Effective Therapies for Ocular Injuries by Vesicating Agents

起泡剂治疗眼损伤的有效方法

• 批准号: 8333167
• 负责人: Rajesh Agarwal
• 金额: $ 75.45万
• 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 2017-08-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8333167
• 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; 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. PUBLIC HEALTH RELEVANCE: Despite the imminent threat of use as warfare and terrorist agents, effective therapies against vesicating chemical agents, sulfur mustard (SM)-, nitrogen mustard (NM)- and lewisite (LEW)-induced devastating ocular injuries, remain elusive. This is mainly due to the lack of established injury models, and inadequate study on the pathogenesis of eye lesions and associated mechanism/s; inappropriate engineering facilities to use these agents in experimental settings are an additional concern. Accordingly, the goals of this application are: a) develop NM-, SM- and LEW-induced ocular injury models, and define the associated mechanisms, and b) perform efficacy studies with mechanism-driven therapeutic agents. Our goals are supported by preliminary studies in rabbit corneal organ culture showing that NM-causes an increase in the inflammatory, vesication, and angiogenic responses, which are significantly reduced by the treatment with approved anti-inflammatory and antibiotic drugs as well as a natural flavanone, silibinin. Overall, the present application will test the hypothesi that most of the mechanisms involved in ocular injuries by vesicating agents 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. We anticipate that the study outcomes here will add to our understanding of the mechanism/s of action of NM-, SM- and LEW-induced ocular injuries, and identify effective mechanism-based broad-spectrum agent/s that, alone or in combination, provide safe and effective therapies against vesicating agents-induced ocular injuries in humans.

描述（由申请人提供）：尽管暴露于发泡剂硫芥子气（SM）、氮芥子气（NM）和砷泡泡剂刘易斯酸（LEW）会造成迫在眉睫的威胁和毁灭性的眼部伤害，但在大规模伤亡的情况下，有效的治疗方法仍然难以捉摸。这主要是由于缺乏成熟的动物损伤模型，对眼部病变的发病机制和相关机制的研究不足。这类研究的另一个实际限制是缺乏发泡剂的可用性和在实验环境中使用它们的适当设施。因此，本研究的首要目标是建立一种与泡泡剂（NM、SM和LEW）诱导眼损伤模型相关的综合策略，并确定相关机制。一旦实现，这将有助于我们对机制驱动的治疗剂进行疗效研究；这是这个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，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；抗炎药地塞米松和抗生素强力霉素（一种MMP抑制剂）以及天然药物水飞脂素均可显著降低纳米颗粒诱导的上皮厚度、上皮间质分离以及VEGF、COX-2和MMP-9水平，尽管水平不同。总的来说，基于上述理论基础和初步数据，本申请是可交付成果驱动的，并提出了一个假设，即去泡剂NM、SM和LEW引起眼部损伤的大多数机制遵循相似的途径，并且通过靶向这些途径，我们将能够开发出有效的广谱治疗去泡剂引起的眼部损伤。我们的具体目标是：1。充分表征和建立眼部损伤模型与囊泡剂。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、水肿和新生血管相关的机制。2. 评价机制靶向药物（单独或联合）和水飞蓟宾（一种多效药物，对起泡剂引起的皮肤损伤有很强的治疗效果）治疗眼部的疗效