Ocular Surface最新文献_第10页

Desiccation stress triggers and exacerbates experimental ocular Graft-versus-host-disease 干燥应激触发并加剧实验性眼移植物抗宿主病

IF 5.9 1区医学 Q1 OPHTHALMOLOGY

Ocular Surface

Pub Date : 2025-04-24 DOI: 10.1016/j.jtos.2025.04.008

Uta Gehlsen , Martina Maass , Daniela Stary , Svenja Wagener-Ryczek , Gwen Musial , Manolis Pasparakis , Cintia S. de Paiva , Michael E. Stern , Philipp Steven

Introduction

Chronic ocular graft-versus-host disease (oGVHD) is one of the most common complications after allogeneic hematopoietic stem cell transplantation (aHSCT). Recent studies indicate that desiccating stress by air-conditioning in transplantation wards increases the incidence of oGVHD. To test the hypothesis that experimental desiccating stress is a risk factor for oGVHD a mouse model of oGVHD was subjected to experimental desiccating stress.

Materials/Methods: A previously established chemo-induced minor-mismatch mouse model of oGVHD was used. One group was challenged with desiccating stress for 18 days and compared to non-desiccated GVHD animals. Clinical phenotyping was performed weekly and ocular tissue and regional lymph nodes were collected on days 7 and 28 for flow-cytometry, tear film cytokine analysis, histology for corneal lymphatics and dendritic cell counts, and corneal gene expression.

Results

Desiccating stress leads to significant earlier and more severe systemic and oGVHD accompanied by higher numbers of activated corneal dendritic cells, higher expression of TNF in tear film and earlier corneal lymphangiogenesis. Gene expression analysis suggests that systemic GVHD severity may influence oGVHD. Different inflammatory pathways are upregulated at d28 following desiccating stress in contrast to non-desiccated GVHD.

Conclusions

The data presented strengthens the hypothesis, that desiccating stress during aHSCT is a risk factor for oGVHD. Together with already published clinical data, there is increasing evidence that implicates protecting patients from desiccation during the engraftment of allogeneic hematopoietic stem cells. Furthermore, specific prophylactic therapies should be developed and tested to reduce the incidence and severity of oGVHD.

慢性眼部移植物抗宿主病（oGVHD）是同种异体造血干细胞移植（aHSCT）后最常见的并发症之一。最近的研究表明，移植病房的空调干燥压力增加了oGVHD的发病率。为了验证实验性干燥应激是oGVHD危险因素的假设，我们对oGVHD小鼠模型进行了实验性干燥应激。材料/方法：采用先前建立的化学诱导的oGVHD小鼠小错配模型。其中一组受到干燥压力18天，并与未干燥的GVHD动物进行比较。每周进行临床表型分型，于第7天和第28天采集眼部组织和区域淋巴结进行流式细胞术、泪膜细胞因子分析、角膜淋巴管组织学和树突状细胞计数以及角膜基因表达。结果干燥应激可导致系统性和oGVHD的早期和严重程度，并伴有活化的角膜树突状细胞数量增加，泪膜中TNF表达增加，角膜淋巴管生成提前。基因表达分析提示全身性GVHD严重程度可能影响oGVHD。与非干燥GVHD相比，干燥应激后28天不同的炎症通路上调。结论：上述数据强化了aHSCT期间的干燥应激是oGVHD的危险因素这一假设。加上已经发表的临床数据，越来越多的证据表明，在同种异体造血干细胞移植过程中，保护患者免受干燥。此外，应该开发和测试特定的预防性疗法，以减少oGVHD的发病率和严重程度。

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引用次数: 0

Ocular graft-versus-host disease: Experience, incidence, and treatment outcomes at a university-based tertiary care ophthalmology center 眼移植物抗宿主病：一所大学三级保健眼科中心的经验、发病率和治疗结果

IF 5.9 1区医学 Q1 OPHTHALMOLOGY

Ocular Surface

Pub Date : 2025-04-11 DOI: 10.1016/j.jtos.2025.04.006

Zeenal G. Dabre , Tanya Sheth , Elias Hernandez , Jessica Mun , Diana Hernandez , Nancy Ascencio , Christian Kim , Monazzah Sarwar , Kiera Byrne , Anubhav Pradeep , Damiano Rondelli , Christine Mun , Sandeep Jain

Objective

This study describes the clinical experience, incidence, and outcomes of treating chronic ocular graft-versus-host disease (oGVHD) at a tertiary care ophthalmology center.

