yang
- Stem Bank Company, Busan, Korea
- Department of Ophthalmology, College of Medicine, Kosin University, #34 Amnam-dong, Suh-ku, Busan, 602-702, Korea
| | - Jong Sik Kim
- Department of Anatomy, College of Medicine, Kosin University, Busan, Korea
| | - Ki Dong Kwon
- Department of Ophthalmology, College of Medicine, Kosin University, #34 Amnam-dong, Suh-ku, Busan, 602-702, Korea
| | - Byung Chul Yu
- Department of Preventive Medicine, College of Medicine, Kosin University, Busan, Korea
| | - Sang Joon Lee
- Department of Ophthalmology, College of Medicine, Kosin University, #34 Amnam-dong, Suh-ku, Busan, 602-702, Korea.
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Pillai A, Patel S, Ranadive I, Desai I, Balakrishnan S. Fibroblast growth factor-2 signaling modulates matrix reorganization and cell cycle turnover rate in the regenerating tail of Hemidactylus flaviviridis. Acta Histochem 2020; 122:151464. [PMID: 31780191 DOI: 10.1016/j.acthis.2019.151464] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2019] [Revised: 11/06/2019] [Accepted: 11/06/2019] [Indexed: 12/17/2022]
Abstract
Lizards restore their lost tail by the recruitment of multipotent cells which are selectively differentiated into varied cell types so as to sculpt a new tail. The precise coordination of the events involved in this complex process requires crosstalk between many signaling molecules and differential regulation of several mediators that facilitate the achievements of various milestones of regeneration. Fibroblast growth factor-2 is one such signaling molecule which activates a number of intracellular signaling pathways. Herein, the regulatory role of FGF2 during tail regeneration in Hemidactylus flaviviridis was investigated. Upon inhibition of FGFR using SU5402, the FGF2 levels were found to be significantly reduced at both transcript and protein level. Further, the compromised levels of the gelatinases, namely MMP2 and MMP9 in the tail tissues of treated lizards indicate that FGF2 regulates the activity of these enzymes perhaps to facilitate the recruitment of multipotent mesenchymal cells (blastema). The in vivo 5BrdU incorporation assay showed a lower cell proliferation rate in FGF2 signal inhibited animals during all the proliferative stages of regeneration studied. This observation was substantiated by decreased levels of PCNA in treated group. Moreover, from the combined results of Caspase-3 localization and its expression levels in the regenerates of control and SU5402 treated lizards it can be deduced that FGF2 signal regulates apoptosis as well during early stages of regeneration. Overall, the current study indicates beyond doubt that FGF2 signaling plays a pivotal role in orchestrating the matrix reorganization and cell cycle turnover during lizard tail regeneration.
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Wei A, Wang K, Wang Y, Gong L, Xu J, Shao T. Evaluation of corneal cross-linking as adjuvant therapy for the management of fungal keratitis. Graefes Arch Clin Exp Ophthalmol 2019; 257:1443-1452. [PMID: 31041523 DOI: 10.1007/s00417-019-04314-1] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2018] [Revised: 02/27/2019] [Accepted: 04/01/2019] [Indexed: 11/26/2022] Open
Abstract
PURPOSE To evaluate the efficacy of corneal cross-linking (CXL) as adjuvant therapy for the treatment of fungal ulcerative keratitis. METHODS Forty-one patients with fungal ulcerative keratitis were recruited and assigned into two randomized controlled groups. These groups were treated with CXL combined with antifungal medications (CXL-M) or antifungal medications alone (M). The ulcers were assessed by slit-lamp biomicroscopy, slit-lamp images, in vivo confocal microscopy (IVCM), and anterior segment optical coherence tomography (AS-OCT). The patients were followed up before surgery/first visit (FV), 1 day after surgery, 1 and 2 weeks, and 1, 2, 3, 4, 5, and 6 months after surgery/FV. RESULTS In the cured patients, the area of corneal ulcers, the duration of ulcer healing, the time to non-observed fungal hyphae by IVCM, the number of antifungal medications, the frequency of administered medications, and the maximum ulcer depth decreased significantly after CXL (all P < 0.05) compared with the M group. There were no significant differences in either corneal thickness or epithelial thickness of ulcers after healing between 5 and 6 months after surgery in the CXL-M group, while these were increased significantly at 6 months compared with 5 months after FV in the M group (both P < 0.05). CONCLUSIONS In our study, CXL accelerated healing of the fungal ulcers, shortened the treatment duration, and minimized the need for medications and surgery. It appears that CXL is an effective procedure and adjuvant therapy for managing fungal keratitis.
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Affiliation(s)
- Anji Wei
- Department of Ophthalmology, Eye, Ear, Nose, and Throat Hospital, School of Shanghai Medicine, Fudan University, 83 Fenyang Road, Shanghai, 20003, China
| | - Kaidi Wang
- Department of Ophthalmology, Eye, Ear, Nose, and Throat Hospital, School of Shanghai Medicine, Fudan University, 83 Fenyang Road, Shanghai, 20003, China
| | - Yan Wang
- Department of Ophthalmology, Eye, Ear, Nose, and Throat Hospital, School of Shanghai Medicine, Fudan University, 83 Fenyang Road, Shanghai, 20003, China
| | - Lan Gong
- Department of Ophthalmology, Eye, Ear, Nose, and Throat Hospital, School of Shanghai Medicine, Fudan University, 83 Fenyang Road, Shanghai, 20003, China
| | - Jianjiang Xu
- Department of Ophthalmology, Eye, Ear, Nose, and Throat Hospital, School of Shanghai Medicine, Fudan University, 83 Fenyang Road, Shanghai, 20003, China
| | - Tingting Shao
- Department of Ophthalmology, Eye, Ear, Nose, and Throat Hospital, School of Shanghai Medicine, Fudan University, 83 Fenyang Road, Shanghai, 20003, China.
