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Marfan syndrome (MFS) is a well-described genetic connective tissue disease that heightens the risk of cardiovascular, ocular, pulmonary, and other emergencies in affected individuals. The wide range of phenotypic presentations, spanning from mild, chronic, and asymptomatic to acute and life-threatening, can pose challenges in diagnosing MFS when disease manifestations are subtle. We report a pathogenetic variant of MFS characterized by subtle systemic findings that was identified only after the patient presented with visual changes and pain associated with angle closure, despite a medical history indicating other pathologies linked to this condition. This case underscores the importance of recognizing the varied and sometimes subtle clinical features of MFS. Vigilance in identifying the constellation of findings associated with MFS can enhance its diagnosis and treatment outcomes by enabling appropriate and timely referrals for prophylactic evaluation and care to address potentially life-threatening complications.
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Purpose: Blood flow (BF) of the retinal and choroidal vasculatures can be quantitatively imaged using MRI. This study sought to improve methods of data acquisition and analysis for MRI of layer-specific retinal and choroidal BF and then applied this approach to detect reduced ocular BF in a well-established mouse model of glaucoma from both eyes. Methods: Quantitative BF magnetic resonance imaging (MRI) was performed on glaucomatous DBA/2J and normal C57BL/6J mice. Arterial spin labeling MRI was applied to image retinal and choroidal BF using custom-made dual eye coils that could image both eyes during the same scan. Statistics using data from a single eye or two eyes were compared. BF values were calculated using two approaches. The BF rate per quantity of tissue was calculated as commonly done, and the peak BF values of the retinal and choroidal vasculatures were taken. Additionally, the BF rate per retinal surface area was calculated using a new analysis approach to attempt to reduce partial volume and variability by integrating BF over the retinal and choroidal depths. Results: Ocular BF of both eyes could be imaged using the dual coil setup without effecting scan time. Intraocular pressure was significantly elevated in DBA/2J mice compared to C57BL/6J mice (P<0.01). Both retinal and choroidal BF were significantly decreased in DBA/2J mice in comparison to the age-matched normal C57BL/6J mice across all measurements (P < 0.01). From simulations, the values from the integrated BF analysis method had less partial volume effect, and from in vivo scans, this analysis approach also improved power. Conclusion: The dual eye coil setup allows bilateral eye data acquisition, increasing the amount of data acquired without increasing acquisition times in vivo. The reduced ocular BF found using the improved acquisition and analysis approaches replicated the results of previous studies on DBA/2J mice. The ocular hypertensive stress-induced BF reduction found within these mice may represent changes associated with glaucomatous progression.
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Purpose: We describe a case of Classic Kaposi's sarcoma in a functionally monocular patient following a COVID19 vaccine booster and provide compelling evidence that suggests the booster was a relevant co-factor in the initiation of the disease process. Observations: The patient presented with red, irritated conjunctival area described as "bubbling" in her right eye. While her past medical history includes hypercholesterolemia and hypertension, she had no history of a compromised immune system. Her ophthalmologic history is more complex including treatment for glaucoma. The patient has 20/20 uncorrected vision OD and LP OS. Due to her ocular co-morbidities, the patient initially received interferon alpha 2-B qid for 6 weeks. However, topical therapy failed to decrease the size of the conjunctival lesions. After referral to Radiation Oncology, the right eye/orbit was treated with electron beam therapy for 1 month which caused a marked decrease in the size and vascularity of the conjunctival lesions. A slow improvement continued during followup. Conclusion and importance: In that the vaccine booster preceded the cancer, it appears etiologic to the appearance of Kaposi's sarcoma. The patient's monocular vision and glaucoma complicated her treatment. This case expands on current concepts of cofactors needed for the development of Kaposi's sarcoma in that vaccine booster administration was relevant to tumor progression and both clinical and mechanistic evidence is presented to support this hypothesis.
