ANALYSIS OF CYTOTOXIC MECHANISMS OF ACTIVATED EOSINOPHILS IN BILIARY CELL INJURY : ESTABLISHMENT OF AN ANIMAL MODEL FOR PRIMARY BILIARY CIRRHOSIS

胆道细胞损伤中活化的嗜酸性粒细胞的细胞毒机制分析：原发性胆汁性肝硬化动物模型的建立

• 批准号: 09670555
• 负责人: MAEDA Takashi
• 金额: $ 1.66万
• 依托单位: KOCHI MEDICAL SCHOOL
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1997
• 资助国家: 日本
• 起止时间: 1997 至 1998
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09670555/
• 关键词: PRIMARY BILIARY CIRRHOSIS; EOSINOPHIL; LPS; IL-5; KUPFFER CELL

Activated eosinophilic infiltration is a common histological feature in diseased liver such as chronic rejection of transplanted liver, GVHD, or primary biliary cirrhosis (PBC) resembling chronic CVHD.In such conditions, it is suggested that activated eosinophils play an important role in liver damages, though precise mechanisms have not been analyzed. Using IL-5 transgenic (IL5Tg) mouse, we have first established an experimental model of liver injury caused by activated eosinophils.lL5Tg mice (C3H/HeN-TgN(IL-5)Imeq) have been established and provided from DR.Tominaga, Kochi Medical School. Although this mouse exhibits marked eosinophilia (30-70%) in the periphery, tissue injuries are not observed in any organs. IL5Tg mice were injected with 25 mug of LPS (Salmonella minesota Re 595) interaperitoneally and sacrificed 2 weeks later. Histological examinations showed marked portal inflammation with eosinophilic infiltrations (>50%) in portal tracts and extensive lobutar necrosis surround … More by marked eosinophils. Some small bile ducts were degenerated and destructed with eosinophihic aggregates, where eositiophilic infiltrations into ductal epithelium were observed. Electron microscopic examinations showed degranulation of eosinophilic cytotoxic granules into the ductal cells. Tissue injuries other than liver were almost absent in IL5Tg mice. in control mice (C3H/HeN), LPS injection did not induced any tissue injuries.Spleen cells (2x107 cells ; eosinophils>50%) from IL5Tg primed with LPS were transferred into none-transgenic mice (C3H/HeN) intravenously, but any tissue injuries were never induced. This result suggests that in addition to activated eosinophils, another factors such as various cytokines including TNF a released from LPS stimulated Kupffer cells are necessary for the induction of eosinophilic hepatic injury. Further analysis for dynamic changes of cytokines or chemokines, which are related to chemotaxis and degranulation of activated eosinophils, is needed for understanding the hepatic injury in this animal model. Less

活化的嗜酸性粒细胞浸润是肝脏肝脏中常见的组织学特征，例如慢性抑制移植的肝脏，GVHD或原发性胆汁性肝硬化（PBC）在这种情况下类似于慢性CVHD。在这种情况下，这表明激活嗜酸性嗜酸性在肝脏中起重要作用，但已在肝脏中扮演重要的作用。使用IL-5转基因（IL5TG）小鼠，我们首先建立了由活化的嗜酸性粒细胞引起的肝损伤的实验模型。LL5TG小鼠（C3H/HEN-TGN（IL-5）IMEQ）由Kochi医学院托米尼加博士提供。尽管该小鼠在外围表现出标记为嗜酸性粒细胞的（30-70％），但在任何器官中均未观察到组织损伤。将IL5TG小鼠注射25杯Lps（Salmonella Minesota re 595），并在2周后处死。组织学检查显示了门粒细胞浸润（> 50％）的门户注射标志性的门户，并在门户区域和围绕围绕的广泛的叶虫坏死感中进行……更多。一些小胆管被解脱并用嗜酸性的骨料破坏，在该聚集体中，观察到嗜酸性浸润成导管上皮。电子显微镜检查表明，嗜酸性细胞毒性颗粒脱粒为导管细胞。 IL5TG小鼠几乎没有肝脏的组织损伤。在对照小鼠（C3H/HEN）中，LPS注射没有诱导任何组织损伤。从LPS引发的IL5TG中的杂化细胞（2x107细胞；嗜酸性粒细胞> 50％）将其转移到非直交小鼠（C3H/HER）中，但从未引起任何组织损伤。该结果表明，除了活化的嗜酸性粒细胞外，还有其他因素，包括从LPS刺激的kupffer细胞中释放出的各种细胞因子，对于诱导嗜酸性粒细胞肝损伤是必需的。在这种动物模型中，需要进一步分析与趋化因子或趋化因子的动态变化，这与趋化性和活化嗜酸性粒细胞的脱粒有关。较少的