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Giannaccare G, Pellegrini M, Taroni L, Bernabei F, Senni C, Grendele A, Scorcia V, Campos EC. Corneal biomechanical alterations in patients with chronic ocular Graft Versus-Host Disease. PLoS One 2019; 14:e0213117. [PMID: 31022204 PMCID: PMC6483170 DOI: 10.1371/journal.pone.0213117] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2019] [Accepted: 04/11/2019] [Indexed: 12/14/2022] Open
Abstract
Purpose To compare corneal biomechanics between patients with ocular graft versus-host disease (oGVHD) and healthy subjects (controls), and to further correlate these values with ocular and hematological characteristics. Materials and methods The following procedures were performed in oGVHD patients and controls: Schirmer test (ST), break-up time (BUT), corneal and conjunctival staining, tear matrix metalloproteinase-9 (MMP-9) assay (InflammaDry test, Rapid Pathogen Screening, Inc, Sarasota, FL). Corneal biomechanics were calculated by using ocular response analyzer (ORA, Reichert Instruments, Depew, New York, USA). The Mann-Whitney U test was used to compare continuous variables between oGVHD patients and controls. Correlations of corneal biomechanics with ocular and hematological parameters were examined using Spearman's correlation. Results A total of 45 oGVHD patients (mean age ± SD, 51.5 ± 7.1 years) and 34 controls (47.8 ± 6.1 years) were included. Patients with oGVHD showed significantly lower values of corneal hysteresis (CH) and corneal resistance factor (CRF) compared to controls (respectively, 9.4 ± 1.8 mmHg vs 11.6 ± 1.6 and 9.7 ± 1.4 mmHg vs 12.3 ± 1.3; always p<0.001). Twenty-nine of the oGVHD eyes (64.4%) were strong-positive for MMP-9, while 16 (35.6%) were weak-positive. Conversely, only 4 of the control eyes (11.8%) were weak-positive for MMP-9. In patients with oGVHD, CH was significantly correlated with corneal staining (Rs = -0.316, p = 0.035), conjunctival staining (Rs = -0.437, p = 0.003), ST (Rs = 0.390, p = 0.008), BUT (Rs = 0.423, p = 0.004), oGVHD severity grade (Rs = -0.383, p = 0.009), and MMP-9 positivity grade (Rs = -0.429, p = 0.003), while CRF was correlated only with corneal staining (Rs = -0.317, p = 0.034). Conclusions Corneal biomechanics are reduced in patients with oGVHD, and CH is negatively correlated with disease severity grade and MMP-9 tear levels.
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Affiliation(s)
- Giuseppe Giannaccare
- Ophthalmology Unit, S.Orsola-Malpighi University Hospital, University of Bologna, Bologna, Italy
- * E-mail:
| | - Marco Pellegrini
- Ophthalmology Unit, S.Orsola-Malpighi University Hospital, University of Bologna, Bologna, Italy
| | - Leonardo Taroni
- Ophthalmology Unit, S.Orsola-Malpighi University Hospital, University of Bologna, Bologna, Italy
| | - Federico Bernabei
- Ophthalmology Unit, S.Orsola-Malpighi University Hospital, University of Bologna, Bologna, Italy
| | - Carlotta Senni
- Ophthalmology Unit, S.Orsola-Malpighi University Hospital, University of Bologna, Bologna, Italy
| | - Arianna Grendele
- Ophthalmology Unit, S.Orsola-Malpighi University Hospital, University of Bologna, Bologna, Italy
| | - Vincenzo Scorcia
- Department of Ophthalmology, University of “Magna Graecia”, Catanzaro, Italy
| | - Emilio C. Campos
- Ophthalmology Unit, S.Orsola-Malpighi University Hospital, University of Bologna, Bologna, Italy
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Dua HS, Said DG, Messmer EM, Rolando M, Benitez-del-Castillo JM, Hossain PN, Shortt AJ, Geerling G, Nubile M, Figueiredo FC, Rauz S, Mastropasqua L, Rama P, Baudouin C. Neurotrophic keratopathy. Prog Retin Eye Res 2018; 66:107-131. [DOI: 10.1016/j.preteyeres.2018.04.003] [Citation(s) in RCA: 253] [Impact Index Per Article: 36.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2017] [Revised: 04/05/2018] [Accepted: 04/06/2018] [Indexed: 01/09/2023]
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Cruzat A, Gonzalez-Andrades M, Mauris J, AbuSamra DB, Chidambaram P, Kenyon KR, Chodosh J, Dohlman CH, Argüeso P. Colocalization of Galectin-3 With CD147 Is Associated With Increased Gelatinolytic Activity in Ulcerating Human Corneas. Invest Ophthalmol Vis Sci 2018; 59:223-230. [PMID: 29340650 PMCID: PMC5771460 DOI: 10.1167/iovs.17-23196] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Purpose Galectin-3 is a carbohydrate-binding protein known to promote expression of matrix metalloproteinases, a hallmark of ulceration, through interaction with the extracellular matrix metalloproteinase inducer CD147. The aim of this study was to investigate the distribution of galectin-3 in corneas of patients with ulcerative keratitis and to determine its relationship to CD147 and the presence of gelatinolytic activity. Methods This was an observational case series involving donor tissue from 13 patients with active corneal ulceration and 6 control corneas. Fixed-frozen sections of the corneas were processed to localize galectin-3 and CD147 by immunofluorescence microscopy. Gelatinolytic activity was detected by in situ zymography. Results Tissue from patients with active corneal ulceration showed a greater galectin-3 immunoreactivity in basal epithelia and stroma compared with controls. Immunofluorescence grading scores revealed increased colocalization of galectin-3 and CD147 in corneal ulcers at the epithelial–stromal junction and within fibroblasts. Quantitative analysis using the Manders' colocalization coefficient demonstrated significant overlap in corneas from patients with ulcerative keratitis (M1 = 0.29; M2 = 0.22) as opposed to control corneas (M1 = 0.01, P < 0.01; M2 = 0.02, P < 0.05). In these experiments, there was a significant positive correlation between the degree of galectin-3 and CD147 colocalization and the presence of gelatinolytic activity. Conclusions Our results indicate that concomitant stimulation and colocalization of galectin-3 with CD147 are associated with increased gelatinolytic activity in the actively ulcerating human cornea and suggest a mechanism by which galectin-3 may contribute to the degradation of extracellular matrix proteins during ulceration.
