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

摘要 弥漫性肺出血是一种以肺出血、炎症、血管炎、 和急性呼吸衰竭。它具有很高的死亡率，而且没有任何有效的治疗方法。弥漫性肺 出血可发生在全身性自身免疫性疾病、全身性脉管炎和器官疾病患者中。 移植，以及接触有毒物质，如异氰酸酯、偏苯三酸酐和某些 杀虫剂，强效可卡因等娱乐药物，以及某些化疗药物 药物丙基硫氧嘧啶和二苯基海因。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，很难接触到受影响的组织， 以及缺乏合适的动物模型。观察到一种碳氢油，2，6，10，14-四甲基 十五烷(TMPD)诱导C57BL/6小鼠等正常动物弥漫性肺出血 提供了一个机会来研究弥漫性肺出血的发病机制，特别是收集 早期的致病事件，因为煽动剂的确切时间是已知的。 TMPD(C19H40)是原油中存在的一种烷烃，作为石油分馏的副产品， 作为矿物油的一种成分，以及在许多植物和海洋生物中。人类可能会接触到 通过摄入(食物、药物)、吸入(柴油废气、油雾、 吸入油脂)、皮肤吸收(化妆品、皮肤接触)或注射(意外接种) 一生的历程。事实上，暴露于TMPD已被证明会导致肺、肝脏、 和人类的淋巴结，尽管尚不清楚人类暴露于TMPD是否会导致肺 大出血。一项社区比较研究确实表明，居住在油田废弃场附近的人们 房屋灰尘中TMPD水平的增加会增加免疫调节疾病的患病率，并且 与对照人群相比，他们外周血中B细胞的比例增加。预赛 这项建议中的数据显示，在服用TMPD后，B细胞是最先渗透到肺部的细胞之一， 但对于易发生弥漫性肺出血的动物来说，碳氢化合物油并不是一种控制性的油。 因此，本研究将探讨B细胞在TMPD发病机制中的作用机制。 导致弥漫性肺出血。所获得的发现将形成评估B细胞和 在弥漫性肺出血患者中操作它们。TMPD发病机制的研究进展 肺出血将作为体内操作的模型，以确定潜在的生物标志物和靶点 弥漫性肺出血的治疗，以及将小鼠的发现转换到患有这种疾病的患者身上 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.