Effective Therapies for Ocular Injuries by Vesicating Agents

起泡剂治疗眼损伤的有效方法

• 批准号: 9139458
• 负责人: Rajesh Agarwal
• 金额: $ 73.55万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9139458
• 关键词: Angiogenic Factor; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antibiotics; Apoptotic; Arsenicals; Biological; Biological Markers; Blindness; Bulla; Burn injury; Cell Death; Cessation of life; Chemical Agents; Chemical Weapons; Conjunctivitis; Cornea; Corneal Opacity; Corneal Ulcer; Country; DNA; Data; Deterioration; Development; Dexamethasone; Doxycycline; Engineering; Epithelial; Exhibits; Exposure to; Eye; Eye Injuries; Eyelid structure; Flavanones; Flavonoids; Formulation; Gelatinase B; Goals; Histopathology; Human; Inflammation; Inflammatory; Injury; Lead; Lesion; Matrix Metalloproteinase Inhibitor; Matrix Metalloproteinases; Mechlorethamine; Military Personnel; Modeling; Mustard Agent; Mustard Gas; Necrosis; Organ; Organ Culture Techniques; Oryctolagus cuniculus; Outcome; Outcome Study; Oxidative Stress; PTGS2 gene; Pain; Pathogenesis; Pathology; Pathway interactions; Pharmaceutical Preparations; Play; Proteins; Reporting; Role; Skin injury; Symptoms; Testing; Therapeutic; Therapeutic Agents; Thick; Treatment Efficacy; Ulcer; Vascular Endothelial Growth Factors; Vesicants; Visual; War; base; chemokine; corneal epithelium; crosslink; cytokine; effective therapy; in vivo; lewisite; mass casualty; neovascularization; response; silibinin; targeted agent

DESCRIPTION (provided by applicant): Despite the imminent threat and devastating ocular injuries by exposure to vesicating agents sulfur mustard (SM), nitrogen mustard (NM) and arsenical vesicant, lewisite (LEW), effective therapies in case of a mass casualty remain elusive. This is mainly due to the lack of established animal injury models and inadequate study on the pathogenesis of eye lesions and associated mechanism/s. An additional practical limitation for such studies has also been a lack of availability of vesicating agents and appropriate facilities to use them in experimental settings. Accordingly, the first and foremost goal of this application is to develop a comprehensive strategy related to establishing vesicant agents (NM, SM and LEW)-induced ocular injury models and define the associated mechanisms. Once achieved, this will help us perform efficacy studies with mechanism-driven therapeutic agents; this is the second major goal of this application. Both our goals are supported by preliminary studies in rabbit corneal organ culture showing that NM exposure increases epithelial thickness, apoptotic cell death, epithelial-stromal separation, levels of VEGF, COX-2 and MMP-9; and that approved prescription agents anti-inflammatory drug dexamethasone and antibiotic doxycycline (an MMP inhibitor) as well as a natural agent silibinin significantly reduce NM-induced epithelial thickness, epithelial-stromal separation, and VEGF, COX-2 and MMP-9 levels, albeit at different levels. Overall, based on above rationale and preliminary data, this application is deliverables driven and proposes to test the hypothesis that most of the mechanisms involved in ocular injuries by vesicating agents NM, SM and LEW follow similar pathways, and that , by targeting those pathways, we would be able to develop effective and broad-spectrum therapies against vesicants-induced ocular injuries. Our specific aims are: 1. Fully characterize and establish ocular injury models with vesicating agents. Specifically, we will assess biological alterations and identify associated mechanisms including those related to inflammation, vesication and neovascularization. 2. Evaluate the efficacy of mechanism-targeted agents (alone or in combination) and silibinin (a pleiotropic agent with strong therapeutic efficacy against blistering agents-induced skin injuries) in treating the ocular injuries by NM. 3. Assess and establish the efficacy of the agent/s found effective in treating NM-induced ocular injuries in Aim 2, for the rescue of SM- and LEW-induced ocular injuries in rabbit. We anticipate that the proposed studies will establish useful ocular injury models with vesicants, and add to our understanding of the mechanism/s of action of NM-, SM- and LEW-induced ocular injuries. In addition, these comprehensive study efforts will identify effective broad spectrum mechanism-based agent/s that alone or in combination provide effective therapies against vesicating agents-induced ocular injuries in humans.

描述（由申请人提供）：尽管遭受了威胁和毁灭性的眼部伤害，但暴露于囊泡剂硫芥末（SM），氮芥末（NM）和砷囊泡药物（Lewisite（LEW）），在大规模伤亡中仍然难以捉摸。这主要是由于缺乏已建立的动物损伤模型和对眼病变和相关机制的发病机理的研究不足。此类研究的另一个实际限制也是缺乏在实验环境中使用它们的囊泡剂和适当的设施。因此，本应用的第一个也是最重要的目标是制定与建立囊泡剂（NM，SM和LEW）引起的眼部损伤模型相关的综合策略，并定义了相关的机制。一旦实现，这将有助于我们使用机构驱动的治疗剂进行功效研究。这是该应用程序的第二个主要目标。我们的两个目标都得到了兔角膜器官培养的初步研究的支持，表明NM暴露会增加上皮厚度，凋亡细胞死亡，上皮细胞分离，VEGF，COX-2和MMP-9的水平。并且批准处方药抗炎药物地塞米松和抗生素多西环素（MMP抑制剂）以及天然剂硅酸盐明显降低NM诱导的上皮厚度，上皮细胞分离，上皮分离，vegff，cox-2和MMP-9和MMP-9水平，ALBEIT在不同的水平。 Overall, based on above rationale and preliminary data, this application is deliverables driven and proposes to test the hypothesis that most of the mechanisms involved in ocular injuries by vesicating agents NM, SM and LEW follow similar pathways, and that , by targeting those pathways, we would be able to develop effective and broad-spectrum therapies against vesicants-induced ocular injuries.我们的具体目的是：1。充分表征并建立具有囊泡剂的眼损伤模型。具体而言，我们将评估生物学改变并确定相关机制，包括与炎症，囊泡和新血管形成相关的机制。 2。评估靶向机理的剂量（单独或组合）和硅酸盐素（具有强烈治疗疗效的抗泡器诱导的皮肤损伤的多效剂）在治疗眼部的功效 NM受伤。 3。评估并确定因AIM 2中NM诱导的眼部损伤有效治疗的药物的功效，以挽救兔子中SM和LEW诱导的眼部损伤。我们预计拟议的研究将用囊泡建立有用的眼部损伤模型，并增加我们对NM，SM-和LEW诱导的眼部损伤的作用机理/S的理解。此外，这些全面的研究工作将确定有效的基于广谱机制的药物，单独或结合起来提供有效的疗法，以防止囊泡剂引起的人类造成的眼部损伤。