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Purpose: To evaluate the hypothesis that 3 novel compounds, OXT-328, Q-922, and CL-717 show efficacy in the treatment of oxygen-induced retinopathy (OIR) and whether or not their route of administration is intravitreal, topical, or systemic. Methods: The OIR mouse model, characterized by an avascular area (AVA) and a neovascular area (NVA) of the retina, was used to study retinopathy of prematurity and other retinal diseases characterized by abnormal vessel growth. We measured the effect of our compounds on both the AVA and NVA in whole mounts of mouse retinal tissue. We also evaluated their ability to prevent new vessel formation in chicken chorioallantoic membranes (CAMs). Finally, we measured the in vitro uptake and biodistribution of topically applied CL-717 in human eye explants. Results: In mice with OIR, compared to controls, a single intravitreal administration of Q-922 or OXT-328 significantly reduced both AVA and NVA. CL-717 administered as eye drops over 5 days also reduced AVA and NVA, whereas OXT-328 eye drops had no effect. Q-922 given intraperitoneal (150 mg/kg/day × 5 days) reduced AVA and NVA. Remarkably, explanted human eyes bathed in CL-717 show rapid uptake and biodistribution in ocular tissues. In the chicken CAM model, all 3 compounds reduced the formation of new blood vessels by about one-third. No side effect in mice was observed, except for mild ocular surface irritation with Q-922. Conclusions: Systemic administration of Q-922 or topical administration of CL-717 holds particular promise for a simplified treatment of proliferative retinopathies without the necessity of intravitreal injections.
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Doenças Retinianas , Neovascularização Retiniana , Retinopatia da Prematuridade , Humanos , Animais , Camundongos , Recém-Nascido , Oxigênio , Vasos Retinianos , Animais Recém-Nascidos , Distribuição Tecidual , Doenças Retinianas/tratamento farmacológico , Inibidores da Angiogênese/farmacologia , Inibidores da Angiogênese/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Neovascularização Retiniana/induzido quimicamente , Neovascularização Retiniana/tratamento farmacológico , Retinopatia da Prematuridade/tratamento farmacológicoRESUMO
Purpose: To describe a case of bilateral facultative ophthalmomyiasis externa due to Calliphoridae in a 30-year-old male assault victim at a suburban hospital in New York and review the relevant literature. Observations: An adult male was found to have maggot infestation of both eyes and severe secondary injury to the left cornea and ocular surface. He was treated with manual larvae removal, oral ivermectin, broad spectrum IV antibiotics, and topical antibiotics. Anterior segment reconstruction was required. Conclusions and importance: We report the first case of ophthalmomyiasis due to Calliphoridae in the United States and document the vision threatening potential of this rare condition. Timely examination by an ophthalmologist with early debridement may help prevent vision-threatening sequelae.
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Background: Chemotherapy-induced peripheral neuropathy (CIPN), a side effect of chemotherapy, is particularly difficult to treat. We explored whether phosphosulindac (PS), a modified NSAID, could treat CIPN. Methods: CIPN was induced in male C57BL/6 J mice by paclitaxel, vincristine or oxaliplatin. Mechanical allodynia was measured with the von Frey test and cold allodynia with the acetone test. To determine the preventive effect of PS, it was administered 2 days before the induction of CIPN. Mouse Lewis lung carcinoma xenografts were used to determine if PS altered the chemotherapeutic efficacy of paclitaxel. Cultured cell lines were used to evaluate the effect of PS on neuroinflammation. Results: Treatment with each of the three chemotherapeutic agents used to induce CIPN lowered the mechanical allodynia scores by 56 to 85% depending on the specific agent. PS gel was applied topically 3x/day for 16-22 days to the hind paws of mice with CIPN. This effect was dose-dependent. Unlike vehicle, PS returned mechanical allodynia scores back to pre-CIPN levels. PS had a similar effect on paclitaxel-induced CIPN cold allodynia. Sulindac, a metabolite of PS, had no effect on CIPN. PS significantly prevented CIPN compared to vehicle. Given concomitantly with paclitaxel to mice with lung cancer xenografts, PS relieved CIPN without affecting the anticancer effect of paclitaxel. The enantiomers of PS were equally efficacious against CIPN, suggesting the therapeutic suitability of the racemate PS. There were no apparent side effects of PS. PS suppressed the levels of IL-6, IL-10, CXCL1, and CXCL2 induced by paclitaxel in a neuroblastoma cell line, and macrophage activation to the M1 proinflammatory phenotype. Conclusion: Topically applied PS demonstrated broad therapeutic and preventive efficacy against CIPN, preserved the anticancer effect of paclitaxel, and was safe. Its anti-CIPN effect appears to be mediated, in part, by suppression of neuroinflammation. These data support further evaluation of topical PS for the control of CIPN.