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Affiliation(s)
- Andrea Cruzat
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States.,Department of Ophthalmology, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Miguel Gonzalez-Andrades
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States
| | - Jérôme Mauris
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States
| | - Dina B AbuSamra
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States
| | - Preethi Chidambaram
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States
| | - Kenneth R Kenyon
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States.,New England Eye Center and Department of Ophthalmology, Tufts University, Boston, Massachusetts, United States
| | - James Chodosh
- Howe Laboratory and Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States
| | - Claes H Dohlman
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States
| | - Pablo Argüeso
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States
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Comparison of Collagen Cross-Linking and Amniotic Membrane Transplantation in an Experimental Alkali Burn Rabbit Model. Cornea 2018; 36:1106-1115. [PMID: 28704317 DOI: 10.1097/ico.0000000000001276] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
PURPOSE To compare the effects of collagen cross-linking (CXL) and amniotic membrane transplantation (AMT) on acute corneal alkali burns. METHODS After establishment of an alkali burn model, 32 rabbits were divided into 4 groups: control group, AMT group, CXL group, and AMT + CXL (combined) group. Clinical parameters, including epithelial wound, opacity, ulceration, and neovascularization, were evaluated on postinjury days 1, 7, 14, and 18. Histological parameters were examined in hematoxylin/eosin (H&E) and Masson trichrome-stained corneal sections. Immunohistochemical analyses, including a terminal deoxynucleotidyl transferase-mediated biotin-deoxyuridine triphosphate nick-end labeling assay and cluster of differentiation 68 (CD68) labeling, were performed to determine the apoptotic index and macrophage activation. RESULTS On postinjury day 18, the epithelial wound of AMT {4.08% [interquartile range (IQR), 0.68%-5.22%]}, CXL [1.84% (IQR, 0.01%-3.89%)], and combined [3.44% (IQR, 0.01%-4.36%)] groups were significantly lower than the control [15.23% (IQR, 9.86%-23.06%)] group (P = 0.003). No significant difference was detected between the groups in terms of opacity (P = 0.303). Neovascularization was the least severe in the CXL group [16.18% (IQR, 8.39%-21.28%)] and the most severe in the AMT [34.47% (IQR, 17.71%-62.77%)] and combined [35.12% (IQR, 31.96%-59.98%)] groups on day 18 (P = 0.033). Significant increases in the apoptotic index and CD68 labeling were detected in the CXL and combined groups compared with those in the control group (P = 0.047 and P = 0.001, respectively). CONCLUSIONS CXL treatment is an effective adjuvant treatment for promoting reepithelialization, reducing inflammation and neovascularization, and preventing ulceration in acute alkali burns. Providing AMT after suppressing inflammation may be a more effective treatment.
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Liu Y, Huang Y, Xu Y, Qu P, Wang M. Memantine protects against ischemia/reperfusion-induced brain endothelial permeability. IUBMB Life 2018. [PMID: 29542225 DOI: 10.1002/iub.1729] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Affiliation(s)
- Yingying Liu
- Department of neurology; The fifth Affiliated Hospital of Harbin Medical University; Daqian Heilongjiang China
| | - Yudiao Huang
- Department of neurology; The fifth Affiliated Hospital of Harbin Medical University; Daqian Heilongjiang China
| | - Yueyue Xu
- Department of Nursing; The fifth Affiliated Hospital of Harbin Medical University; Daqian Heilongjiang China
| | - Peng Qu
- Department of neurology; The fifth Affiliated Hospital of Harbin Medical University; Daqian Heilongjiang China
| | - Minghua Wang
- Department of neurology; The fifth Affiliated Hospital of Harbin Medical University; Daqian Heilongjiang China
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Masuda I, Matsuo T, Okamoto K, Matsushita K, Ohtsuki H. Two Cases of Corneal Perforation after Oral Administration of Nonsteroidal Anti-Inflammatory Drugs: Oral Nsaid-Induced Corneal Damage. Eur J Ophthalmol 2018; 20:454-6. [DOI: 10.1177/112067211002000230] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Affiliation(s)
- Ikuya Masuda
- Department of Ophthalmology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama
| | - Toshihiko Matsuo
- Department of Ophthalmology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama
| | - Kazuo Okamoto
- Department of Ophthalmology, Kawasaki Hospital, Kawasaki Medical School, Okayama - Japan
| | - Kyoko Matsushita
- Department of Ophthalmology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama
| | - Hiroshi Ohtsuki
- Department of Ophthalmology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama
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Cheng BF, Gao YX, Lian JJ, Guo DD, Liu TT, Xie YF, Wang L, Yang HJ, Wang M, Feng ZW. Anti-inflammatory effects of pitavastatin in interleukin-1β-induced SW982 human synovial cells. Int Immunopharmacol 2017; 50:224-229. [DOI: 10.1016/j.intimp.2017.06.032] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2017] [Revised: 06/09/2017] [Accepted: 06/28/2017] [Indexed: 02/06/2023]
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Wolf M, Maltseva I, Clay SM, Pan P, Gajjala A, Chan MF. Effects of MMP12 on cell motility and inflammation during corneal epithelial repair. Exp Eye Res 2017; 160:11-20. [PMID: 28442300 DOI: 10.1016/j.exer.2017.04.007] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2016] [Revised: 03/31/2017] [Accepted: 04/18/2017] [Indexed: 11/25/2022]
Abstract
Corneal epithelial defects are a common cause of ocular morbidity and can result in corneal scarring if they do not heal properly. Matrix metalloproteinases (MMPs) are extracellular matrix proteinases that regulate multiple aspects of corneal repair. We have previously shown that MMP12 has a protective effect on corneal fibrosis through its regulation of neutrophil and macrophage infiltration and angiogenesis in a chemical injury model involving full thickness damage to the cornea. However, the role of MMP12 in injuries limited to the corneal epithelium is relatively unknown. This study investigates the reparative effects of MMP12 following isolated corneal epithelial injury. Using a corneal epithelial debridement injury model performed on corneas of wild-type (WT) mice, we show that Mmp12 is expressed early following corneal epithelial injury with highest expression levels at 8 h after injury and lower expression levels at 4 and 8 days after injury. We investigated whether MMP12 has an effect on the rate of epithelial repair and cell migration using in vivo and in vitro scratch assays performed on WT and Mmp12-/- mice. We found that loss of MMP12 results in a slower scratch wound repair rate both in vivo and in vitro. We also found that corneas of Mmp12-/- mice have decreased neutrophil infiltration following injury. Loss of MMP12, however, does not affect cell proliferation in the center of the wounds. These data support a role of MMP12 in promoting early repair processes following corneal epithelial injury by enhancing epithelial cell migration and neutrophil infiltration.
