Eosinophil Peroxidase in Allergic Inflammation

过敏性炎症中的嗜酸性粒细胞过氧化物酶

• 批准号: 7505972
• 负责人: ARNE SLUNGAARD
• 金额: $ 44.7万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-20 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7505972
• 关键词: 3-nitrotyrosine; Adenocarcinoma; Agonist; Allergic; Amino Acids; Animals; Anions; Antibodies; Apoptosis; Apoptotic; Area; Asthma; Attenuated; Biological Markers; Blood; Blood Circulation; Bromides; Buffers; Carcinogens; Cells; Chloride Ion; Chlorides; Chronic; Clinical; Communities; Consumption; Crossbreeding; Cyanides; Cytoplasmic Granules; Data; Detection; Development; Dextran Sulfate; Dietary Supplementation; Dietary intake; Disease; Disseminated eosinophilic collagen disease; Employee Strikes; Feces; Food; Gene Expression; Generations; Glycosides; Goals; Grant; Hepatic; Human; Hydrogen Peroxide; Hypersensitivity; Hypochlorous Acid; Hypochlorous Acids; In Situ; In Vitro; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Injury; Irrigation; Knockout Mice; Leukocytes; Liquid substance; Loeffler' s Endocarditis; Lysine; Malignant - descriptor; Mammalian Cell; Mediating; Metabolic; Microscopic; Modeling; Monitor; Mouse Protein; Mus; Necrosis; Nitrites; Oral; Ovalbumin; Oxidants; Parasites; Parasitic Diseases; Pathogenesis; Pathologic; Pathology; Patients; Peroxidase; Peroxidases; Phagocytes; Phenotype; Physiological; Play; Poison; Post-Translational Protein Processing; Proteins; Public Health; Reaction; Relative (related person); Respiratory Burst; Role; Role playing therapy; Serum; Severities; Site; Small inducible cytokine A24; Smoke; Supplementation; Symptoms; System; Testing; Therapeutic; Thiocyanates; Thiosulfate Sulfurtransferase; Tissues; Toxic effect; Transcription Coactivator; Transgenic Model; Ulcerative Colitis; Vegetables; Weight; Work; base; carcinogenesis; cytotoxic; eosinophil; eosinophil peroxidase; hypobromous acid; in vivo; neutrophil; novel; oxidation; peripheral blood; prevent; thiocyanate

DESCRIPTION (provided by applicant): Eosinophil (EO) phagocytes can damage host tissue and contribute to the pathogenesis of allergic inflammatory diseases such as asthma and inflammatory bowel diseases (IBD). EO specific granules are endowed with abundant amounts of EO peroxidase (EPO) and a vigorous respiratory burst that generates H2O2 to fuel the generation of other oxidants. However, little is known about the contribution of EPO-mediated oxidative damage to the pathology of eosinophilic inflammatory states. We find that three unusual substrates -- bromide (Br-), nitrite (NO2-), and thiocyanate (SCN-) -- compete for oxidation by EPO in physiologic fluids in the presence of H2O2, yielding, respectively, HOBr, NO2, and HOSCN. The relative toxicity of these oxidants for human cells is HOBr > NO2 >> HOSCN; yet EPO preferentially oxidizes SCN- > NO2- > Br-. We hypothesize that SCN- "buffers" against generation by EPO of the more cytotoxic NO2-- and Br-- based oxidants and consequently serum SCN- levels, which are dietarily determined, may modulate EPO toxicity. The overall goal of our proposed work is to examine the hypothesis that that EPO-generated oxidants impose damage in a substrate-determined manner to host tissue and EOs themselves. Our first specific aim s to test the hypothesis that substrate modulation of EPO toxicity by dietary supplementation with either thiocyanate or its metabolic precursors, cyanide-like compounds, ameliorates the severity of inflammatory bowel disease in a murine dextran sulfate model. Our second specific aim is to test the hypothesis that in a novel murine IL- 5/Eotaxin-2 (I5/E2) transgenic model of asthma, 1) crossbreeding with EPO-/- mice, 2) pharmacologic inhibition of EPO enzymatic activity, and 3) dietary SCN- supplementation all ameliorate the severe asthmatic phenotype which develops in these animals both spontaneously and after ovalbumin (OVA) sentitization and challenge. The third specific aim is to test the hypothesis that the EPO/H2O2/SCN- system functions through an NF-(B-dependent mechanism to inhibit eosinophil apoptosis and deleterious secondary necrotic degranulation. These studies, if successful, will prove a role for EPO-mediated oxidant damage in the pathogenesis of asthma and IBD and suggest a simple strategy for its treatment-- i.e., dietary supplementation with inexpensive and innocuous SCN/-- that could be applied to these and other allergic inflammatory diseases even in impoverished communities. PUBLIC HEALTH RELEVANCE: In this grant we will test whether thiocyanate, a simple, inexpensive and non-toxic chemical compound found in vegetables, can be ingested to treat asthma and ulcerative colitis, two serious allergic diseases. We believe this is possible because thiocyanate blunts tissue damage caused by eosinophils, a type of white cell that causes allergic symptoms and diseases. If these studies succeed, we will have discovered a simple, cheap and safe way to treat allergies.

