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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

基本信息

批准号：
9182833
负责人：
Ram Raj Singh
金额：
$ 19.25万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-01 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9182833
关键词：
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 CXC Chemokines 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 Injection of therapeutic agent Isocyanates Life Ligands Liver Location Lung Lupus Lymphoid Mediating Mineral Oil Molecular Mus Myeloid Cells Oils Organ Organ Transplantation Pathogenesis Pathway interactions Patients Peritoneal Peritoneum Pesticides Petroleum Pharmaceutical Preparations Phenytoin Plants Pleura Pleural Pleural cavity Poison Population Control Prevalence Pristane Propylthiouracil Public Health Pulmonary Inflammation Recreational Drugs Role Severities Site Skin Skin Absorption Syndrome Testing Time Tissues Toxin Translating Vasculitis Work base cell type 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

项目摘要

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.

摘要