Amelioration of Vesicant-Induced Skin Injury by High Dose 25-Hydroxyvitamin D

高剂量 25-羟基维生素 D 改善出疱剂引起的皮肤损伤

• 批准号: 8545673
• 负责人: Kurt Lu
• 金额: $ 78.9万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-15 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8545673
• 关键词: 25-hydroxyvitamin D; Acute; Address; Aftercare; Alkylating Agents; Attenuated; Autologous; Automobile Driving; Biological Assay; Biological Markers; Bulla; Calcifediol; Calcitriol; Cancer Patient; Carmustine; Cell Death; Cells; Cellular Infiltration; Chemicals; Cholecalciferol; Clinical; Clinical Trials; Cutaneous; Data; Dermatology; Development; Dose; Epithelial Cells; Evaluation; Event; Exhibits; Exposure to; Genetically Engineered Mouse; Health; Hour; Human; Immune; Immune response; Impaired wound healing; In Vitro; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Injury; Knockout Mice; Lead; Macrophage Activation; Mechlorethamine; Mediating; Medical center; Medicine; Modeling; Monitor; Morbidity - disease rate; Mus; Mustard; Mustard Gas; NF-kappa B; Nitrosourea Compounds; Oral; Organ; Oxidative Stress Induction; Patients; Process; Production; Recruitment Activity; Regulator Genes; Reporting; Research Infrastructure; Sampling; Serum; Severities; Signaling Molecule; Site; Skin; Specificity; Staining method; Stains; Stimulus; Study models; Supplementation; Symptoms; System; Techniques; Testing; Therapeutic Intervention; Tissues; Translating; Tumor Necrosis Factor-alpha; Universities; University Hospitals; Vesicants; Vitamin D; Vitamin D3 Receptor; Work; Wound Healing; attenuation; biological adaptation to stress; chemotherapy; cohort; human NOS2A protein; human tissue; in vivo; inhibitor/antagonist; keratinocyte; lewisite; macrophage; migration; monocyte; mouse model; multidisciplinary; nitrosative stress; novel; novel therapeutics; prevent; prospective; response; success; translational approach; translational study; weapons

DESCRIPTION (provided by applicant): Direct cutaneous exposure to vesicants such as nitrogen mustard or nitrogen mustard-related nitrosoureas (BCNU (carmustine)) produce dose-dependent symptoms that are varied in onset, severity and duration of wound healing. Although exposure to the vesicant itself evokes a primary injury (1st hit), the direct insult to the skin results in a delayed influx of activated hyper-inflammatory monocyte/macrophages (M) that constitute an additional insult to the skin (2nd hit) that promotes catastrophic skin injury. However, the interval between the first and second tissue hits represents a countermeasure opportunity. Attenuation of M activation by vitamin D has been reported, and in a clinical anecdotal confirmation of this effect, we have recently treated a patient who exhibited a persistent toxic skin response following topical BCNU treatment using oral vitamin D. This success leads us to hypothesize that attenuating hyper-activated M with 25(OH) D3 will be an effective countermeasure that halts progression of skin destruction, a key morbidity factor following exposure to vesicants. The multidisciplinary translational approach presented here that takes advantage of a strong infrastructure in the Departments of Dermatology and Medicine at Case Western Reserve University and University Hospitals Case Medical Center. Human clinical trial samples as well as murine in vivo and in vitro samples will be used assess the potential for vitamin D to act as a countermeasure to skin damage elicited by M activation following nitrosurea and nitrogen mustard exposure. We have organized a team of national experts to evaluate our progress and help identify complementary approaches to the proposed work. Using human clinical samples obtained from ongoing trials of alkylating agents as well as murine skin samples obtained post-treatment with mechlorethamine we propose to assess: 1.) The level of M infiltration and activation using induction of the soluble signaling molecules TNFa and iNOS in pre- and post-BCNU exposed tissue. We will further 2.) Determine whether vitamin D supplementation modulates tissue destruction and if this is mediated by changes in M¿ activation. Use of a macrophage-restricted VDR knockout mouse system will confirm the specificity of M mediated response. Finally, we will 3.) Begin a vitamin D interventional trial utilizing patients exposed to topical BCNU and nitrogen mustard to assess alteration of inflammatory biomarkers, cellular infiltration and immunohistochemical staining of hyper-activated M in patients while monitoring changes in serum vitamin D levels from baseline to post-therapy. Serum collected pre- and post- supplementation will be assayed for direct suppression of autologous macrophage activation in vitro. Successful implementation of this strategy is likely to save lives in the event of mass exposure as vitamin D is safe and widely available. Demonstration that vitamin D-related compounds protect against tissue destruction mediated by vesicants will lead to advanced evaluation of this potential therapeutic intervention.

描述（由申请方提供）：直接皮肤暴露于起疱剂，如氮芥或氮芥相关亚硝基脲（BCNU（卡莫司汀）），会产生剂量依赖性症状，这些症状的发作、严重程度和伤口愈合持续时间各不相同。尽管暴露于发泡剂本身引起原发性损伤（第一次撞击），但对皮肤的直接损伤导致活化的高度炎症单核细胞/巨噬细胞（M）的延迟流入，这构成对皮肤的额外损伤（第二次撞击），从而促进灾难性皮肤损伤。然而，第一次和第二次组织撞击之间的间隔表示对策机会。已经报道了维生素D对M激活的减弱作用，在对这种作用的临床轶事证实中，我们最近治疗了一名患者，该患者在使用口服维生素D局部BCNU治疗后表现出持续的毒性皮肤反应。这一成功使我们假设，用25（OH）D3减弱超活化M将是一种有效的对策，可以阻止皮肤破坏的进展，皮肤破坏是暴露于水疱剂后的一个关键发病因素。这里介绍的多学科翻译方法利用了凯斯西储大学和大学医院凯斯医学中心皮肤科和医学系的强大基础设施。将使用人临床试验样本以及鼠体内和体外样本评估维生素D作为亚硝基脲和氮芥暴露后M活化引起的皮肤损伤对策的潜力。我们组织了一个国家专家小组，以评估我们的进展，并帮助确定对拟议工作的补充办法。使用从正在进行的烷化剂试验中获得的人类临床样品以及用氮芥治疗后获得的鼠皮肤样品，我们建议评估：1.在BCNU暴露前和暴露后的组织中，使用可溶性信号分子TNF α和iNOS诱导的M浸润和活化水平。我们将继续2）。确定维生素D补充是否调节组织破坏，以及这是否是由M？激活的变化介导的。使用巨噬细胞限制性VDR敲除小鼠系统将证实M介导的应答的特异性。最后，我们将（3）。开始一项维生素D干预试验，利用暴露于局部BCNU和氮芥的患者，评估患者炎症生物标志物、细胞浸润和超活化M的免疫组化染色的变化，同时监测血清维生素D水平从基线到治疗后的变化。将测定补充前和补充后收集的血清对体外自体巨噬细胞活化的直接抑制。由于维生素D是安全的，而且可以广泛获得，因此成功实施这一战略有可能在大规模接触维生素D的情况下挽救生命。证明维生素D相关化合物可防止由水疱剂介导的组织破坏，将导致对这种潜在治疗干预的高级评估。