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Affiliation(s)
- Marie Wolf
- Department of Ophthalmology, University of California, San Francisco, CA, United States
| | - Inna Maltseva
- Department of Anatomy, University of California, San Francisco, CA, United States
| | - Selene M Clay
- Department of Ophthalmology, University of California, San Francisco, CA, United States
| | - Peipei Pan
- Department of Ophthalmology, University of California, San Francisco, CA, United States
| | - Abhinay Gajjala
- University of Rochester School of Medicine and Dentistry, Rochester, NY, United States
| | - Matilda F Chan
- Department of Ophthalmology, University of California, San Francisco, CA, United States; Francis I. Proctor Foundation, University of California, San Francisco, CA, United States.
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McKay TB, Hjortdal J, Priyadarsini S, Karamichos D. Acute hypoxia influences collagen and matrix metalloproteinase expression by human keratoconus cells in vitro. PLoS One 2017; 12:e0176017. [PMID: 28426715 PMCID: PMC5398580 DOI: 10.1371/journal.pone.0176017] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2017] [Accepted: 04/04/2017] [Indexed: 01/10/2023] Open
Abstract
Keratoconus (KC) is a progressive corneal ectasia linked to thinning of the central cornea. Hard contact lenses, rigid gas permeable lenses, and scleral lenses are the primary treatment modalities for early to mid- stages of KC to correct refractive error and astigmatism that develops as a result of an irregular corneal structure. These treatments are associated with significant drawbacks, including reduced availability of the tear film and oxygen to the corneal epithelium and stroma. However, it remains unknown whether hypoxia affects corneal integrity in the KC pathobiology. A number of studies have associated elevated oxidative stress with KC both in vitro and ex vivo. We hypothesized that KC-derived corneal fibroblasts are more susceptible to hypoxia-induced oxidative stress compared to healthy controls leading to exacerbation of corneal thinning in KC. This study investigated the effects of hypoxia on ECM secretion, assembly, and matrix metalloproteinase (MMP) expression in human corneal fibroblasts from healthy controls (HCFs) and KC patients (HKCs) in vitro. HCFs and HKCs were cultured in 3D constructs for 3 weeks and maintained or transferred to normoxic (21% O2) or hypoxic (2% O2) conditions, respectively, for 1 additional week. At the 4 week time-point, constructs were isolated and probed for Collagen I, III, and V, keratocan and MMP-1, -2, -3, -9, and -13, as well as hypoxia markers, hypoxia inducible factor-1α and lactoferrin. Conditioned media was also collected and probed for Collagen I, III, and V by Western blot. Thickness of the ECM assembled by HCFs and HKCs was measured using immunofluorescence microscopy. Results showed that hypoxia significantly reduced Collagen I secretion in HKCs, as well as upregulated the expression of MMP-1 and -2 with no significant effects on MMP-3, -9, or -13. ECM thickness was reduced in both cell types following 1 week in a low oxygen environment. Our study shows that hypoxia influences collagen and MMP expression by HKCs, which may have consequential effects on ECM structure in the context of KC.