Methods

This retrospective analysis included 413 post-hematopoietic stem cell transplant patients. Ocular GVHD was diagnosed using the international chronic oGVHD consensus group criteria. Based on the severity of the initial presentation and the topical treatment received accordingly, patients with definite oGVHD were divided into three groups: Group A received combination of steroids, serum tears, and pooled human immunoglobulin; Group B received steroids and serum tears; and Group C received steroids only. Treatment response was analyzed using Wilcoxon rank-sum and Kruskal-Wallis test.

Results

53 % of patients presented with definite oGVHD manifestations at the initial visit with 16 % of these patients presenting with only ocular manifestations of chronic GVHD. Among those initially categorized as none or probable oGVHD only 18 % progressed to definite oGVHD during the follow-up period. Patients in treatment group A and B showed significant reduction (p < 0.01) in corneal staining at follow-up compared to initial visit. However, corneal staining reduction in treatment group C did not achieve significance (p = 0.06). Visual analogue scale scores decreased in all groups, with treatment group A (p < 0.01), group B (p < 0.01), and group C (p = 0.014) each showing improvement in symptoms at follow-up compared to initial visit.

Conclusion

The high incidence of oGVHD in post-HSCT patients may be related to belated referral to eye care providers. Initiating combinatorial treatment that is based on the severity of oGVHD manifestations results in significant clinical improvement.

目的介绍某三级保健眼科中心治疗慢性眼部移植物抗宿主病（oGVHD）的临床经验、发病率和结果。方法对413例造血干细胞移植后患者进行回顾性分析。眼部GVHD的诊断采用国际慢性oGVHD共识组标准。根据初始表现的严重程度和相应的局部治疗，将明确的oGVHD患者分为三组：A组接受类固醇、血清泪液和混合人免疫球蛋白联合治疗；B组给予类固醇和血清泪液；C组仅接受类固醇治疗。采用Wilcoxon秩和和Kruskal-Wallis检验分析治疗反应。结果53%的患者在初次就诊时表现出明确的oGVHD表现，其中16%的患者仅表现为慢性GVHD的眼部表现。在最初被归类为无或可能oGVHD的患者中，只有18%的患者在随访期间发展为明确的oGVHD。治疗组A、B组患者表现明显降低(p <；与初次就诊相比，随访时角膜染色差异为0.01)。而C组角膜染色减少无显著性意义（p = 0.06）。各组视觉模拟量表评分均下降，A组(p <；0.01)， B组(p <；0.01)和C组（p = 0.014）在随访时均显示与初次就诊相比症状有所改善。结论移植后患者oGVHD的高发可能与转诊较晚有关。根据oGVHD表现的严重程度启动联合治疗可显著改善临床。

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引用次数: 0

Pipeline: Therapeutics – Two views of off-label use 管道：治疗学-超说明书使用的两种观点

IF 5.9 1区医学 Q1 OPHTHALMOLOGY

Ocular Surface

Pub Date : 2025-04-10 DOI: 10.1016/j.jtos.2025.04.005

Gary D. Novack

引用次数: 0

Acanthamoeba keratitis treatment outcomes compared for drug delivery by protocol versus physician's individualised treatment 棘阿米巴角膜炎的治疗结果比较方案给药与医生个体化治疗。

IF 5.9 1区医学 Q1 OPHTHALMOLOGY

Ocular Surface

Pub Date : 2025-04-07 DOI: 10.1016/j.jtos.2025.03.008

John K.G. Dart , Vincenzo Papa , Paolo Rama , Karl Anders Knutsson , Saj Ahmad , Scott Hau , Sara Sanchez , Antonella Franch , Federica Birattari , Pia Leon , Adriano Fasolo , Ewa Mrukwa-Kominek , Katarzyna Jadczyk-Sorek , Fiona Carley , Hossain Parwez , Darwin C. Minassian

Purpose

To compare Acanthamoeba keratitis (AK) outcomes for treatment delivered using a detailed protocol versus physician's individualised treatment.

Methods

This double cohort study compared the outcomes of these different delivery methods for PHMB 0.02 % and diamidine 0.1 % dual therapy. The primary outcome was the medical cure rate without surgery within 12 months (MCR_12) and the secondary was visual acuity. Any change of treatment, any surgery, or treatment for >12 months was a failure. Outcomes were both unadjusted and adjusted, using multivariable analysis, for baseline differences affecting outcomes. Patients were from two centres in Milan and London treated at different times; the individualised cohort (1991–2012) and per-protocol cohort (2017–2021).