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The endothelial layer of the cornea plays a critical role in regulating its hydration by actively controlling fluid intake in the tissue via transporting the excess fluid out to the aqueous humor. A damaged corneal endothelial layer leads to perturbations in tissue hydration and edema, which can impact corneal transparency and visual acuity. We utilized a non-contact terahertz (THz) scanner designed for imaging spherical targets to discriminate between ex vivo corneal samples with intact and damaged endothelial layers. To create varying grades of corneal edema, the intraocular pressures of the whole porcine eye globe samples (n = 19) were increased to either 25, 35 or 45 mmHg for 4 h before returning to normal pressure levels at 15 mmHg for the remaining 4 h. Changes in tissue hydration were assessed by differences in spectral slopes between 0.4 and 0.8 THz. Our results indicate that the THz response of the corneal samples can vary according to the differences in the endothelial cell density, as determined by SEM imaging. We show that this spectroscopic difference is statistically significant and can be used to assess the intactness of the endothelial layer. These results demonstrate that THz can noninvasively assess the corneal endothelium and provide valuable complimentary information for the study and diagnosis of corneal diseases that perturb the tissue hydration.
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Doenças da Córnea , Espectroscopia Terahertz , Suínos , Animais , Máquina de Vetores de Suporte , Córnea/fisiologia , Endotélio Corneano/diagnóstico por imagem , Doenças da Córnea/diagnóstico , Espectroscopia Terahertz/métodos , EdemaRESUMO
Purpose: Dry eye disease (DED) is classified as aqueous deficient, evaporative, or mixed. We investigated the therapeutic effect of the novel anti-inflammatory drug phosphosulindac (PS) in rabbit models of DED encompassing its pathogenesis, and its transition to chronicity. Methods: We treated three rabbit models of DED with PS (hydrogel formulation) or vehicle topically applied 1 × /day. We induced aqueous-deficient DED (acute and chronic) by injecting Concanavalin A into lacrimal glands; evaporative DED by injecting into the upper eyelid inactivated Mycobacterium tuberculosis in complete Freund's adjuvant; and mixed DED through desiccative stress, induced by holding open the eye for 3 h. We determined corneal sensitivity, tear break-up time (TBUT), Schirmer's tear test (STT), tear osmolality, and fluorescein staining of the ocular surface. Results: PS reversed all abnormal DED parameters. In acute DED, PS dose dependently normalized corneal sensitivity and tear osmolality; and improved TBUT, STT, and fluorescein staining. PS normalized corneal sensitivity and improved all other parameters in chronic aqueous-deficient DED. In evaporative DED, PS normalized corneal sensitivity and improved TBUT and fluorescein staining (osmolality and STT were not significantly changed in this model). In the desiccative stress model, PS improved TBUT and fluorescein staining but had no effect on STT or tear osmolality. Conclusions: PS rapidly reversed almost all DED parameters in its three subtypes. The normalization of the suppressed corneal sensitivity suggests the possibility of marked symptomatic relief by PS. The hydrogel formulation allows once-daily dosing. PS merits further development as a potential treatment for DED.