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Affiliation(s)
- Tina B. McKay
- Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States of America
| | - Jesper Hjortdal
- Department of Ophthalmology, Aarhus University Hospital, Aarhus, Denmark
| | - Shrestha Priyadarsini
- Department of Ophthalmology/Dean McGee Eye Institute, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States of America
| | - Dimitrios Karamichos
- Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States of America
- Department of Ophthalmology/Dean McGee Eye Institute, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States of America
- * E-mail:
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Arafat SN, Robert MC, Abud T, Spurr-Michaud S, Amparo F, Dohlman CH, Dana R, Gipson IK. Elevated Neutrophil Elastase in Tears of Ocular Graft-Versus-Host Disease Patients. Am J Ophthalmol 2017; 176:46-52. [PMID: 28073648 DOI: 10.1016/j.ajo.2016.12.026] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2016] [Revised: 12/27/2016] [Accepted: 12/30/2016] [Indexed: 12/20/2022]
Abstract
PURPOSE To investigate the levels of neutrophil elastase (NE), matrix metalloproteinases (MMPs), and myeloperoxidase (MPO) in tear washes of patients with ocular graft-vs-host disease (oGVHD). DESIGN Case-control study. METHODS Based on established criteria, oGVHD patients (n = 14; 28 eyes) and age-/sex-matched healthy controls (n = 14; 28 eyes) were enrolled. Tear washes were collected and analyzed for NE using a single-analyte enzyme-linked immunosorbent assay (ELISA). MMPs (1, 2, 3, 7, 8, 9, 12), MPO, and tissue inhibitor of matrix metalloproteinase (TIMP)-1 were analyzed using multianalyte bead-based ELISA assays. Total MMP activity was measured using a fluorimetric assay. Correlation studies were performed between NE, MMP-8, MMP-9, and MPO within study groups. RESULTS NE, MMP-8, MMP-9, and MPO levels were elevated in oGVHD tears when compared with controls (P < .0001). NE was the most elevated analyte. MMP activity was higher and TIMP-1 levels were lower in oGVHD than in control (P < .0001). In oGVHD, NE significantly correlated with MMP-8 (r = 0.92), MMP-9 (r = 0.90), and MPO (r = 0.79) (P < .0001). MMP-8 correlated with MMP-9 (r = 0.96, P < .0001), and MPO (r = 0.60, P = .001). MMP-9 correlated with MPO (r = 0.55, P = .002). In controls, NE, MMP-9, and MPO significantly correlated with each other (P < .0001). CONCLUSIONS The marked increase in NE in oGVHD tears that correlated strongly with elevated MMP-8, MMP-9, and MPO suggests a common neutrophilic source and provides evidence of neutrophil activity on the ocular surface of oGVHD patients.
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Affiliation(s)
- Samer N Arafat
- Schepens Eye Research Institute-Massachusetts Eye and Ear, Harvard Medical School, Boston, Massachusetts; Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts
| | - Marie-Claude Robert
- Schepens Eye Research Institute-Massachusetts Eye and Ear, Harvard Medical School, Boston, Massachusetts; Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts
| | - Tulio Abud
- Schepens Eye Research Institute-Massachusetts Eye and Ear, Harvard Medical School, Boston, Massachusetts; Department of Ophthalmology and Visual Sciences, Paulista School of Medicine, Federal University of Sao Paulo-UNIFESP, Sao Paulo, Brazil
| | - Sandra Spurr-Michaud
- Schepens Eye Research Institute-Massachusetts Eye and Ear, Harvard Medical School, Boston, Massachusetts
| | - Francisco Amparo
- Schepens Eye Research Institute-Massachusetts Eye and Ear, Harvard Medical School, Boston, Massachusetts; Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts
| | - Claes H Dohlman
- Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts
| | - Reza Dana
- Schepens Eye Research Institute-Massachusetts Eye and Ear, Harvard Medical School, Boston, Massachusetts; Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts
| | - Ilene K Gipson
- Schepens Eye Research Institute-Massachusetts Eye and Ear, Harvard Medical School, Boston, Massachusetts.
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Tear Matrix Metalloproteinases and Myeloperoxidase Levels in Patients With Boston Keratoprosthesis Type I. Cornea 2017; 35:1008-14. [PMID: 27191670 DOI: 10.1097/ico.0000000000000893] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
PURPOSE To investigate the tear levels of matrix metalloproteinases (MMPs), myeloperoxidase (MPO), and tissue inhibitor of metalloproteinase-1 in eyes after Boston keratoprosthesis type I (B-KPro) implantation and to correlate these markers with the established B-KPro prognostic categories. METHODS Tear washes were collected from 40 patients (7 with autoimmune disease, 2 with chemical burn, and 31 with other noncicatrizing diagnoses). Tear levels of MMPs, MPO, and tissue inhibitor of metalloproteinase-1 were quantified using multianalyte bead-based enzyme-linked immunosorbent assays. The total MMP activity was determined using a fluorimetric assay. The analytes were compared to the underlying diagnosis and other clinical factors. RESULTS The MMP-8, MMP-9, and MPO levels were markedly elevated in the eyes with B-KPro (80 ± 31, 291 ± 77, and 244 ± 33 pg/μg, respectively). Chemical burn was associated with significantly higher tear MMP-8 (474 ± 376 pg/μg) and MMP-9 levels (1300 ± 635 pg/μg) compared with noncicatrizing diseases (MMP-8: 41 ± 15 pg/μg, P = 0.02 and MMP-9: 196 ± 57 pg/μg, P = 0.02) and higher MMP-9 levels compared with autoimmune diseases (MMP-8: 96 ± 65 pg/μg, P = 0.21 and MMP-9: 306 ± 196 pg/μg, P = 0.04). Similar analyte levels were observed in the B-KPro eye and the contralateral non-B-KPro eye of patients with bilateral diseases. MMP-8, MMP-9, and total MMP activities correlated strongly with each other. CONCLUSIONS In the eyes with B-KPro, tear MMP-8 and MMP-9 levels seem to be related to the underlying ocular surface pathology and not significantly influenced by the presence of the prosthesis.
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Bouhout S, Robert MC, Deli S, Harissi-Dagher M. Corneal Melt after Boston Keratoprosthesis: Clinical Presentation, Management, Outcomes and Risk Factor Analysis. Ocul Immunol Inflamm 2017; 26:693-699. [PMID: 28080168 DOI: 10.1080/09273948.2016.1269930] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
PURPOSE To determine the presentation, risk factors, and outcomes of keratolysis after Boston type I keratoprosthesis (B-KPro). METHODS Retrospective chart review. RESULTS A total of 16 (14%) of the 110 eyes (96 patients) which underwent B-KPro implantation developed keratolysis at an average 20 ± 11 months. Retroprosthetic membrane (RPM), infectious keratitis, and corneal dellen were identified in 31%, 25%, and 13% of corneal melts, respectively. Five eyes had keratolysis without a readily identifiable cause. RPM (odds-ratio, OR = 4.4, p = 0.02) and infectious keratitis (OR = 17.6, p<0.0005) were confirmed as significant risk factors. Retinal detachment (p = 0.001) and choroidal detachment (p = 0.003) were more common in eyes with keratolysis. Management included B-KPro removal or exchange (n = 7), amniotic membrane transplantation (n = 1), tectonic corneal transplantation (n = 2), medical treatment (n = 4), and observation (n = 2). CONCLUSIONS The risk of keratolysis following B-Kpro increases with the development of RPM and infectious keratitis. Patients with keratolysis had higher complication rates and should receive rigorous monitoring.