Results

The individualised cohort included 96 and the per-protocol 47 patients. Both unadjusted and adjusted results were similar. The unadjusted outcomes for both centres combined showed significantly improved outcomes for per-protocol treatment with a 1.59-fold improvement in MCR_12 (95 % CI 1.40–1.80, p < 0.001) and a 2.1-fold increase in visual acuity ≥20/25 (95 % CI 1.34–3.29, p < 0.001). Amongst potential confounding factors examined, neither baseline AK disease stage, treatment centre nor the type of diamidine significantly influenced outcomes.

Conclusions

This study shows significant advantages for the use of protocol delivered versus individualised treatment for AK. The use of evidence-based treatment delivery protocols, like the one used here for AK, might improve outcomes for all causes of microbial keratitis and could offer practitioners and patients the benefit of having an easy-to-follow drug delivery protocol, with known outcomes.

目的：比较棘阿米巴角膜炎（AK）的治疗结果提供了一个详细的方案和医生的个体化治疗。方法：本双队列研究比较了0.02% PHMB和0.1%二胺双重治疗的不同给药方式的结果。主要观察指标为12个月内不手术治愈率（MCR_12），次要观察指标为视力。任何治疗方法的改变，任何手术，或长达12个月的治疗都是失败的。采用多变量分析，对影响结果的基线差异进行了未调整和调整。来自米兰和伦敦两个中心的患者在不同时间接受治疗；个体化队列（1991-2012）和按方案队列（2017-2021）。结果：个体化队列96例，按方案47例。未调整和调整后的结果相似。两个中心未经调整的合并结果显示，按方案治疗的结果显著改善，MCR_12改善1.59倍（95% CI 1.40 - 1.80, p < 0.001），视力≥20/25增加2.1倍（95% CI 1.34 - 3.29, p < 0.001）。在检查的潜在混杂因素中，基线AK疾病分期、治疗中心和二胺类型均未显著影响结果。结论：这项研究显示了使用方案传递与个性化治疗AK的显著优势。使用循证治疗方案，如这里使用的AK，可能会改善所有原因的微生物角膜炎的结果，并可以为医生和患者提供一个易于遵循的药物给药方案，已知的结果。

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引用次数: 0

Expert consensus on pediatric dry eye: Insights from a European Delphi study 专家对儿童干眼症的共识：来自欧洲德尔菲研究的见解

IF 5.9 1区医学 Q1 OPHTHALMOLOGY

Ocular Surface

Pub Date : 2025-04-05 DOI: 10.1016/j.jtos.2025.04.004

Edoardo Villani , Paolo Nucci , Jose Manuel Benitez-del-Castillo , Annegret Dahlmann-Noor , Wolf Alexander Lagrèze , Dominique Bremond-Gignac , PeDED Delphi Group

Context

Dry Eye Disease (DED) is a symptomatic multifactorial condition of the ocular surface, primarily characterized by tear film instability, which can lead to ocular surface damage. While traditionally associated with adults, recent studies have shown a significant prevalence of DED in pediatric populations, exacerbated by modern lifestyle changes such as increased screen time and environmental factors. Pediatric DED (PeDED) often goes underdiagnosed due to a lack of tailored diagnostic tools and the misattribution of symptoms to other conditions.

Methods

This Delphi study, conducted by a European panel of six ophthalmology experts sought to address expert consensus in pending challenges of PeDED.

Results

Over two rounds of surveys, 34 experts reached consensus on 39 of 46 statements, highlighting the need for age-specific diagnostic criteria and treatment protocols. The study identified environmental and lifestyle factors, such as screen time and ocular allergies, as significant risk factors for PeDED. There was strong consensus on the importance of adapting adult DED definitions and treatment approaches to better suit pediatric patients. The study also emphasized the cautious use of treatments like topical steroids or oral macrolides, especially in younger children.

Conclusion

The findings underscore the necessity for standardized clinical practices in diagnosing and managing PeDED, with a focus on improving the quality of life for affected children. Further research is required to validate these findings and develop comprehensive guidelines that cater to the unique needs of the pediatric population.

