Blocking Arsenicals-induced Cutaneous Injury

 描述（由申请人提供）：砷剂，如路易氏剂、二乙基氯胂、二苯基氯胂和二苯基氰胂已被确定为潜在的战争威胁剂，可用于化学战。已知局部暴露于这些药剂会导致严重的皮肤起泡和炎症。在本申请中，我们将测试上述砷剂是否在小鼠（有毛但剃毛）和小型猪模型中引起与人类报告相似的多发性皮肤起泡和炎症效应。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，在无毛小鼠模型砷渗透皮肤，破裂的皮肤屏障功能的结果与紧密连接和水/甘油运输的蛋白质的破坏。这些作用主要通过激活河马信号通路蛋白雅普等介导。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）信号转导介导的。UPR途径是由砷依赖性活性氧（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，我们将揭示这些复杂的信号通路之间的串扰是否导致疼痛性水泡和炎症的发病机制。基于这些新的数据，研究小分子如UPR信号传导抑制剂（也称为化学分子伴侣）、4-苯基丁酸和salubrinal单独或与砷螯合剂、英国抗路易氏剂（BAL）或抗氧化剂N-乙酰半胱氨酸组合阻断这些分子靶点是否可以阻断这些作用也很有吸引力。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，用于阻断皮肤暴露于这些化学品后疼痛的严重皮肤损伤。我们还建议测试皮肤暴露于这些化学品是否表现出全身损伤，以及局部应用这些解毒剂是否可以预防这些化学品的全身效应。提出了三个具体目标，每个目标都有自己的里程碑，以揭示砷剂在两种动物模型中的发病机制，并开发针对这些药物的潜在解毒剂，并确定其有效性。如果发现有效，基于其已知毒性特征和FDA批准用于其他皮肤起泡和炎症无关病症的先导化合物很可能很容易获得批准。拟议研究的结果很可能对在不幸的情况下大规模人口接触这类战争威胁化学品的情况下保护人类健康产生重大影响。

 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.