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Anti-Inflamatórios/farmacologia , Síndromes do Olho Seco/patologia , Compostos Organofosforados/farmacologia , Sulindaco/análogos & derivados , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/efeitos adversos , Preparações de Ação Retardada , Modelos Animais de Doenças , Hidrogéis , Aparelho Lacrimal/efeitos dos fármacos , Compostos Organofosforados/administração & dosagem , Compostos Organofosforados/efeitos adversos , Concentração Osmolar , Coelhos , Sulindaco/administração & dosagem , Sulindaco/efeitos adversos , Sulindaco/farmacologia , Lágrimas/efeitos dos fármacosRESUMO
PURPOSE: To develop a more efficient impression cytology (IC) method for the transfer of ocular surface cells onto glass microscope slides for cytochemical, immunocytochemical, and immunofluorescence studies. METHODS: Cells are lifted off the ocular surface with a mixed cellulose ester membrane and then firmly attached to a glass slide using a novel triblock copolymer comprised of collagen type I, polyethylenimine and poly-L-lysine (CPP), and crosslinking cells and glass slide by heating and cooling. The membrane is removed intact after softening it with a butanol/ethanol solution. Transfer of cells is complete in about 10-15 minutes and is ready for staining. The efficiency of our cell transfer method was compared to current methods based on poly-L-lysine and albumin paste. RESULTS: Our method ensured almost complete transfer of cells. In contrast, the transfer of rabbit conjunctiva cells onto poly-L-lysine-covered slides was 37.5 ± 6.3% lower, and onto albumin-paste covered slides 62.5 ± 5.6% lower (mean ± SD); the transfer of rabbit goblet cells was even less efficient. The new method was also more efficient for transfer of cells from human oral mucosa obtained by IC. Transferred cells were successfully stained with H&E, chemiluminescence, and immunofluorescence agents. Using our method, we stained ocular surface cells for S100A4 and ATF4, both of which play a role in the pathophysiology of dry eye disease. We obtained similar results with oral mucosal cells, suggesting the generalizability of our approach. We propose an explanation for the strong adhesion of cells to the glass slide, which is based on their interactions with the triblock copolymer. CONCLUSIONS: We developed a novel approach for the efficient and rapid transfer of cells obtained by IC onto glass microscope slides using a novel copolymer. Compared to available methods, our improved approach makes IC robust and simple, and should increase its diagnostic yield and clinical applicability.
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Técnicas Citológicas/tendências , Células Caliciformes/citologia , Microscopia/métodos , Polímeros/farmacologia , Idoso , Animais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Animais , CoelhosRESUMO
Drug development, resource- and time-intensive, extensively employs cell-based assays to assess the efficacy and safety of candidate drugs. The widely used immortalized cell lines, experimentally convenient, have limited predictive value. In contrast, ex-vivo models more faithfully reproduce diseases but are technically challenging to establish. To address this need, we developed a simplified process for ex-vivo cell culture, demonstrating its feasibility in ocular surface cells. Conjunctival cells were harvested by impression cytology and grown on mixed cellulose ester membrane filters (MCFs). Human and rabbit conjunctival cells cultured on MCFs are 100% viable at 24 h, and 43% viable at 72 h. A gene expression study evaluating 84 genes involved in ocular inflammation demonstrated that ex-vivo culturing maintains intact the expression of two thirds of these genes in human cells. That these cells are suitable for the assessment of ocular drugs was demonstrated by studying the effect of phosphosulindac (PS), a small molecule under development for the treatment of dry eye disease, in both human and rabbit conjunctival cells. PS, for example, suppressed the expression of CXCL10, a cytokine participating in the pathogenesis of dry eye disease, in human and in rabbit conjunctival cells cultured ex-vivo by 32% and 70%, respectively. Conjunctival cells cultured ex-vivo can be transfected to evaluate mechanistic questions. We successfully transfected such cells with a plasmid expressing luciferase under the control of an IFN-γ-responsive promoter or its control plasmid. IFN-γ stimulated luciferase expression by 85% in cells with the responsive plasmid but not in controls; PS significantly suppressed this induction by 37% without affecting the control plasmid. These findings demonstrate that human and rabbit conjunctival cells cultured ex-vivo with our method are viable and maintain their biological integrity; respond to biological and pharmacological agents; and are transfectable with informative plasmids. The unique advantage of this method is to potentially accelerate the development of novel drugs for the treatment of ocular surface diseases, and to advance our understanding of ocular surface pathophysiology.
