Effective Therapies for Ocular Injuries by Vesicating Agents

描述（由申请人提供）：尽管暴露于起泡剂硫芥（SM）、氮芥（NM）和砷起泡剂路易氏剂（LEW）会造成迫在眉睫的威胁和毁灭性的眼部损伤，但在大规模伤亡的情况下，有效的治疗方法仍然难以实现。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。这种研究的另一个实际限制是缺乏起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开发与建立发泡剂（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，这将有助于我们使用机制驱动的治疗药物进行疗效研究;这是本申请的第二个主要目标。在兔角膜器官培养中的初步研究支持了我们的两个目标，显示NM暴露增加上皮厚度、凋亡细胞死亡、上皮-基质分离、VEGF、考克斯-2和MMP-9的水平;而批准的处方药抗炎药地塞米松和抗生素强力霉素（MMP抑制剂）以及天然试剂水飞蓟宾显著降低NM诱导的上皮厚度、上皮-基质分离以及VEGF、考克斯-2和MMP-9水平，尽管是在不同的层面上。总体而言，基于上述基本原理和初步数据，本申请是可交付成果驱动的，旨在检验以下假设：发泡剂NM、SM和LEW引起眼损伤的大部分机制遵循相似的途径，通过靶向这些途径，我们将能够开发针对发泡剂诱导的眼损伤的有效和广谱疗法。我们的具体目标是：1.充分表征和建立水泡剂眼损伤模型。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，水疱和新血管形成相关的机制。2.评价机制靶向药物（单独或联合）和水飞蓟宾（一种对起泡剂诱导的皮肤损伤具有较强治疗效果的多效性药物）治疗眼部疾病的疗效。 伤害NM 3.评估并确定目标2中发现的有效治疗NM诱导的眼损伤的药物的有效性，以挽救SM和LEW诱导的兔眼损伤。我们预计，拟议的研究将建立有用的眼损伤模型与水疱剂，并增加我们的理解的机制/S的NM-，SM-和LEW诱导的眼损伤。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可提供有效的治疗方法，以对抗人类中由起泡剂诱导的眼损伤。

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.