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Affiliation(s)
- Soumaya Bouhout
- a Faculty of Medicine, McGill University , Montréal , Québec , Canada
| | - Marie-Claude Robert
- b Department of Ophthalmology , Centre Hospitalier de l'Université de Montréal , Montréal , Québec , Canada
| | - Sousans Deli
- c Faculty of Medicine, Université de Montréal , Montréal , Québec , Canada
| | - Mona Harissi-Dagher
- b Department of Ophthalmology , Centre Hospitalier de l'Université de Montréal , Montréal , Québec , Canada
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Liu Y, Kan M, Li A, Hou L, Jia H, Xin Y, Liu Y. Inhibitory Effects of Tranilast on Cytokine, Chemokine, Adhesion Molecule, and Matrix Metalloproteinase Expression in Human Corneal Fibroblasts Exposed to Poly(I:C). Curr Eye Res 2016; 41:1400-1407. [PMID: 27115203 DOI: 10.3109/02713683.2015.1127389] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Purpose/Aim: Viral infection of the cornea can result in inflammation and scarring and eventually cause blindness. Polyinosinic-polycytidylic acid [poly(I:C)], an analog of viral double-stranded RNA, induces the synthesis of various cytokines, chemokines, adhesion molecules, and matrix metalloproteinases (MMPs) in corneal fibroblasts. The effects of tranilast on the expression of these molecules in human corneal fibroblasts were examined. MATERIALS AND METHODS Human corneal fibroblasts were cultured with or without poly(I:C) or tranilast. The release of the proinflammatory cytokine interleukin (IL)-6 and of the chemokines IL-8 and monocyte chemotactic protein-1 (MCP-1) was measured with enzyme-linked immunosorbent assays. The expression of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), MMP-1, and MMP-3 was evaluated by immunoblot or immunofluorescence analysis. The phosphorylation of mitogen-activated protein kinases (MAPKs), c-Jun (a component of the transcription factor AP-1), and IκB-α (an endogenous inhibitor of the transcription factor NF-κB) was examined by immunoblot analysis. RESULTS Tranilast inhibited in a concentration- and time-dependent manner the production of IL-6, IL-8, MCP-1, ICAM-1, VCAM-1, MMP-1, and MMP-3 by corneal fibroblasts exposed to poly(I:C). It also inhibited the poly(I:C)-induced phosphorylation of c-Jun and the MAPK JNK without affecting that of IκB-α or the MAPKs ERK and p38. CONCLUSIONS Tranilast inhibited proinflammatory cytokine, chemokine, adhesion molecule, and MMP expression in human corneal fibroblasts exposed to poly(I:C), with these effects likely being mediated by attenuation of JNK-AP-1 signaling. Tranilast might therefore be expected to limit immune cell infiltration and stromal degradation associated with viral infection of the cornea.
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Affiliation(s)
- Ye Liu
- a Department of Pathology , First Hospital of Jilin University , Jilin , PR , China
| | - Mujie Kan
- b Department of Biochemistry , College of Basic Medicine, Jilin University , Jilin , PR China
| | - Aipeng Li
- c Department of Ophthalmology , First Hospital of Jilin University , Jilin , PR China
| | - Lulu Hou
- c Department of Ophthalmology , First Hospital of Jilin University , Jilin , PR China
| | - Hui Jia
- c Department of Ophthalmology , First Hospital of Jilin University , Jilin , PR China
| | - Ying Xin
- d Key Laboratory of Pathology, Ministry of Education , Jilin University , Jilin , PR China
| | - Yang Liu
- c Department of Ophthalmology , First Hospital of Jilin University , Jilin , PR China
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Walter MNM, Dehsorkhi A, Hamley IW, Connon CJ. Supra-molecular assembly of a lumican-derived peptide amphiphile enhances its collagen-stimulating activity. Biomater Sci 2016; 4:346-54. [PMID: 26626506 PMCID: PMC4743677 DOI: 10.1039/c5bm00428d] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2015] [Accepted: 11/20/2015] [Indexed: 11/21/2022]
Abstract
C16-YEALRVANEVTLN, a peptide amphiphile (PA) incorporating a biologically active amino acid sequence found in lumican, has been examined for its influence upon collagen synthesis by human corneal fibroblasts in vitro, and the roles of supra-molecular assembly and activin receptor-like kinase ALK receptor signaling in this effect were assessed. Cell viability was monitored using the Alamar blue assay, and collagen synthesis was assessed using Sirius red. The role of ALK signaling was studied by receptor inhibition. Cultured human corneal fibroblasts synthesized significantly greater amounts of collagen in the presence of the PA over both 7-day and 21-day periods. The aggregation of the PA to form nanotapes resulted in a notable enhancement in this activity, with an approximately two-fold increase in collagen production per cell. This increase was reduced by the addition of an ALK inhibitor. The data presented reveal a stimulatory effect upon collagen synthesis by the primary cells of the corneal stroma, and demonstrate a direct influence of supra-molecular assembly of the PA upon the cellular response observed. The effects of PA upon fibroblasts were dependent upon ALK receptor function. These findings elucidate the role of self-assembled nanostructures in the biological activity of peptide amphiphiles, and support the potential use of a self-assembling lumican derived PA as a novel biomaterial, intended to promote collagen deposition for wound repair and tissue engineering purposes.
