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

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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.