ROLE OF KUPFFER CELLS IN CHEMICAL TOXICITY

枯否细胞在化学毒性中的作用

• 批准号: 3285070
• 负责人: Debra L Laskin
• 金额: $ 13.71万
• 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 1988-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3285070
• 关键词: Kupffer's cell; acetaminophen; bromobenzenes; carbon tetrachloride; chemotaxis; cytotoxicity; detoxification; electrodes; enzyme linked immunosorbent assay; free radicals; hepatotoxin; immunodiffusion; immunofluorescence technique; liver function; liver toxic disorder; monoclonal antibody; necrosis; pathologic process; phagocytosis; spectrometry; superoxides; tissue /cell culture

Kupffer cells are fixed macrophages that line the hepatic sinusoids. These cells serve as a selective filter to remove particulate matter from the portal circulation and to defend the hepatic parenchyma against endotoxin. Following liver injury, Kupffer cells become "activated". They display enhanced phagocytosis, chemotaxis, cytotoxicity and release reactive mediators. Although the function of Kupffer cells and their biological mediators in normal systemic host defense has been established, their potential role in chemical induced hepatic injury is unknown. We have been studying the hepatotoxic effects of the analgesic acetaminophen. Using isolated perfused rat liver, we observed an inhibition of hepatic respiration and selective pericentral necrosis 24 hrs following treatment of fasted rats with acetaminophen. Interestingly, in fed rats, although there were no apparent signs of necrosis, we did observe a large infiltration of mononuclear cells into the pericentral region of the liver lobule. It is our hypothesis that the mononuclear cell infiltrate is composed of newly recruited and "activated" Kupffer cells, and that these cells contribute to hepatocellular injury caused by acetaminophen. The overall objective of this proposal is to characterize the mechanism by which "activated" Kupffer cells accumulate in the liver following acetaminophen treatment, and to elucidate their potential role in hepatotoxicity. For these studies, we will use isolated hepatocytes and Kupffer cells maintained in culture in conjunction with isolated perfused liver. In preliminary experiments we found that conditioned medium from hepatocytes treated with acetaminophen, but not acetaminophen itself, induced Kupffer cell chemotaxis and superoxide anion release and stimulated Kupffer cell phagocytosis. This suggests that acetaminophen injured hepatocytes release factors that attract and "activate" macrophages. We will use biophysical and biochemical techniques to characterize these factors and their roles in chemical induced liver injury.

Kupffer细胞是固定的巨噬细胞，可将肝弦正弦线排成一列。 这些 细胞用作选择性过滤器，从 门户循环并捍卫肝实质对内毒素的影响。 肝损伤后，库普弗细胞被“激活”。 他们显示 增强的吞噬作用，趋化性，细胞毒性和释放反应性 调解人。 虽然Kupffer细胞及其生物学的功能 已经建立了正常全身宿主防御的调解人 化学诱导的肝损伤中的潜在作用尚不清楚。 我们去过 研究镇痛性对乙酰氨基酚的肝毒性作用。 使用 孤立的灌注大鼠肝脏，我们观察到肝的抑制作用 治疗后24小时的呼吸和选择性周围坏死 用对乙酰氨基酚的禁食大鼠。 有趣的是，在美联储的老鼠中 没有明显的坏死迹象，我们确实观察到了一个大的 单核细胞渗入肝脏的周围区域 小叶。 我们的假设是单核细胞浸润是 由新招募和“激活”的库普弗细胞组成，这些细胞 细胞导致对乙酰氨基酚引起的肝细胞损伤。 这 该建议的总体目的是表征该机制 在后面，“激活”的库普弗细胞积聚在肝脏中 对乙酰氨基酚的治疗，并阐明其潜在的作用 肝毒性。 对于这些研究，我们将使用孤立的肝细胞和 kupffer细胞在培养中与孤立的灌注一起培养 肝。 在初步实验中，我们发现从 用对乙酰氨基酚治疗的肝细胞，但不是对乙酰氨基酚本身 诱导的库普弗细胞趋化性和超氧化阴离子释放并刺激 Kupffer细胞吞噬作用。 这表明对乙酰氨基酚受伤 肝细胞释放吸引和“激活”巨噬细胞的因子。 我们 将使用生物物理和生化技术来表征这些 因素及其在化学诱导的肝损伤中的作用。