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Anti-Inflamatórios não Esteroides/uso terapêutico , Túnica Conjuntiva/efeitos dos fármacos , Avaliação de Medicamentos/métodos , Síndromes do Olho Seco/tratamento farmacológico , Compostos Organofosforados/uso terapêutico , Sulindaco/análogos & derivados , Adulto , Idoso , Animais , Técnicas de Cultura de Células , Sobrevivência Celular , Celulose/análogos & derivados , Celulose/química , Quimiocina CXCL10/metabolismo , Túnica Conjuntiva/metabolismo , Desenvolvimento de Medicamentos , Feminino , Perfilação da Expressão Gênica , Humanos , Luciferases/metabolismo , Masculino , Pessoa de Meia-Idade , Plasmídeos , Coelhos , Reação em Cadeia da Polimerase em Tempo Real , Sulindaco/uso terapêutico , Obtenção de Tecidos e Órgãos , TransfecçãoRESUMO
Dry eye disease (DED), which is a prevalent disease that still lacks successful treatment options, remains a major challenge in ophthalmology. Multiple animal models of DED have been used to decipher its pathophysiology and to develop novel treatments. These models use mice, rats, rabbits, cats, dogs and non-human primates. Each model assesses aspects of DED by focusing on elements of the lacrimal functional unit, which controls the homeostasis of the tear film. The present review outlines representative DED animal models and assesses their contribution to the study of DED. Murine models are the most extensively used, followed by rabbit models; the latter offer the advantage of larger eyes, a favorable biochemical profile for drug studies, experimental ease and relatively low cost, contrasting with non-human primates, which, although closer to humans, are not as accessible and are expensive. No comprehensive 'ideal' animal model encompassing all aspects of human DED exists nor is it feasible. Investigators often choose an animal model based on their experimental needs and the following four features of a given model: The size of the eye, its biochemical composition, the available research reagents and cost. As research efforts in DED expand, more refined animal models are needed to supplement the enormous contribution made to date by existing models.
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Elevated intraocular pressure (IOP) results in endothelial layer damage that can induce corneal hydration perturbations. We investigated the potential of terahertz spectroscopy in measuring the IOP levels through mapping corneal water content. We controlled the IOP levels in ex vivo rabbit and porcine eye samples while monitoring the change in corneal hydration using a terahertz time-domain spectroscopy (THz-TDS) scanner. Our results showed a statistically significant increase in the THz reflectivity between 0.4 and 0.6 THz corresponding to the increase in the IOP. Endothelial layer damage was confirmed using scanning electron microscopy (SEM) of the corneal biopsy samples. Our empirical results indicate that the THz-TDS can be used to track IOP levels through the changes in corneal hydration.
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The pathophysiology of dry eye disease (DED) remains largely unknown, accounting in part for the lack of successful treatments. We explored the pathophysiology of DED using a rabbit model of chronic DED induced with 3 weekly injections of Concanavalin A into the periorbital lacrimal glands. The transcriptome of full-thickness's conjunctival tissue from rabbits with DED and from normal controls was determined using microarrays and, as needed, confirmatory real-time polymerase chain reactions. Results were subjected to bioinformatic analysis. DED induced large-scale changes in gene transcription involving 5,184 genes (22% of the total). Differentially expressed genes could be segregated into: functional modules and clusters; altered pathways; functionally linked genes; and groups of individual genes of known or suspected pathophysiological relevance to DED. A common feature of these subgroups is the breadth and magnitude of the changes that encompass ocular immunology and essentially all aspects of cell biology. Prominent changes concerned innate and adaptive immune responses; ocular surface inflammation; at least 25 significantly altered signaling pathways; a large number of chemokines; cell cycle; and apoptosis. Comparison of our findings to the limited extant transcriptomic data from DED patients associated with either Sjogren's syndrome or non-Sjogren's etiologies revealed a significant correlation between human and rabbit DED transcriptomes. Our data, establishing the large-scale transcriptomic changes of DED and their potential similarity to the human, underscore the enormous complexity of DED; establish a robust animal model of DED; will help expand our understanding of its pathophysiology; and could guide the development of successful therapeutic strategies.
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Síndromes do Olho Seco , Transcriptoma , Animais , Quimiocinas/metabolismo , Humanos , Inflamação , Aparelho Lacrimal , Coelhos , LágrimasRESUMO
Purpose: Inflammation of the ocular surface is central to dry eye disease (DED). The anti-inflammatory agent phospho-sulindac (PS) at a high dose was efficacious against DED in a rabbit model. We assessed the dose, formulation and structure dependence of PS's effect. Methods: In rabbits with concanavalin A-induced DED we evaluated a range of PS concentrations (0.05%-1.6%) and dosing frequencies, assessed the duration of its effect with PS in 2 solution formulations and one emulsion formulation, and compared the efficacy of PS to that of sulindac, and of the structurally similar phospho-ibuprofen amide. We determined tear breakup time (TBUT) (tear stability), Schirmer's tear test (tear production), and by esthesiometry corneal sensitivity (symptoms). We also determined the biodistribution in the eye of topically applied PS. Results: PS in a solution formulation, given as eye drops q.i.d. was efficacious starting at a dose of 0.1%. The effect was apparent after 2 days of treatment and lasted at least 8 days after the last dose. Both signs (evidenced by TBUT and Schirmer's test) and symptoms (measured by corneal sensitivity) improved significantly. The best formulation was the solution formulation; a cyclodextrin-based formulation was also successful but the emulsion formulation was not. PS and its metabolites were essentially restricted to the anterior chamber of the eye. Sulindac and phospho-ibuprofen amide had no efficacy on DED. Conclusions: PS is efficacious against DED. Its effect, encompassing signs, and symptoms, are dose, formulation, and structure dependent. PS has therapeutic promise and merits further development.
