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

摘要 弥漫性肺出血是肺出血、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 出血可发生在患有全身性自身免疫性疾病、全身性血管炎和器官炎的患者中。 移植，以及暴露于有毒物质如异氰酸酯、偏苯三酸酐和某些 杀虫剂，娱乐性药物如快克可卡因，以及药物如某些化疗药物， 试剂，丙基硫氧嘧啶和二苯基乙内酰脲。弥漫性肺出血发病机制的研究进展 由于临床表现的异质性，缺乏接触受影响组织的途径， 缺乏合适的动物模型。观察到烃油，2，6，10，14-四甲基 十五烷（TMPD）在其他正常动物如C57 BL/6小鼠中诱导弥漫性肺出血 提供了一个研究弥漫性肺出血发病机制的机会，特别是收集 早期发病事件，因为确切的时间煽动剂是已知的。 TMPD（C19 H40）是原油中存在的烷烃，作为石油分馏的副产物， 也是矿物油的一种成分，存在于许多植物和海洋生物中。人类可以接触到 通过摄入（食物，药物），吸入（柴油机废气，油雾， 吸入摄入的油）、皮肤吸收（化妆品、皮肤接触）或注射（意外接种） 生命的历程事实上，暴露于TMPD已被证明会导致肺部，肝脏， 和淋巴结，尽管尚不清楚人类暴露于TMPD是否会导致肺 出血一项社区比较研究确实表明，居住在油田废物场附近的人， 室内灰尘中TMPD水平的增加会增加免疫介导疾病的患病率， 与对照群体相比，其外周血中B细胞的比例增加。初步 该建议中的数据显示B细胞是在施用TMPD后首先渗入肺的细胞， 而不是对照烃油在易患弥漫性肺出血的动物中的作用。 因此，本提案将研究B细胞在TMPD发病机制中的作用机制。 导致弥漫性肺出血所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作它们。TMPD诱导的发病机制研究 肺出血将作为体内操作的模型，以鉴定潜在的生物标志物和靶点， 治疗弥漫性肺出血，以及将小鼠的发现转化为这种疾病的患者。 严重的，通常是致命的紊乱。

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.