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: 7866659
• 负责人: ARNE SLUNGAARD
• 金额: $ 45.49万
• 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/7866659
• 关键词: 3-nitrotyrosine; Adenocarcinoma; Agonist; Allergic; Allergic Disease; Allergic inflammation; 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; 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; Peroxidases; Phagocytes; Phenotype; Physiological; Play; Poison; Post-Translational Protein Processing; Proteins; Reaction; Relative (related person); Respiratory Burst; Role; 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; oxidative damage; peripheral blood; prevent; public health relevance

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）吞噬细胞会损害宿主组织，并有助于过敏性炎性疾病（例如哮喘和炎症性肠病）（IBD）的发病机理。 EO特异性颗粒赋予了大量的EO过氧化物酶（EPO）和剧烈的呼吸爆发，从而产生H2O2，以促进其他氧化剂的产生。然而，关于EPO介导的氧化损伤对嗜酸性炎性态病理学的贡献知之甚少。我们发现三种异常的底物 - 溴化物（BR-），亚硝酸盐（NO2-）和硫氰酸硫氰酸酯（SCN-） - 在H2O2存在下，EPO在生理流体中竞争氧化，分别屈服，分别为HOBR，NO2和HOSCN。这些氧化剂对人类细胞的相对毒性是HOBR> NO2 >> HOSCN。然而，EPO优先氧化SCN-> no2-> br-。我们假设SCN-“缓冲液”对EPO的发电量具有更大的细胞毒性NO2-和BR-基于基于BR-的氧化剂，以及饮食确定的血清SCN水平可能调节EPO的毒性。我们提出的工作的总体目标是检查以下假设：epo生成的氧化剂以底物确定的方式施加损害，以宿主组织和EOS本身。我们的第一个特定目的是检验以下假设：通过补充硫氰酸酯或其代谢前体（氰化物样化合物）对EPO毒性的底物调节，可以改善米氨酸硫酸盐硫酸盐硫酸盐模型中炎症性肠病的严重程度。我们的第二个具体目的是检验以下假设：在新型的鼠IL-5/eotaxin-2（i5/e2）哮喘的转基因模型中，1）与epo-/ - 小鼠杂交，2）对EPO酶活性的药理抑制作用，以及3）饮食中的SCN-补充所有杂质的动物，并培养了所有杂色的动物。椭圆形（OVA）senditization和挑战。第三个具体目的是检验以下假说：EPO/H2O2/SCN-系统通过NF-（依赖B依赖性的机制抑制嗜酸性粒细胞凋亡和有害的次生坏死性脱粒的机制。补充廉价且无害的SCN/ - 即使在贫困的社区中也可以应用于这些和其他过敏性炎症性疾病。 公共卫生相关性：在这笔赠款中，我们将测试硫氰酸盐是一种在蔬菜中发现的一种简单，廉价和无毒的化合物，可以摄入以治疗两种严重的过敏性疾病来治疗哮喘和溃疡性结肠炎。我们认为这是可能的，因为硫氰酸酯会钝性组织损害由嗜酸性粒细胞造成的组织损伤，嗜酸性粒细胞是一种导致过敏症状和疾病的白色细胞。如果这些研究成功，我们将发现一种简单，廉价且安全的方法来治疗过敏。