Neutrophils and Hepatotoxicity

中性粒细胞和肝毒性

基本信息

批准号：
7911415
负责人：
Robert Andrew Roth
金额：
$ 18.84万
依托单位：
MICHIGAN STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-06 至 2012-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7911415
关键词：
Address Aflatoxin B1 Alcohols Ally Animal Model Animals Anticoagulants Antisense Oligonucleotides Antisense RNA Attention Cathepsin G Cell Death Cell Death Signaling Process Cell membrane Cells Cessation of life Chemicals Chemosensitization Chlorpromazine Complement Deposition Development Dose Drug Interactions Drug toxicity Elastases Environment Exposure to Fibrin Genes Goals Grant HIF1A gene Heat shock proteins Hemostatic Agents Hemostatic function Heparin Hepatocyte Hepatotoxicity Hypoxia In Vitro Indium Inflammation Inflammatory Injury Intoxication Knowledge Lead Leukocyte Elastase Leukocytes Lipopolysaccharides Liver Liver diseases Liver parenchyma Mediating Mediator of activation protein Modeling Molecular Monocrotaline Oxygen Pathogenesis Pathway interactions Peptide Hydrolases Pharmaceutical Preparations Play Predisposition Prevention Principal Investigator Protein Disulfide Isomerase Proteomics Ranitidine Rattus Reaction Relative (related person)Research Role Signal Transduction System Testing Time Tissues Toxic effect Xenobiotics base cell injury cell killing cytotoxic experience hypoxia inducible factor 1 improved in vivo in vivo Model killings neutrophil overexpression prevent programs protective effect public health relevance release factor response small hairpin RNA stress protein

项目摘要

DESCRIPTION (provided by applicant): The capacity of modest inflammation to potentiate hepatotoxic responses to drugs (e.g., ranitidine) and other xenobiotic agents has been characterized in several animal models. A common finding is that both neutrophils (PMNs) and hemostasis with consequent tissue hypoxia are critical players in inflammation- potentiated hepatotoxicity. Activated PMNs kill hepatic parenchymal cells (HPCs) through the release of toxic proteases such as elastase and cathepsin G. Recently, we found that the killing of HPCs by PMN elastase is accelerated and potentiated by hypoxia. The goals of the proposal are to test the hypothesis that hypoxia and PMN proteases interact to cause HPC injury during drug-inflammation interaction and to begin to understand the molecular basis for this interaction. The influence of hypoxia on the development and dose-responsiveness of HPC killing by PMN proteases in vitro and the importance of this interaction in a drug-inflammation model in vivo will be determined. Since hypoxia-inducible factor-1 alpha (HIF-1 alpha) can initiate cell death signaling and is expressed before the onset of hepatotoxicity during drug-inflammation interaction in vivo, we will delineate its role in HPC killing during hypoxia/PMN protease interaction in vitro and during drug-inflammation interaction in vivo. Finally, since PMN proteases destroy protein disulfide isomerase (PDI), a cytoprotective hypoxic stress protein in HPC membranes, the role of PDI inactivation in elastase/hypoxia-mediated HPC death will be explored. Pharmacological, antisense oligonucleotide, conditional null and gene overexpression approaches will be employed in these studies to provide knowledge of mechanisms by which a hypoxic environment likely to occur during inflammatory conditions enhances the capacity of cytotoxic PMN proteases to damage HPCs. The results will contribute to understanding inflammatory tissue injury generally and how inflammation acts as a susceptibility factor for toxicity due to drugs and other xenobiotic agents. Public Health Relevance: Drug toxicity and many liver diseases involve white blood cells such as neutrophils operating in an oxygen-deficient tissue environment to cause liver injury. Understanding how neutrophils interact with oxygen deficiency to promote liver injury could lead to better ways to prevent or treat adverse drug reactions and other types of inflammatory liver injury.

描述（由申请人提供）：在几种动物模型中，已经表征了对药物（例如，雷尼替丁）和其他异种生物剂的增强肝毒性反应的适度肝毒性反应的能力。一个普遍的发现是，中性粒细胞（PMN）和止血性伴有组织缺氧是炎症增强的肝毒性的关键参与者。活化的PMN通过释放诸如弹性蛋白酶和组织蛋白酶G的毒性蛋白酶杀死肝实质细胞（HPC）。最近，我们发现PMN弹性酶杀死HPCS的HPC被吸收并受到缺氧的增强。该提案的目标是检验以下假设：缺氧和PMN蛋白酶相互作用以在药物炎症相互作用期间引起HPC损伤，并开始理解这种相互作用的分子基础。缺氧对PMN蛋白酶在体外杀死HPC杀死HPC的发育和剂量反应的影响以及这种相互作用在体内的药物感染模型中的重要性。由于低氧诱导因子-1α（HIF-1α）可以启动细胞死亡信号，并在体内药物感染相互作用期间在肝毒性发作之前表达，因此我们将描述其在缺氧/PMN蛋白酶相互作用期间在体外和药物IM-Inflammatimation Interaction Intactaction Intaction Intaction Intaction Intaction Intactaction in Vivo中的作用。最后，由于PMN蛋白酶破坏了蛋白质二硫异构酶（PDI），因此将探索PDI失活在弹性酶/缺氧介导的HPC死亡中PDI失活的作用。在这些研究中，将采用药理，反义寡核苷酸，条件为NULL和基因过表达方法，以提供有关在炎症条件下可能发生的低氧环境增强细胞毒性PMN蛋白酶对HPC损害HPC的能力的知识。结果将有助于理解炎症组织损伤，以及炎症如何充当因药物和其他异种生物剂引起的毒性的易感因素。公共卫生相关性：药物毒性和许多肝脏疾病涉及白细胞，例如在缺氧组织环境中运作的中性粒细胞，以引起肝损伤。了解中性粒细胞如何与氧缺乏症相互作用以促进肝损伤可能导致更好的方法来预防或治疗不良药物反应和其他类型的炎症性肝损伤。