KUPFFER CELL MODULATION OF CHEMICAL-INDUCED LIVER INJURY

库普弗细胞(KC)构成最大的固定巨噬细胞群 在身体里。尽管这些细胞在去除 颗粒、细胞和有毒物质，它们也可以释放有毒物质 可能导致肝脏损伤的介质。激活KC的代理可以 增强其他化学物质的肝毒性 对最小的组织损伤做出反应，释放有毒的介体。 最近，有研究表明，大剂量的维生素A(视黄醇) 增强四氯化碳所致的肝损伤。这个机制是通过 哪种维生素A引起这种增强是通过它的激活能力 KC，也许还有其他吞噬细胞。当肝细胞受到损伤时， 四氯化碳(CCl4)，活化的KC反应过度 产生和释放活性氧物种。这些氧气 自由基促进肝细胞脂质过氧化，这是一种与 随着肝脏损伤的戏剧性增强。这些发现导致了 对这一假设。KC函数的调制可以改变 化学性肝损伤研究进展。这个项目的总体目标是 研究项目是为了更好地了解KC的调制功能 会影响肝脏对有毒化学物质的反应，并阐明 一种化学物质增强肝毒性的重要机制 另一个人的。具体目标是：1)更准确地描述 根据治疗剂量和持续时间加强损害 维生素A，以及剂量的CCl4；确定其他维甲酸是否 引起这种增强，并将这些变化与 KC的激活；中性粒细胞、其他单核细胞和 淋巴细胞对化学性肝损伤增强反应的影响 还将评估损伤情况；2)确定氧气的作用 这种增强作用中的自由基和脂质过氧化以及 超氧化物歧化酶、过氧化氢酶和去铁肟的阻断程度 增强作用；3)确定维生素A是否增强 其他环境化学品(CHCl3、镉、 二氯苯等)通过类似的机制；4)在 肝细胞与KC共培养的体外体系进一步明确 这些类型在接触化学物质时的相互作用，以及5) 确定KC释放的活性氧物种是否解释了 Fischer-344大鼠对1，2-二氯苯肝毒性的敏感性。 这项工作对健康的影响是重大的，因为 共同接触维生素A和环境的机会 肝毒是非常真实的。其次，鉴于目前的重点是 免疫调节药物的发展，了解这一点将是重要的 免疫细胞如KC的调节如何改变对 目标组织为其他化学物质(环境污染物， 化疗药物等)。

Kupffer cells (KC) constitute the largest population of fixed macrophages in the body. Although these cells play a critical role In the removal of particulates, cells and toxic substances, they can also release toxic mediators that may produce liver Injury. Agents that activate KC may potentiate the hepatotoxicity of other chemicals through an enhanced release of toxic mediators In response to minimal tissue injury. Recently, it has been shown that large doses of vitamin A (retinol) potentiate carbon tetrachloride induced liver injury. The mechanism by which vitamin A causes this potentiation is via Its ability to activate KC and perhaps other phagocytic cells. Upon damage to the hepatocytes by carbon tetrachloride (CCl4), the activated KC respond with an over production and release of reactive species of oxygen. These oxygen radicals promote peroxidation of hepatocyte lipids, an event associated with the dramatic potentiation in liver injury. These findings have led to the hypothesis. that modulation of KC function can alter the progression of chemical-induced liver injury. The overall goals of this research project are to better understand how modulation of KC function can Influence the liver's response to toxic chemicals and to elucidate an important mechanism by which one chemical potentiates the hepatotoxicity of another. The specific aims are to: 1) more precisely characterize the potentiation of damage with respect to the dose and duration of treatment with vitamin A, and with the dose Of CCl4; determine if other retinoids cause this potentiation, and correlate these changes with the state of activation of KC; the contribution of neutrophils, other monocytes and lymphocytes to the potentiated response of chemical induced hepatic injury will also be evaluated; 2) to determine the role of oxygen radicals and lipid peroxidation in this potentiation as well as the degree to which superoxide dismutase, catalase and desferoximine block the potentiation; 3) to determine If vitamin A potentiates the hepatotoxicity of other environmental chemicals (CHCl3, cadmium, dichlorobenzene, among others) by a similar mechanism; 4) to develop in vitro systems for the co-culture of hepatocytes and KC to further define Interactions between these types upon chemical exposure, and 5) to determine if reactive oxygen species released from KC explains the susceptibility of Fischer-344 rats to 1,2-dichlorobenzene hepatotoxicity. The health implications of this work are significant since the opportunity for co-exposure to vitamin A and environmental hepatotoxicants Is very real. Secondly, with the current emphasis on the development of immunomodulatory drugs, it will be important to understand how modulation of immune cells such as KC can alter the response of target tissues to other chemicals (environmental pollutants, chemotherapeutic agents, etc.).