干眼病（DED）是一种有症状的多因素眼表疾病，主要特征是泪膜不稳定，可导致眼表损伤。虽然传统上与成人有关，但最近的研究表明，儿童人群中DED的患病率很高，并且由于现代生活方式的改变（如屏幕时间增加和环境因素）而加剧。由于缺乏量身定制的诊断工具以及将症状错误地归因于其他疾病，儿科DED经常被误诊。该德尔菲研究由6名欧洲眼科专家组成的小组进行，旨在解决PeDED面临的挑战中的专家共识。结果在两轮调查中，34位专家对46项声明中的39项达成共识，强调了针对年龄的诊断标准和治疗方案的必要性。该研究确定了环境和生活方式因素，如屏幕时间和眼部过敏，是ed的重要风险因素。对于调整成人DED的定义和治疗方法以更好地适应儿科患者的重要性，人们达成了强烈的共识。该研究还强调了局部类固醇或口服大环内酯类药物等治疗方法的谨慎使用，特别是在年幼的儿童中。结论本研究结果强调了在诊断和管理PeDED时标准化临床实践的必要性，重点是提高患儿的生活质量。需要进一步的研究来验证这些发现，并制定全面的指导方针，以满足儿科人群的独特需求。

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引用次数: 0

Pard3 promotes corneal epithelial stratification and homeostasis by regulating apical-basal polarity, cytoskeletal organization and tight junction-mediated barrier function Pard3 通过调节顶端-基底极性、细胞骨架组织和紧密连接介导的屏障功能，促进角膜上皮分层和平衡。

IF 5.9 1区医学 Q1 OPHTHALMOLOGY

Ocular Surface

Pub Date : 2025-04-04 DOI: 10.1016/j.jtos.2025.04.001

Mehak Vohra , Simran Kumar , Peri Sohnen , Satinder Kaur , Sudha Swamynathan , Tomonori Hirose , Zbynek Kozmik , Shivalingappa K. Swamynathan

Purpose

To document the expression of apical-basal polarity (ABP) determinants in the mouse corneal epithelium (CE) and elucidate the functions of Pard3 in establishment and maintenance of ABP, stratification, homeostasis, and barrier function in the CE.

Methods

Pard3^Δ/ΔC mice (Pard3^LoxP/LoxP; Aldh3A1-Cre/+) with cornea-specific Pard3 ablation were generated by breeding Aldh3A1-Cre/+ with Pard3^LoxP/LoxP mice. The control (Aldh3A1-Cre/+ or Pard3^LoxP/LoxP alone) and Pard3^Δ/ΔC corneal histology, ocular surface properties, barrier function, and actin cytoskeleton were assessed by Haematoxylin and Eosin staining of paraformaldehyde-fixed, paraffin-embedded tissues, scanning electron microscopy, fluorescein staining, and phalloidin staining, respectively. The expression of specific markers of interest was evaluated by qRT-PCR, immunoblots and immunofluorescent staining.

Results

Dynamic changes were observed in the expression and localization of ABP determinants as the CE stratified and matured between post-natal day 5 (PN5) and PN52. Adult Pard3^Δ/ΔC CE contained fewer cell layers with rounded basal cells, and loosely adherent superficial cells lacking microplicae. Adult Pard3^Δ/ΔC CE also displayed impaired barrier function with decreased expression of tight junction, adherens junction, and desmosome components, disrupted actin cytoskeletal organization, increased proliferation, and upregulation of transcription factors that drive epithelial-mesenchymal transition (EMT).

Conclusions

Disruption of ABP in Pard3^Δ/ΔC CE, altered expression of cell junction complex components and disorganized actin cytoskeleton, increased cell proliferation, and upregulated EMT transcription factors suggest that the ABP-determinant Pard3 promotes CE features while suppressing mesenchymal cell fate. Collectively, these results elucidate that Pard3-mediated ABP is essential for CE stratification, homeostasis and barrier function.

