A Novel Approach to Restore Sight after Corneal Chemical Injury

角膜化学损伤后恢复视力的新方法

基本信息

批准号：
10330580
负责人：
Haydee E.P. Bazan
金额：
$ 17.82万
依托单位：
LSU HEALTH SCIENCES CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-02-01 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10330580
关键词：
Alkalies Anti-Inflammatory Agents Arachidonic Acids Area Blindness Burn injury Cell Transplantation Cells Characteristics Chemical Burns Chemical Injury Chemicals Clinical Clinical Research Combined Modality Therapy Cornea Corneal Injury Corneal Stroma Corneal Ulcer Data Disease Emergency Situation Endothelium Epidermal Growth Factor Epithelial Experimental Models Extracellular Matrix Eye Eye Injuries Fibroblasts Flow Cytometry Future General Population Immunofluorescence Immunologic Infiltration Inflammation Inflammatory Inflammatory Response Injury Keratoplasty Laboratories Mesenchymal Stem Cells Metabolic Myofibroblast Necrosis Outcome Perforation Property Rattus Recurrence Reporting Research Stromal Cells T-Lymphocyte Testing Therapeutic Uses Time Tissues Transplantation Ulcer Visual Visual impairment Work base burn model cell stroma corneal burn corneal epithelium corneal repair cytokine improved in vivo innovation limbal lipid mediator lipoxin A4 macrophage melting neovascularization neutrophil novel novel strategies ocular surface preservation prevent protective effect reconstitution repaired sex sight restoration treatment response treatment strategy wound wound healing

项目摘要

Abstract Chemical burns to the eye are potentially blinding ocular injuries and constitute an ocular emergency requiring immediate assessment and initiation of treatment. They also constitute between 7-10% of the eye injuries in the general population. Out of all chemical injuries, alkali injuries are the most common and the most deleterious. Recurrent epithelial erosions, severe stromal inflammation, neovascularization, corneal ulceration and perforation are all prevalent complications of alkali burns. Currently, there is no successful treatment for severe damage to the cornea or to maintain corneal transparency. This proposal builds upon our previous findings that the lipid mediator, lipoxin A4 (LxA4), stimulates epithelial and endothelial wound healing, is involved in the reparative action of epidermal growth factor, and inhibits the inflammatory response stimulated after corneal injury. In addition, after severe alkali burn, there is a shortage of repair fibroblasts in ulcerated corneas, which is needed to synthesize components of the extracellular matrix (ECM) and to repair the stroma. The organizing hypothesis of the proposed research is that controlling the intense inflammatory response with LxA4 and reconstituting the ECM by stromal cell transplantation in a severe alkali burn model will avoid ulceration and neovascularization, thereby improving the visual outcome after severe ocular chemical injuries. We will test this hypothesis by pursuing two specific aims. In Specific Aim 1, we will use a severe rat alkali burn model (both sexes) to assess the action of LxA4 in in vivo clinical parameters and in inflammatory cytokines and conversion of macrophages type 1 (M1) to M2 by flow cytometry and immunofluorescence. In Specific Aim 2, we will investigate the anti-inflammatory action of the limbal stromal cells and combine treatment with LxA4 defined in Specific Aim 1 with cell transplantation of repair fibroblasts in the rat alkali burn model. We will determine clinical scores, presence of inflammatory cells, and ECM components after an early (3 days) and late (5 days) cell transplantation. The proposed studies, if successful, will target new approaches to investigate a novel treatment to control intense inflammation, to preserve the globe, and possibly, to restore transparency.

抽象的眼睛的化学灼伤可能会引起眼部损伤，构成了眼睛紧急状态立即评估和开始治疗。它们还构成了7-10％的眼部损伤一般人口。在所有化学损伤中，碱性受伤是最常见和最有害的。复发性上皮侵蚀，严重的基质炎症，新血管形成，角膜溃疡和穿孔都是碱烧伤的普遍并发症。目前，没有成功的治疗损害角膜或保持角膜透明度。这项建议是基于我们以前的发现脂质介质脂蛋白A4（LXA4）刺激上皮和内皮伤口愈合，参与表皮生长因子的修复作用，并抑制角膜后刺激的炎症反应受伤。此外，在严重的碱性燃烧后，溃疡角膜的修复成纤维细胞短缺，需要合成细胞外基质（ECM）的组件并修复基质。组织拟议研究的假设是控制用LXA4的强烈炎症反应并通过严重的碱燃烧模型中的基质细胞移植来重构ECM 溃疡和新血管形成，从而改善了严重的眼化学后的视觉结果受伤。我们将通过追求两个具体目标来检验这一假设。在特定的目标1中，我们将使用严重的老鼠碱性燃烧模型（两个性别），以评估LXA4在体内临床参数和炎症中的作用通过流式细胞术和免疫荧光，细胞因子和巨噬细胞1（M1）型巨噬细胞转化为M2。在特定的目标2，我们将研究缘层间基细胞的抗炎作用，并结合处理在特定目标1中定义的LXA4与大鼠碱燃烧模型中修复成纤维细胞的细胞移植。我们将在早期（3天）后确定临床评分，炎症细胞的存在和ECM成分晚期（5天）细胞移植。拟议的研究（如果成功）将针对调查的新方法一种用于控制强烈炎症的新颖治疗方法，以保护地球，甚至可以恢复透明度。