Effective Therapies for Ocular Injuries by Vesicating Agents

起泡剂治疗眼损伤的有效方法

• 批准号: 8726411
• 负责人: Rajesh Agarwal
• 金额: $ 74.69万
• 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 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8726411
• 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; Drug Formulations; Engineering; Epithelial; Exhibits; Exposure to; Eye; Eye Injuries; Eyelid structure; Flavanones; Flavonoids; 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; 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

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）：尽管暴露于起泡剂硫芥（SM）、氮芥（NM）和砷起泡剂、路易斯（LEW）会造成迫在眉睫的威胁和毁灭性的眼部损伤，但在发生大规模伤亡的情况下，有效的治疗方法仍然难以捉摸。这主要是由于缺乏建立的动物损伤模型以及对眼部病变发病机制和相关机制的研究不足。此类研究的另一个实际限制还在于缺乏发泡剂和在实验环境中使用它们的适当设施。因此，本申请的首要目标是制定与建立起泡剂（NM、SM 和 LEW）诱导的眼损伤模型相关的综合策略并定义相关机制。一旦实现，这将有助于我们利用机制驱动的治疗药物进行疗效研究；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，该研究表明，NM 暴露会增加上皮厚度、凋亡细胞死亡、上皮-基质分离、VEGF、COX-2 和 MMP-9 的水平；批准的处方药抗炎药地塞米松和抗生素强力霉素（一种 MMP 抑制剂）以及天然药物水飞蓟宾可显着降低 NM 诱导的上皮厚度、上皮基质分离以及 VEGF、COX-2 和 MMP-9 水平，尽管处于不同的级别。总体而言，基于上述基本原理和初步数据，该应用程序是可交付成果驱动的，并提出测试以下假设：起泡剂 NM、SM 和 LEW 引起眼部损伤的大多数机制都遵循相似的途径，并且通过针对这些途径，我们将能够开发针对出疱剂引起的眼损伤的有效且广谱的疗法。我们的具体目标是： 1. 充分表征并建立使用起泡剂的眼损伤模型。具体来说，我们将评估生物学改变并确定相关机制，包括与炎症、起泡和新血管形成相关的机制。 2. 评估机制靶向药物（单独或联合）和水飞蓟宾（一种对起泡剂引起的皮肤损伤具有强大治疗效果的多效药物）治疗眼部疾病的疗效 NM 造成的伤害。 3. 评估并确定目标 2 中发现的可有效治疗 NM 引起的眼损伤的药剂的功效，以拯救 SM 和 LEW 引起的兔子眼损伤。我们预计所提出的研究将建立有用的起泡剂眼损伤模型，并加深我们对 NM、SM 和 LEW 引起的眼损伤作用机制的理解。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，这些药物单独或组合提供针对起泡剂引起的人类眼损伤的有效疗法。