Blocking Arsenicals-induced Cutaneous Injury

阻止砷引起的皮肤损伤

• 批准号: 8928418
• 负责人: Mohammad Athar
• 金额: $ 73.35万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-15 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8928418
• 关键词: Acids; Acute; Amines; Animal Model; Antidotes; Antioxidants; Area; Arsenic; Arsenicals; Attenuated; Biological; Biological Assay; Biological Markers; Biological Models; Blood capillaries; British; Bulla; Carrier Proteins; Categories; Cell Degranulation; Chelating Agents; Chemical Agents; Chemical Warfare; Chemical Warfare Agents; Chemicals; Clinical; Cutaneous; Cysteine; DNA Alkylation; DNA Damage; Data; Dermal; Dermatology; Development; Digestion; Dose; Edema; Effectiveness; Eicosanoids; Epidermis; Erythema; Event; Exposure to; Extravasation; FDA approved; Family suidae; Filament; Glutathione; Glycerol; Health protection; Hepatic Tissue; Human; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Injury; Intercept; Kinetics; Lead; Lesion; Leukocytes; Liquid substance; Lung; Mediating; Miniature Swine; Modeling; Molecular; Molecular Biology; Molecular Chaperones; Molecular Target; Molecular Weight; Mus; Mustard Agent; Organ; Outcome; Oxidative Stress; Pain; Pathogenesis; Pathway interactions; Penetration; Peptide Hydrolases; Population; Process; Production; Protective Agents; Proteins; Reaction; Reactive Nitrogen Species; Reactive Oxygen Species; Regulation; Regulatory Pathway; Renal Tissue; Reporting; Research; Rupture; Scientist; Signal Pathway; Signal Transduction; Skin; Subcutaneous Tissue; Testing; Therapeutic; Tight Junctions; Time; Tissues; Topical application; Toxic effect; Toxicology; United States National Institutes of Health; Vesicants; Vesicle; Visual; War; Water; attenuation; base; capillary; chemokine; cytokine; diphenyl; experience; in vitro Assay; inhibitor/antagonist; interest; keratinocyte; lewisite; macrophage; mast cell; novel; occludin; pre-clinical; prevent; programs; public health relevance; research study; response; screening; skin lesion; small molecule; translational approach; water channel

 DESCRIPTION (provided by applicant): Arsenicals, such as lewisite, diethylchloroarsine, diphenyl chlorarsine, and diphenyl cyanoarsine have been identified as potential war-threat agents, which could be used in chemical warfare. Topical exposure to these agents is known to result in severe cutaneous blistering and inflammation. In this application, we will test whether these arsenicals as listed above cause similar multiple cutaneous blistering and inflammatory effects in murine (haired but shaved) and mini-pig models as reported in humans. We will also investigate the molecular mechanisms by which these effects are manifested in these animal model systems. Our preliminary data indicate that in hairless murine model arsenicals by penetrating skin, rupture the cutaneous barrier functions as a consequence of disruption of proteins associated with tight junctions and water/glycerin transport. These effects are mediated mainly via activation of hippo signaling pathway protein, Yap besides others. Our data also show that the acute inflammation is mediated through the activation of unfolded protein response (UPR) signaling. UPR pathway is triggered by the arsenicals-dependent reactive oxygen species (ROS) production and activation of DNA damage response signaling. Based on these preliminary results, we will unravel whether crosstalk between these intricate signaling pathways results in the pathogenesis of painful blisters and inflammation. Based on these novel data, it is also tempting to investigate whether blocking these molecular targets by small molecules such as UPR signaling inhibitors also known as chemical chaperones, 4- phenylbutyric acid and salubrinal alone or in combination with arsenic chelator, British anti-lewisite (BAL) or antioxidant N-acetyl cysteine may intercept these effects. This will provide a molecular pathogenesis-based translational approach to develop effective interceptors/antidotes for blocking painful severe skin damage following cutaneous exposure to these chemicals. We are also proposing to test whether cutaneous exposure to these chemicals manifests systemic damage and whether topical application of these antidotes can prevent systemic effects of these chemicals. Three specific aims, each with their own milestones, are proposed to unravel the mechanism of pathogenesis by arsenicals in two animal models and to develop potential antidotes against these agents with defined window of their effectiveness. It is highly likely thatif found effective, the lead compounds based on their known toxicity profile and FDA approved use for other cutaneous blistering and inflammation-unrelated conditions can easily be approved. The outcome of the proposed research is likely to have a significant impact on human health protection in the unfortunate event of mass population exposure to this category of war-threat chemicals.

 说明书(申请人提供)：刘易斯、二乙基氯砷、二苯基氯砷和二苯氰砷等军火库已被确定为潜在的战争威胁剂，可用于化学战。众所周知，局部暴露于这些药物会导致严重的皮肤起泡和炎症。在这项应用中，我们将测试上面列出的这些军火药是否会在小鼠(有毛但没有毛)和小型猪模型中引起类似的多发性皮肤起泡和炎症效应，这一点在人类模型中得到了报道。我们还将研究这些效应在这些动物模型系统中表现出来的分子机制。我们的初步数据表明，在无毛小鼠模型中，通过穿透皮肤，皮肤屏障功能的破坏是与紧密连接和水/甘油运输相关的蛋白质中断的结果。这些作用主要通过激活河马信号通路蛋白、YAP等途径来实现。我们的数据还表明，急性炎症是通过激活未折叠蛋白反应(UPR)信号来介导的。UPR通路是由砷依赖的活性氧物种(ROS)的产生和DNA损伤反应信号的激活触发的。基于这些初步结果，我们将解开这些错综复杂的信号通路之间的串扰是否导致疼痛水泡和炎症的发病机制。基于这些新的数据，也很容易研究是否小分子，如UPR信号抑制剂，也称为化学伴侣，4-苯基丁酸和Salubrine单独或与砷螯合剂，英国抗路易斯汀(BAL)或抗氧化剂N-乙酰半胱氨酸一起阻断这些作用。这将提供一种基于分子发病机制的翻译方法，以开发有效的拦截剂/解毒剂来阻止皮肤暴露于这些化学物质后的疼痛和严重皮肤损伤。我们还建议测试皮肤暴露于这些化学物质是否表现出全身损害，以及局部应用这些解毒剂是否可以防止这些化学物质的全身影响。提出了三个特定的目标，每个目标都有自己的里程碑，以揭示砷化合物在两个动物模型中的致病机制，并开发针对这些药物的潜在解毒剂，并确定其有效性窗口。如果发现有效，根据已知的毒性特征和FDA批准的用于其他皮肤起泡和炎症无关疾病的先导化合物，很可能很容易获得批准。拟议的研究结果可能会对人类健康保护产生重大影响，因为不幸的是，如果人们大量接触这类具有战争威胁的化学品。