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

• Project/Area Number: 09670555
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: KOCHI MEDICAL SCHOOL
• Principal Investigator: MAEDA Takashi Kochi Medical School FIRST DEPARTMENT OF INTERNAL MEDICINE Assistant Professor, 医学部附属病院, 講師 (80183606)
• Co-Investigator(Kenkyū-buntansha): IWASAKI Shinji Kochi Medical School FIRST DEPARTMENT OF INTERNAL MEDICINE Research Associate, 医学部, 助手 (10232654)
• Project Period (FY): 1997 – 1998
• Project Status: Completed (Fiscal Year 1998)
• Budget Amount: ¥2,600,000 (Direct Cost: ¥2,600,000); Fiscal Year 1998: ¥1,100,000 (Direct Cost: ¥1,100,000); Fiscal Year 1997: ¥1,500,000 (Direct Cost: ¥1,500,000)
• Keywords: PRIMARY BILIARY CIRRHOSIS / EOSINOPHIL / LPS / IL-5 / KUPFFER CELL

Research Abstract

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 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.