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Composição de Medicamentos , Síndromes do Olho Seco/tratamento farmacológico , Compostos Organofosforados/administração & dosagem , Compostos Organofosforados/química , Sulindaco/análogos & derivados , Administração Tópica , Animais , Síndromes do Olho Seco/metabolismo , Síndromes do Olho Seco/patologia , Masculino , Compostos Organofosforados/farmacocinética , Coelhos , Sulindaco/administração & dosagem , Sulindaco/química , Sulindaco/farmacocinética , Distribuição TecidualRESUMO
PURPOSE: To evaluate whether principal component analysis (PCA) can assess various diagnostic tests of dry eye disease (DED), providing a simplified, more informative measure of disease status than individual clinical test parameters (ICTP). MATERIALS AND METHODS: ICTP were analyzed using PCA in two groups of normal rabbits (Groups 1 and 2). Group 3, not truly normal, was also assessed. DED was induced in Group 1 by complete dacryoadenectomy; in Groups 2 and 3 by injection of concanavalin A. Tear break up time, tear osmolarity, Schirmer's tear test and rose bengal staining were the ICTP measured in all groups. Statistical analysis including descriptive statistics, t test, correlation coefficients and PCA was done. PCA using ICTP data from Group 1 generated axes; Group 2 and 3 were plotted over these axes. RESULTS: All groups had induction of DED. Correlations for all ICTP were in the correct direction and were strongest for Group 1 and weakest in Group 3. PCA clearly separated DED and normal eyes. Principal component (PC) 1, made up of nearly equal contributions from the four clinical tests, explained 73% of the variation and provided a means to separate normal from DED. PC 1 values under 0.52 can be mathematically defined as DED. Of all pairwise comparisons, PC 1 vs PC 2 and PC 1 vs PC 3 were the most informative providing excellent spatial separation and additional information regarding DED status. CONCLUSIONS: PCA proved useful for evaluating DED providing a simpler, more comprehensive assessment than ICTP. PC 1 is a valuable, clinically relevant, and informative metric for DED status and severity having superior diagnostic value and statistical strength compared to ICTP. Spatial information on biplots of PC 1 vs PC 3 is also informative. PCA, and specifically PC 1, has the potential to serve as a biomarker for DED.
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Técnicas de Diagnóstico Oftalmológico , Modelos Animais de Doenças , Síndromes do Olho Seco/diagnóstico , Análise de Componente Principal/métodos , Lágrimas/fisiologia , Animais , Síndromes do Olho Seco/fisiopatologia , Masculino , Concentração Osmolar , Coelhos , Lágrimas/químicaRESUMO
Perturbation of normal corneal water content is a common manifestation of many eye diseases. Terahertz (THz) imaging has the potential to serve as a clinical tool for screening and diagnosing such corneal diseases. In this study, we first investigate the diffusive properties of a corneal phantom using simultaneous THz time-domain spectroscopy (THz-TDS) and gravimetric measurements. We will then utilize a variable-thickness diffusion model combined with a stratified composite-media model to simulate changes in thickness, hydration profile, and the THz-TDS signal as a function of time. The simulated THz-TDS signals show very good agreement with the reflection measurements. Results show that the THz-TDS technique can be used to understand water diffusion dynamics in corneal phantoms as a step towards future in vivo quantitative hydration sensing.
