ROLE OF KUPFFER CELLS IN CHEMICAL TOXICITY

枯否细胞在化学毒性中的作用

• 批准号: 3285073
• 负责人: Debra L Laskin
• 金额: $ 23.07万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 1984
• 资助国家: 美国
• 起止时间: 1984-12-01 至 1992-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3285073
• 关键词: Kupffer's cell; acetaminophen; bromobenzenes; carbon tetrachloride; chemotaxis; cytotoxicity; detoxification; electrodes; enzyme linked immunosorbent assay; enzyme mechanism; flow cytometry; fluorescence microscopy; free radicals; hepatotoxin; immunodiffusion; immunofluorescence technique; laboratory rat; liver function; liver toxic disorder; monoclonal antibody; necrosis; pathologic process; phagocytosis; spectrometry; superoxides; tissue /cell culture

Kupffer cells are macrophages that line the hepatic sinusoids. These cells function to remove foreign and particulate matter from the portal circulation. In response to tissue injury, Kupffer cells become activated. They display enhanced biochemical and functional reactivity and release highly reactive and toxic mediators. We have been studying the potential role of activated Kupffer cells and their mediators in chemically induced hepatotoxicity. For these studies, we focused on the analgesic, acetaminophen as a model hepatotoxicant. Twenty-four hr following treatment of rats with acetaminophen, we observed an infiltration of mononuclear cells into centrilobular regions of the liver in the absence of necrosis. We hypothesized that these infiltrated cells consisted of newly recruited and "activated" macrophages and that they contribute to acetaminophen hepatotoxicity. In support of this hypothesis, we demonstrated that Kupffer cells from the livers of acetaminophen treated rats display morphological and functional characteristics of activated macrophages. We also showed that macrophage accumulation and activation in the liver is mediated, in part, by a factor (H-MAF) released from acetaminophen injured hepatocytes. In addition, Kupffer cells that accumulate in the liver following acetaminophen treatment are nonspecifically activated to kill hepatocytes. Taken together, these data support our model that activated liver macrophages contribute to hepatotoxicity. It is the purpose of the present proposal to extend these findings. We plan to analyze biochemical mechanisms of Kupffer cell activation following hepatotoxicant treatment. We will also use the fluorescence activated cell sorter to characterize soluble immune mediators released by Kupffer cells and hepatocytes, and to examine the interaction of Kupffer cells with other inflammatory cells in the liver. These studies should provide clues on the mechanisms underlying the contribution of Kupffer cells to chemically-induced hepatotoxicity.

kupffer细胞是巨噬细胞的巨噬细胞。 这些细胞起作用以去除异物和颗粒物 从门户流通。 为了应对组织损伤，库普弗 细胞被激活。 它们显示增强的生化和 功能反应性和高度反应性和有毒 调解人。 我们一直在研究激活的潜在作用 Kupffer细胞及其介体在化学诱导的 肝毒性。 对于这些研究，我们专注于镇痛药 对乙酰氨基酚作为模型肝毒性。 二十四小时 用对乙酰氨基酚处理大鼠后，我们观察到 单核细胞浸润到中心区域 肝脏在没有坏死的情况下。 我们假设这些 浸润细胞由新招募和“激活”组成 巨噬细胞及其对对乙酰氨基酚的贡献 肝毒性。 为了支持这一假设，我们证明了 来自对乙酰氨基酚处理大鼠肝脏的kupffer细胞 显示激活的形态和功能特征 巨噬细胞。 我们还表明巨噬细胞的积累和 肝脏中的激活部分由因子（H-MAF）介导 从对乙酰氨基酚受伤的肝细胞中释放。 此外， 在肝脏中积聚的库普弗细胞以下 对乙酰氨基酚的治疗被非特异性激活以杀死 肝细胞。 综上所述，这些数据支持我们的模型 活化的肝巨噬细胞有助于肝毒性。 这是 本提案扩展这些发现的目的。 我们 计划分析库普弗细胞的生化机制 肝毒性治疗后的激活。 我们还将使用 荧光激活的细胞分辨率以表征可溶性 库普弗细胞和肝细胞释放的免疫介质，以及 检查Kupffer细胞与其他 肝脏中的炎性细胞。 这些研究应提供 Kupffer贡献的基础机制的线索 细胞具有化学诱导的肝毒性。