目的：研究小鼠角膜上皮（CE）中顶基极性（ABP）决定因子的表达，并阐明par3在角膜上皮中ABP的建立和维持、分层、稳态和屏障功能中的作用。方法：Pard3Δ/ΔC小鼠(Pard3LoxP/LoxP；Aldh3A1-Cre/+与Pard3LoxP/LoxP小鼠杂交产生具有角膜特异性par3消融的Aldh3A1-Cre/+。对照（Aldh3A1-Cre/+或Pard3LoxP/LoxP单独）和Pard3Δ/ΔC分别通过多聚甲醛固定组织、石蜡包埋组织的Haematoxylin和Eosin染色、扫描电镜、荧光素染色和phalloidin染色来评估角膜组织学、眼表特性、屏障功能和肌动蛋白细胞骨架。通过qRT-PCR、免疫印迹和免疫荧光染色评价感兴趣的特异性标志物的表达。结果：在出生后第5天（PN5）和第52天之间，随着CE的分层和成熟，ABP决定因子的表达和定位发生了动态变化。成人Pard3Δ/ΔC CE的细胞层较少，基底细胞为圆形，表面细胞贴壁松散，缺乏微皱褶。成人Pard3Δ/ΔC CE也表现出屏障功能受损，紧密连接、粘附连接和桥粒成分的表达减少，肌动蛋白细胞骨架组织被破坏，增殖增加，驱动上皮-间质转化（EMT）的转录因子上调。结论：Pard3Δ/ΔC CE中ABP的破坏，细胞连接复合物组分和无组织肌动蛋白细胞骨架的表达改变，细胞增殖增加，EMT转录因子上调，表明ABP决定因子par3促进CE特征，同时抑制间充质细胞的命运。总的来说，这些结果阐明了pard3介导的ABP对CE分层、体内平衡和屏障功能至关重要。

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引用次数: 0

Prevalence and antimicrobial susceptibility pattern of coagulase-negative Staphylococci isolated from ocular infections: A systematic review and meta-analysis 眼部感染中分离的凝固酶阴性葡萄球菌的患病率和抗菌药物敏感性模式：一项系统综述和荟萃分析。

IF 5.9 1区医学 Q1 OPHTHALMOLOGY

Ocular Surface

Pub Date : 2025-04-04 DOI: 10.1016/j.jtos.2025.03.006

Abolfazl Rafati Zomorodi , Maryam Mohammadi , Zahra Gholizadeh Farshi , Mohammad Hassan Parvizi Mashhadi , Sasan Pourbagher Benam , Mohammad Motamedifar

Bacteria are the leading cause of ocular infections (OIs), accounting for 32 %–74 % of cases globally. Coagulase-negative Staphylococci (CoNS) are frequently identified as the main causative pathogens of all types of OIs. This study systematically reviewed the prevalence of CoNS and their resistance rates to ciprofloxacin, chloramphenicol, tetracycline, and trimethoprim/sulfamethoxazole in OIs worldwide.

We conducted a comprehensive search of publications from January 1, 2000, to May 19, 2024, using three major databases: Scopus, Web of Science, and PubMed. Statistical analyses were performed with Stata 14.0, employing the Metaprop package to calculate pooled prevalence and confidence intervals. A random-effects model with double arcsine transformations stabilized variance in meta-analyses, and publication bias was evaluated using the “metabias” command. If bias was detected, we adjusted prevalence using the trim-and-fill method. A significant level of 0.05 was set for all analyses.

Out of 2116 articles, 214 were eligible for data extraction. The pooled prevalence of CoNS isolates in OIs was 25 % (95 % CI: 21–28; I² = 99.7 %), with Europe showing the highest prevalence at 30 % (95 % CI: 15–46; I²: 99.9 %) and Asia the lowest at 21 % (95 % CI: 19–24; I²: 98.68 %). The pooled prevalence of resistance among CoNS isolates from patients with OIs was 27 % (95 % CI: 19–35) for ciprofloxacin, 23 % (95 % CI: 12–34) for chloramphenicol, 41 % (95 % CI: 33–49) for tetracycline, and 40 % (95 % CI: 29–51) for trimethoprim/sulfamethoxazole.

In conclusion, CoNS are significant pathogens in OIs, highlighting the need for improved diagnostic tests and updated management guidelines globally.