描述（由申请人提供）：嗜酸性粒细胞（EO）吞噬细胞可以损伤宿主组织并促进过敏性炎症疾病（例如哮喘和炎症性肠病（IBD））的发病机制。 EO 特定颗粒含有大量的 EO 过氧化物酶 (EPO) 和剧烈的呼吸爆发，产生 H2O2 来促进其他氧化剂的产生。然而，人们对 EPO 介导的氧化损伤对嗜酸性粒细胞炎症状态病理学的贡献知之甚少。我们发现三种不常见的底物——溴化物 (Br-)、亚硝酸盐 (NO2-) 和硫氰酸盐 (SCN-)——在 H2O2 存在的情况下，在生理液中竞争被 EPO 氧化，分别产生 HOBr、NO2 和 HOSCN。这些氧化剂对人体细胞的相对毒性为HOBr>NO2>>HOSCN；但EPO优先氧化SCN->NO2->Br-。我们假设 SCN-“缓冲”EPO 生成更具细胞毒性的 NO2- 和 Br-- 基氧化剂，因此血清 SCN- 水平（由饮食决定）可能调节 EPO 毒性。我们提出的工作的总体目标是检验以下假设：EPO 产生的氧化剂以底物决定的方式对宿主组织和 EO 本身造成损害。我们的第一个具体目标是测试以下假设：通过饮食补充硫氰酸盐或其代谢前体、氰化物样化合物来调节 EPO 毒性的底物，可改善小鼠硫酸葡聚糖模型中炎症性肠病的严重程度。我们的第二个具体目标是测试这样的假设：在新型小鼠 IL-5/Eotaxin-2 (I5/E2) 转基因哮喘模型中，1) 与 EPO-/- 小鼠杂交，2) EPO 酶活性的药理学抑制，以及 3) 膳食 SCN 补充剂均能改善这些动物自发和之后发生的严重哮喘表型。 卵清蛋白 (OVA) 致敏和挑战。第三个具体目标是检验以下假设：EPO/H2O2/SCN 系统通过 NF-(B 依赖性机制) 抑制嗜酸性粒细胞凋亡和有害的继发性坏死脱粒。这些研究如果成功，将证明 EPO 介导的氧化损伤在哮喘和 IBD 发病机制中的作用，并提出一种简单的治疗策略，即饮食 补充廉价且无害的 SCN/-- 即使在贫困社区也可以应用于这些疾病和其他过敏性炎症疾病。 公共健康相关性：在这笔拨款中，我们将测试硫氰酸盐（一种在蔬菜中发现的简单、廉价且无毒的化合物）是否可以通过摄入来治疗哮喘和溃疡性结肠炎这两种严重的过敏性疾病。我们相信这是可能的，因为硫氰酸盐可以减轻嗜酸性粒细胞（一种引起过敏症状和疾病的白细胞）引起的组织损伤。如果这些研究成功，我们将发现一种简单、廉价且安全的治疗过敏的方法。