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Affiliation(s)
- Merlin N M Walter
- Institute of Genetic Medicine, International Centre for Life, Newcastle University, Newcastle upon Tyne, NE1 3BZ, UK.
| | - Ashkan Dehsorkhi
- Department of Chemistry, University of Reading, Whiteknights, Reading, RG6 6AD, UK
| | - Ian W Hamley
- Department of Chemistry, University of Reading, Whiteknights, Reading, RG6 6AD, UK
| | - Che J Connon
- Institute of Genetic Medicine, International Centre for Life, Newcastle University, Newcastle upon Tyne, NE1 3BZ, UK.
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de Alba-Castilla MA, López-Rubio S, Rodríguez-García A. Síndrome erosivo corneal recurrente enmascarado como queratitis epitelial herpética. REVISTA MEXICANA DE OFTALMOLOGÍA 2015. [DOI: 10.1016/j.mexoft.2015.04.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022] Open
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Bian F, Pelegrino FSA, Pflugfelder SC, Volpe EA, Li DQ, de Paiva CS. Desiccating Stress-Induced MMP Production and Activity Worsens Wound Healing in Alkali-Burned Corneas. Invest Ophthalmol Vis Sci 2015. [PMID: 26225631 DOI: 10.1167/iovs.15-16631] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
PURPOSE To evaluate the effects of dry eye on ocular surface protease activity and sight threatening corneal complications following ocular surface chemical injury. METHODS C57BL/6 mice were subjected to unilateral alkali burn (AB) with or without concomitant dry eye for 2 or 5 days. Mice were observed daily for appearance of corneal perforation. Whole corneas were harvested and lysed for RNA extraction. Quantitative real-time PCR was performed to measure expression of inflammation cytokines, matrix metalloproteinases (MMP). Matrix metalloproteinase-9 activity, gelatinase activity, and myeloperoxidase (MPO) activity were evaluated in corneal lysates. Presence of infiltrating neutrophils was evaluated by immunohistochemistry and flow cytometry. RESULTS Eyes subjected to the combined model of AB and dry eye (CM) had 20% sterile corneal perforation rate as soon as 1 day after the initial injury, which increased to 35% by 5 days, delayed wound closure and increased corneal opacity. Increased levels of IL-1β, -6, and MMPs-1, -3, -8, -9, and -13, and chemokine (C-X-C motif) ligand 1 (CSCL1) transcripts were found after 2 days in CM compared with AB corneas. Increased MMP-1, -3, -9, and -13 immunoreactivity and gelatinolytic activity were seen in CM corneas compared with AB. Increased neutrophil infiltration and MPO activity was noted in the CM group compared with AB 2 days post injury. CONCLUSIONS Desiccating stress worsens outcome of ocular AB, creating a cytokine and protease storm with greater neutrophil infiltration, increasing the risk of corneal perforation.
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Tykhomyrov AA, Shram SI, Grinenko TV. [Role of angiostatins in diabetic complications]. BIOMEDIT︠S︡INSKAI︠A︡ KHIMII︠A︡ 2015; 61:41-56. [PMID: 25762598 DOI: 10.18097/pbmc20156101041] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Angiogenesis is a process through which new blood vessels form from pre-existing vessels. Angiogenesis is regulated by a number of factors of peptide nature. Disbalance of angiogenic system appears to be the major causative factor contributing vascular abnormalities in diabetes mellitus, resulting in various complications. Angiostatins, which are kringle-containing fragments of plasminogen/plasmin, are known to be powerful physiological inhibitors of neovascularization. In the present review, current literature data on peculiarities of production of angiostatins and their functioning at diabetes mellitus are summarized and analyzed for the first time. Also, role of angiostatins in the pathogenesis of typical diabetic complications, including retinopathies, nephropathies and cardiovascular diseases, is discussed. Data presented in this review may be useful for elaboration of novel effective approaches for diagnostics and therapy of vascular abnormalities in diabetes mellitus.
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Abstract
PURPOSE The aim of this study was to develop a modified ex vivo corneal cross-linking method that increases stromal resistance to enzymatic degradation for use as a carrier for the Boston keratoprosthesis. METHODS Ex vivo cross-linking of human corneas was performed using Barron artificial anterior chambers. The corneas were deepithelialized, pretreated with riboflavin solution (0.1% riboflavin/20% dextran), and irradiated with ultraviolet A (UV-A) light (λ = 370 nm, irradiance = 3 mW/cm) for various durations. The combined effect of UV-A and gamma (γ) irradiation was also assessed using the commercially available γ-irradiated corneal donors. The corneas were then trephined and incubated at 37°C with 0.3% collagenase A solution. The time to dissolution of each cornea was compared across treatments. RESULTS Deepithelialized corneas (no UV light, no riboflavin) dissolved in 5.8 ± 0.6 hours. Cross-linked corneas demonstrated increased resistance to dissolution, with a time to dissolution of 17.8 ± 2.6 hours (P < 0.0001). The corneal tissues' resistance to collagenase increased with longer UV-A exposure, reaching a plateau at 30 minutes. Cross-linking both the anterior and posterior corneas did not provide added resistance when compared with cross-linking the anterior corneas only (P > 0.05). γ-irradiated corneas dissolved as readily as deepithelialized controls regardless of whether they were further cross-linked (5.6 ± 1.2 hours) or not (6.1 ± 0.6 hours) (P = 0.43). CONCLUSIONS Collagen cross-linking of the deepithelialized anterior corneal surface for 30 minutes conferred optimal resistance to in vitro keratolysis by collagenase A.