细菌是眼部感染的主要原因，占全球病例的32%至74%。凝固酶阴性葡萄球菌（con）常被认为是所有类型oi的主要致病病原体。本研究系统回顾了全球oi中con的患病率及其对环丙沙星、氯霉素、四环素和甲氧苄啶/磺胺甲恶唑的耐药率。我们对2000年1月1日至2024年5月19日的出版物进行了全面的检索，使用了三个主要数据库：Scopus， Web of Science和PubMed。采用Stata 14.0进行统计分析，采用Metaprop软件包计算总患病率和置信区间。采用双反正弦变换的随机效应模型稳定了meta分析中的方差，并使用“meta”命令评估发表偏倚。如果检测到偏倚，我们使用修整填充法调整患病率。所有分析的显著水平为0.05。在2,116篇文章中，214篇符合数据提取条件。在oi中，con分离株的总患病率为25% (95% CI: 21-28；I2 = 99.7%)，欧洲的患病率最高，为30% (95% CI: 15-46；I2: 99.9%)，亚洲最低，为21% (95% CI: 19-24；I2: 98.68%)。来自OIs患者的con分离株的总耐药率为环丙沙星27% (95% CI: 19-35)，氯霉素23% (95% CI: 12-34)，四环素41% (95% CI: 33-49)，甲氧苄啶/磺胺甲恶唑40% （95% CI: 29-51）。总之，con是oi的重要病原体，这突出了全球改进诊断检测和更新管理指南的必要性。

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引用次数: 0

A tribute to Gary N. Foulks, M.D. (1944–2025) and his contributions to the ocular surface 致敬Gary N. Foulks， M.D.（1944-2025）和他对《眼表》的贡献。

IF 5.9 1区医学 Q1 OPHTHALMOLOGY

Ocular Surface

Pub Date : 2025-04-02 DOI: 10.1016/j.jtos.2025.03.009

Michael H. Goldstein , Deepinder Dhaliwal , Ed Isbey , Stephen Pflugfelder , Mark J. Mannis , Gary D. Novack

引用次数: 0

Smad4 deficiency ameliorates the progressive corneal stroma thinning caused by the loss of Tbr1 Smad4缺乏可改善由Tbr1缺失引起的进行性角膜基质变薄。

IF 5.9 1区医学 Q1 OPHTHALMOLOGY

Ocular Surface

Pub Date : 2025-04-01 Epub Date: 2025-01-31 DOI: 10.1016/j.jtos.2025.01.013

Yong Yuan , Shingo Yasuda , Kaitlyn L. Funk , Winston Kao , Shizuya Saika , Adam Kaufman , Chia-Yang Liu

Purpose

To understand how Tbr1 and Smad4 play a pivotal role in controlling ECM synthesis versus degradation for maintaining corneal stromal homeostasis and otherwise leading to corneal ectasia.

Methods

Keratocyte-specific and inducible knockout (iKO) of Tbr1, Smad4, or Tbr1/Smad4 double KO (iDKO) mice were generated. OCT was used to assess corneal thickness in vivo. Masson's trichrome and collagen hybridizing peptide stainings were performed to examine collagen expression. Immunostaining with an anti-cathepsin B antibody was used to assess ECM degradation. Cathepsin B inhibitor, CA-074Me, eyedrop was conducted to test its effect on treating stromal thinning in Tbr1 iKO mice.

Results

Tbr1 iKO and Smad4 iKO displayed corneal thinning, but Tbr1 iKO revealed a progressive and more severe pathology than Smad4 iKO. Tbr1 iKO cornea lost most of its stroma and thus a dome shape. Collagen ECM is evenly distributed in Smad4 iKO as well as control littermates but was lost mainly in the anterior stroma of the Tbr1 iKO. Interestingly, Tbr1/Smad4 iDKO ameliorated Tbr1 iKO phenotype. The basal level of Cathepsin b (Ctsb) could be detected in the control stroma but was significantly increased in the Tbr1 iKO stromal cells and this effect was canceled in Tbr1/Smad4 iDKO. CA-074Me eyedrops administration significantly inhibited progressive corneal thinning caused by the Tbr1 iKO.

Conclusion

Our data from Tbr1/Smad4 iDKO argued that Smad4 played a pivotal role in controlling Tbr1-dependent ECM synthesis and Tbr1-independent ECM degradation to maintain corneal stromal integrity and homeostasis.

