Role of Innate B1 B Cells in the Development of Diffuse Lung Hemorrhage

先天 B1 B 细胞在弥漫性肺出血发展中的作用

• 批准号: 9316608
• 负责人: Ram Raj Singh
• 金额: $ 23.1万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9316608
• 关键词: Abnormal Cell; Abnormal Myeloid Cell; Acute respiratory failure; Adoptive Transfer; Affect; Alkanes; Anhydrides; Animal Model; Animals; Antibodies; Antigens; Apoptotic; Autoimmunity; B-Cell Activation; B-Lymphocytes; BLR1 gene; Bioinformatics; Bone Marrow Transplantation; Breathing; C57BL/6 Mouse; CXCL13 gene; Cells; Clinical; Communities; Cosmetics; Crack Cocaine; Data; Development; Diesel Exhaust; Diffuse; Disease; Event; Exposure to; Food; Frequencies; Gene Expression Profiling; Genes; Glean; Greater sac of peritoneum; Hemorrhage; Heterogeneity; Homeostasis; Homing; House Dust; Human; ITGAM gene; Immune; Immunoglobulin M; Individual; Infectious Agent; Infiltration; Inflammation; Ingestion; Injectable; Injection of therapeutic agent; Isocyanates; Ligands; Liver; Location; Lung; Lupus; Lymphoid; Mediating; Mineral Oil; Molecular; Mus; Oils; Organ; Organ Transplantation; Pathogenesis; Pathologic; Pathway interactions; Patients; Peritoneal; Peritoneum; Pesticides; Petroleum; Pharmaceutical Preparations; Phenytoin; Plants; Pleura; Pleural; Pleural cavity; Poison; Population Control; Prevalence; Propylthiouracil; Public Health; Pulmonary Inflammation; Recreational Drugs; Recruitment Activity; Role; Severities; Site; Skin; Skin Absorption; Syndrome; Testing; Tissues; Toxin; Translating; Vasculitis; Work; base; cell type; chemokine; chemokine receptor; chemotherapeutic agent; effective therapy; exposed human population; hexadecane; in vivo Model; lymph nodes; marine organism; mortality; novel; pentadecane; peripheral blood; potential biomarker; systemic autoimmune disease; trafficking; wasting

ABSTRACT Diffuse lung hemorrhage is a distinct clinicopathologic syndrome of lung hemorrhage, inflammation, vasculitis, and acute respiratory failure. It carries a very high mortality, and is without any effective treatment. Diffuse lung hemorrhage can occur in patients with systemic autoimmune diseases, systemic vasculitides, and organ transplantation, and upon exposure to toxic substances such as isocyanates, trimellitic anhydrides, and certain pesticides, recreational drugs such as crack cocaine, and medications such as certain chemotherapeutic agents, propylthiouracil, and diphenylhydantoin. Advances in the pathogenesis of diffuse lung hemorrhage have been hampered because of the heterogeneity of clinical findings, paucity of access to the affected tissue, and the lack of suitable animal models. The observation that a hydrocarbon oil, 2,6,10,14-tetramethyl pentadecane (TMPD), induces diffuse lung hemorrhage in otherwise normal animals such as C57BL/6 mice provides an opportunity to investigate the pathogenesis of diffuse lung hemorrhage, particularly to glean into the early pathogenetic events, since the exact timing of the inciting agent is known. TMPD (C19H40) is an alkane present in crude oils, as a byproduct of the fractional distillation of petroleum, and as a component of mineral oil, and in many plants and marine organisms. Humans can be exposed to substantial amounts of hydrocarbon oils via ingestion (foods, medications), inhalation (diesel exhaust, oil mists, aspiration of ingested oil), skin absorption (cosmetics, skin contact), or injection (accidental inoculation) over the course of lifetime. In fact, an exposure to TMPD has been shown to cause inflammation in the lungs, liver, and lymph nodes in humans, although it is not known whether human exposure to TMPD can cause lung hemorrhage. A community comparison study did show that people living near an oil-field waste site with increased levels of TMPD in house dust had an increased prevalence of immune-mediated disorders, and increased proportions of B cells in their peripheral blood compared to the control population. The preliminary data in this proposal shows that B cells are among the first to infiltrate the lungs after administration of TMPD, but not of a control hydrocarbon oil in animals that are susceptible to develop diffuse lung hemorrhage. Therefore, this proposal will investigate mechanisms of contribution of B cells in the pathogenesis of TMPD- induced diffuse lung hemorrhage. The findings obtained will form the basis for assessing the role of B cells and manipulating them in patients with diffuse lung hemorrhage. Studies of pathogenesis in the TMPD induced lung hemorrhage will serve as a model for in vivo manipulation to identify potential biomarkers and targets of treatment for diffuse lung hemorrhage, as well as to translate the murine findings onto patients with this serious, often fatal, disorder.

抽象的 弥漫性肺出血是一种肺出血，炎症，血管炎， 和急性呼吸衰竭。它具有很高的死亡率，并且没有任何有效的治疗方法。弥漫性肺 全身性自身免疫性疾病，全身性血管和器官的患者可能发生出血 移植，并在暴露于有毒物质时，例如异氰酸酯，三叶酸赤霉素和某些 农药，娱乐性药物（例如可卡因）和某些化学治疗等药物 剂，丙酸硫酸苯胺和二苯基氢化剂。弥漫性肺出血的发病机理的进步 由于临床发现的异质性，受影响的组织的通道很少，因此受到了阻碍 缺乏合适的动物模型。观察到碳氢化合物，2,6,10,14-四甲基 五角烷（TMPD），在否则正常动物（例如C57BL/6小鼠）中诱导弥漫性肺出血 提供了研究弥漫性肺出血的发病机理的机会，特别是要收集到 早期的致病事件，因为已知煽动剂的确切时机。 TMPD（C19H40）是在原油中存在的烷烃，作为石油蒸馏的副产品， 作为矿物油的组成部分，以及许多植物和海洋生物。人类可以暴露于 大量通过摄入（食品，药物），吸入（柴油排气，油雾，雾气， 吸收摄入的油），皮肤吸收（化妆品，皮肤接触）或注射（意外接种） 一生的过程。实际上，已经显示出暴露于TMPD会导致肺，肝脏，肝脏炎症 和人类的淋巴结，尽管尚不清楚人类暴露于TMPD会导致肺 出血。一项社区比较研究确实表明，住在油田废物附近的人们与 房屋灰尘中TMPD水平的升高使免疫介导的疾病的患病率增加，并且 与对照人群相比，外周血中B细胞比例增加。初步 该提案中的数据表明，B细胞是施用TMPD后最早浸润肺的细胞之一， 但没有对照动物中的对照碳氢化合物油，这些动物易于发育弥漫性肺出血。 因此，该建议将研究B细胞在TMPD-发病机理中的贡献机制 诱导的弥漫性肺出血。获得的发现将构成评估B细胞和 在弥漫性肺出血患者中操纵它们。 TMPD诱导的发病机理的研究 肺出血将作为体内操纵的模型，以识别潜在的生物标志物和靶标 弥漫性肺出血的治疗，以及将鼠的发现转化为患者 严重的，通常是致命的混乱。