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Dry eye disease (DED), a multifactorial inflammatory disease of the ocular surface, affects 1 in 6 humans worldwide with staggering implications for quality of life and health care costs. The lack of informative animal models that recapitulate its key features impedes the search for new therapeutic agents for DED. Available DED animal models have limited reproducibility and efficacy. A model is presented here in which DED is induced by injecting the mitogen concanavalin A (Con A) into the orbital lacrimal glands of rabbits. Innovative aspects of this model are the use of ultrasound (US) guidance to ensure optimal and reproducible injection of Con A into the inferior lacrimal gland; injection of Con A into all orbital lacrimal glands that limits compensatory production of tears; and use of periodic repeat injections of Con A that prolong the state of DED at will. DED and its response to test agents are monitored with a panel of parameters that assess tear production, the stability of the tear film, and the status of the corneal and conjunctival mucosa. They include tear osmolarity, tear break-up time, Schirmer's tear test, rose bengal staining, and tear lactoferrin levels. The induction of DED and the monitoring of its parameters are described in detail. This model is simple, robust, reproducible, and informative. This animal model is suitable for the study of tear physiology and of the pathophysiology of DED as well as for the assessment of the efficacy and safety of candidate agents for the treatment of DED.
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Concanavalina A/efeitos adversos , Síndromes do Olho Seco/induzido quimicamente , Aparelho Lacrimal/efeitos dos fármacos , Qualidade de Vida/psicologia , Animais , Modelos Animais de Doenças , Feminino , Humanos , Injeções , Masculino , Coelhos , Reprodutibilidade dos TestesRESUMO
Dry eye disease (DED) is a complex disease with multiple etiologies and variable symptoms, having ocular surface inflammation as its key pathophysiologic step. Despite advances in our understanding of DED, significant knowledge gaps remain. Advances are limited in part due to the lack of informative animal models. The authors recently reported on a method of DED induced by injecting all orbital lacrimal gland (LG) tissues with the lectin concanavalin A. Here, we report a novel model of aqueous-deficient DED based on the surgical resection of all orbital LG (dacryoadenectomy) tissues. Both methods use rabbits because of their similarity to human eyes in terms of the size and structure of the ocular surface. One week after removal of the nictitating membrane, the orbital superior LG was surgically removed under anesthesia, followed by removal of the palpebral superior LG, and finally removal of the inferior LG. Dacryoadenectomy induced severe DED, evidenced by a marked reduction in the tear break up time test and the Schirmer's tear test, and significantly increased tear osmolarity and rose bengal staining. Dacryoadenectomy-induced DED lasted at least eight weeks. There were no complications and animals tolerated the procedure well. The technique can be mastered relatively easily by those with adequate surgical experience and appreciation of the relevant rabbit anatomy. Since this model recapitulates the features of human aqueous-deficient DED, it is suitable for studies of ocular surface homeostasis, DED, and candidate therapeutics.
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Síndromes do Olho Seco/diagnóstico , Doenças do Aparelho Lacrimal/cirurgia , Aparelho Lacrimal/fisiopatologia , Aparelho Lacrimal/cirurgia , Lágrimas/metabolismo , Animais , Modelos Animais de Doenças , Feminino , Humanos , Masculino , CoelhosRESUMO
Corneal melt, an ophthalmological condition in which corneal epithelium is lost accompanied by thinning of the corneal stroma, can lead to corneal perforation and cause loss of vision. Corneal melt is the most serious side effect of topical nonsteroidal anti-inflammatory drugs (NSAIDs), one of the topical treatments of ocular inflammation. NSAID-induced corneal melt (NICM), initially doubted, is real, having been reported by multiple groups. NICM is induced by all but one of the approved ocular NSAIDs and occurs usually in patients whose cornea is compromised by ocular surgery, diabetes, or autoimmune diseases. Its true incidence, most likely low, remains unknown. NSAID dose and duration of treatment may be important for NICM. NICM appears to evolve in two stages: the epithelial stage-marked by a corneal epithelial defect, reduced eicosanoid levels, leukocyte infiltration, and matrix metalloproteinase-facilitated desquamation-and the stromal stage, characterized by degradation of stromal collagen by activated matrix metalloproteinases. Awareness of this ominous side effect, its risk factors, and the need for prompt action once diagnosed, including NSAID discontinuation, will help mitigate the risk of NICM. Further understanding of NICM and development of efficacious treatments or safer alternatives should help eliminate this rare, but severe, side effect of ocular NSAIDs.