目的：了解Tbr1和Smad4如何在控制ECM合成和降解中发挥关键作用，从而维持角膜基质稳态，从而导致角膜扩张。方法：制备角化细胞特异性诱导敲除（iKO） Tbr1、Smad4或Tbr1/Smad4双KO （iDKO）小鼠。OCT在体内评估角膜厚度。马松三色染色和胶原杂交肽染色检测胶原蛋白表达。用抗组织蛋白酶B抗体免疫染色来评估ECM的降解。采用组织蛋白酶B抑制剂CA-074Me滴眼液，观察其对tbr1iko小鼠间质变薄的治疗作用。结果：Tbr1 iKO和Smad4 iKO表现为角膜变薄，但Tbr1 iKO比Smad4 iKO表现为进行性且更严重的病理。tbr1ko角膜失去了大部分基质，因此呈圆顶状。胶原蛋白ECM在Smad4和对照幼崽中均匀分布，但主要在Tbr1幼崽的前间质中丢失。有趣的是，Tbr1/Smad4 iDKO改善了Tbr1 iKO表型。在对照基质中可以检测到组织蛋白酶b （Ctsb）的基础水平，但在Tbr1 iKO基质细胞中显著升高，而在Tbr1/Smad4 iDKO中这种影响被消除。CA-074Me滴眼液可显著抑制由Tbr1 iKO引起的进行性角膜变薄。结论：我们来自Tbr1/Smad4 iDKO的数据表明，Smad4在控制Tbr1依赖性ECM合成和Tbr1非依赖性ECM降解中发挥关键作用，以维持角膜基质的完整性和稳态。

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引用次数: 0

Differential homing of monocytes and neutrophils in the epithelial layer of HSV-1 infected cornea regulates viral dissemination and wound healing 单核细胞和中性粒细胞在HSV-1感染角膜上皮层的差异归巢调节病毒传播和伤口愈合。

IF 5.9 1区医学 Q1 OPHTHALMOLOGY

Ocular Surface

Pub Date : 2025-04-01 Epub Date: 2025-01-08 DOI: 10.1016/j.jtos.2025.01.002

Mizumi Setia, Pratima Krishna Suvas, Mashidur Rana, Anish Chakraborty, Susmit Suvas

Purpose

To ascertain the homing of monocytes and neutrophils in the epithelium versus stroma of HSV-1 infected corneas at different stages of infection and functional significance of their anatomical location in virus-infected corneas.

Methods

The corneas of C57BL/6J mice were infected with HSV-1 McKrae. Mice were euthanized on different days post-infection. The epithelium and stroma were separated from the infected corneas, and flow cytometry was performed to characterize the myeloid cell subsets in the epithelium versus the stromal layers of an infected cornea. MACS columns were used to purify neutrophils or deplete myeloid cells from infected corneas. Corneal epithelial scratch assay was performed to ascertain the impact of neutrophils on epithelium wound healing.

Results

Our results showed a biphasic influx of monocytes in the epithelial but not the stromal layer of HSV-1-infected corneas. Furthermore, we noted the predominance of monocytes over neutrophils in the epithelium and the stromal layer of the cornea during the pre-clinical stage of corneal HSV-1 infection. However, neutrophils were the major myeloid cell subset in the epithelium and stroma during the clinical disease period of infection. Removal of monocytes from the infected epithelial layer during the pre-clinical stage promotes the dissemination of the virus. Interestingly, neutrophils localized in the corneal epithelium inhibit corneal epithelial wound healing.

Conclusions

Together, our data suggest that differential kinetics of monocytes and neutrophils homing in the epithelial layer regulate viral dissemination and epithelial wound healing in HSV-1-infected corneas.

目的：探讨1型单纯疱疹病毒感染角膜不同感染阶段单核细胞和中性粒细胞在上皮和间质中的归巢情况及其在病毒感染角膜中解剖位置的功能意义。方法：C57BL/6J小鼠角膜感染HSV-1 McKrae。小鼠在感染后的不同天数被安乐死。从感染的角膜中分离上皮和间质，用流式细胞术表征感染角膜上皮和间质层中的髓样细胞亚群。用MACS柱从感染的角膜中纯化中性粒细胞或清除髓样细胞。采用角膜上皮划伤实验确定中性粒细胞对角膜上皮创面愈合的影响。结果：我们的结果显示单核细胞双期内流于hsv -1感染的角膜上皮层而非间质层。此外，我们注意到在角膜HSV-1感染的临床前阶段，单核细胞在角膜上皮和间质层中的优势大于中性粒细胞。然而，在感染的临床疾病期间，中性粒细胞是上皮和间质中主要的骨髓细胞亚群。在临床前阶段从受感染的上皮层去除单核细胞会促进病毒的传播。有趣的是，角膜上皮内的中性粒细胞抑制角膜上皮伤口愈合。结论：总之，我们的数据表明，单核细胞和中性粒细胞在上皮层归巢的差异动力学调节了hsv -1感染角膜的病毒传播和上皮伤口愈合。

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