Neutrophils and Hepatotoxicity

中性粒细胞和肝毒性

• 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
• 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

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）：已在多种动物模型中表征了适度炎症增强对药物（例如雷尼替丁）和其他异生物质的肝毒性反应的能力。一个常见的发现是中性粒细胞 (PMN) 和随之而来的组织缺氧的止血是炎症增强肝毒性的关键因素。激活的PMN通过释放弹性蛋白酶和组织蛋白酶G等有毒蛋白酶来杀死肝实质细胞(HPC)。最近，我们发现缺氧会加速和增强PMN弹性蛋白酶对HPC的杀伤作用。该提案的目标是检验缺氧和 PMN 蛋白酶在药物-炎症相互作用过程中相互作用导致 HPC 损伤的假设，并开始了解这种相互作用的分子基础。将确定缺氧对体外 PMN 蛋白酶杀伤 HPC 的发展和剂量反应性的影响，以及这种相互作用在体内药物炎症模型中的重要性。由于缺氧诱导因子 1 α (HIF-1 α) 可以启动细胞死亡信号传导，并在体内药物-炎症相互作用期间肝毒性发生之前表达，因此我们将描述其在体外缺氧/PMN 蛋白酶相互作用期间和体内药物-炎症相互作用期间 HPC 杀伤中的作用。最后，由于 PMN 蛋白酶会破坏蛋白质二硫键异构酶 (PDI)（HPC 膜中的一种细胞保护性缺氧应激蛋白），因此将探讨 PDI 失活在弹性蛋白酶/缺氧介导的 HPC 死亡中的作用。这些研究将采用药理学、反义寡核苷酸、条件无效和基因过表达方法，以提供炎症条件下可能出现的缺氧环境增强细胞毒性 PMN 蛋白酶损害 HPC 的能力的机制知识。这些结果将有助于了解炎症组织损伤的总体情况，以及炎症如何作为药物和其他异生物质毒性的易感因素。公共健康相关性：药物毒性和许多肝脏疾病都涉及白细胞（例如中性粒细胞）在缺氧的组织环境中运行导致肝损伤。了解中性粒细胞如何与缺氧相互作用以促进肝损伤可能会导致更好的方法来预防或治疗药物不良反应和其他类型的炎症性肝损伤。