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Tykhomyrov AA, Shram SI, Grinenko TV. The role of angiostatins in diabetic complications. BIOCHEMISTRY MOSCOW-SUPPLEMENT SERIES B-BIOMEDICAL CHEMISTRY 2014. [DOI: 10.1134/s1990750814020140] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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Rajashekhar G, Shivanna M, Kompella UB, Wang Y, Srinivas SP. Role of MMP-9 in the breakdown of barrier integrity of the corneal endothelium in response to TNF-α. Exp Eye Res 2014; 122:77-85. [DOI: 10.1016/j.exer.2014.03.004] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2014] [Revised: 03/12/2014] [Accepted: 03/14/2014] [Indexed: 01/11/2023]
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Horwitz V, Dachir S, Cohen M, Gutman H, Cohen L, Fishbine E, Brandeis R, Turetz J, Amir A, Gore A, Kadar T. The beneficial effects of doxycycline, an inhibitor of matrix metalloproteinases, on sulfur mustard-induced ocular pathologies depend on the injury stage. Curr Eye Res 2014; 39:803-12. [PMID: 24502433 DOI: 10.3109/02713683.2013.874443] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
PURPOSE Sulfur mustard (SM) induces acute ocular lesions, including erosions and inflammation that may be followed by delayed injuries expressed by epithelial defects and neovascularization (NV). Based on the matrix metalloproteinases (MMPs) activity, we evaluated the clinical and biochemical effects of topical treatment with doxycycline, an MMP inhibitor, targeted to the various injury stages. METHODS Rabbit eyes were exposed to SM vapor. A clinical follow-up was carried out up to 2 months. Tear fluid and cornea samples were collected at different time points for measurements of MMPs activity by zymography. Efficacy of a post-exposure topical doxycycline (2 mg/ml in phosphate buffer saline, ×4/d), targeted to the different phases of the clinical injury, was evaluated. RESULTS Elevated MMP-9 and MMP-2 activities were found in all corneas during the acute injury and in vascularized corneas during the delayed pathology. In the tear fluid, high MMP-9 activity and negligible MMP-2 activity were found in all the exposed eyes until after the appearance of the delayed pathology symptoms. Prolonged doxycycline treatment reduced MMP-9 activity in the tear fluid. During the acute phase, doxycycline treatment reduced corneal MMP-9 activity and the severity of the injury. Targeting the delayed pathology, doxycycline was clinically efficient only when treatment began before NV appearance. CONCLUSIONS This in vivo study showed the involvement of MMP-9 and MMP-2 during different phases of the SM-induced ocular injury, and the potential of doxycycline treatment as a post exposure measure for reducing the acute injury and as a preventive therapy for ameliorating the delayed pathology. The tear fluid provided a non-invasive method for continuous follow-up of MMPs activity and revealed additional beneficial aspects of injury and the treatment.
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Affiliation(s)
- Vered Horwitz
- Department of Pharmacology, Israel Institute for Biological Research , Ness Ziona , Israel
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Neutrophil collagenase, gelatinase, and myeloperoxidase in tears of patients with stevens-johnson syndrome and ocular cicatricial pemphigoid. Ophthalmology 2013; 121:79-87. [PMID: 23962653 DOI: 10.1016/j.ophtha.2013.06.049] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2013] [Revised: 06/27/2013] [Accepted: 06/28/2013] [Indexed: 01/15/2023] Open
Abstract
OBJECTIVE To investigate the levels of matrix metalloproteinases (MMPs), myeloperoxidase (MPO), and tissue inhibitor of metalloproteinase-1 (TIMP-1) in tears of patients with Stevens-Johnson syndrome (SJS) and ocular cicatricial pemphigoid (OCP). DESIGN Prospective, noninterventional cohort study. PARTICIPANTS Four SJS patients (7 eyes), 19 OCP patients (37 eyes), and 20 healthy controls who underwent phacoemulsification (40 eyes). METHODS Tear washes were collected from all patients and were analyzed for levels of MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-12, MPO, and TIMP-1 using multianalyte bead-based enzyme-linked immunosorbent assays. Total MMP activity was determined using a fluorometric assay. Correlation studies were performed between the various analytes within study groups. MAIN OUTCOME MEASURES Levels of MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-12, MPO, and TIMP-1 (in nanograms per microgram of protein) and total MMP activity (in relative fluorescent units per minute per microgram of protein) in tears; MMP-8-to-TIMP-1 ratio; MMP-9-to-TIMP-1 ratio; and the correlations between MMP-8 and MMP-9 and both MMP and MPO. RESULTS MMP-8, MMP-9, and MPO levels were elevated significantly in SJS and OCP tears (SJS>OCP) when compared with controls. The MMP activity was highest in SJS patients, whereas OCP patients and controls showed lower and similar activities. The TIMP-1 levels were decreased in SJS and OCP patients when compared with those in controls, with levels in OCP patients reaching significance. The MMP-8-to-TIMP-1 and MMP-9-to-TIMP-1 ratios were markedly elevated in SJS and OCP tears (SJS>OCP) when compared with those of controls. Across all study groups, MMP-9 levels correlated strongly with MMP-8 and MPO levels, and MMP-8 correlated with MPO, but it did not reach significance in SJS patients. There was no relationship between MMP-7 and MPO. CONCLUSIONS Because MMP-8 and MPO are produced by inflammatory cells, particularly neutrophils, the correlation data indicate that they may be the common source of elevated enzymes, including MMP-9, in SJS and OCP tears. Elevated MMP-to-TIMP ratios and MMP activity suggest an imbalance in tear MMP regulation that may explain the predisposition of these patients to demonstrate corneal melting and chronic complications associated with persistent inflammation. Myeloperoxidase in tears may be a sensitive and specific marker for the quantification of ocular inflammation.
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