| Budget Amount *help |
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2006: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 2005: ¥2,600,000 (Direct Cost: ¥2,600,000)
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| Research Abstract |
High mobility group box1 (HMGB1) is a ubiquitous non-histone chromosomal protein which is released during lethal sepsis, actively from macrophages and passively from necrotic cells. Here, we sought to determine the exact role of HMGB1 in ischemia-reperfusion (I/R) injury of the rat liver and also have shown a protective effect of removal of HMGB1 during I/R injury. A 70% hepatic ischemia for 60 min and 90 min and a global hepatic ischemia for 30 min in rats were used. Serum HMGB1 level, analyzed by ELISA, increased with increasing length of hepatic ischemia, however, remained unchanged in intestinal ischemia. Tissue HMGB1 content, evaluated by Western blotting, decreased after reperfusion. However, it was recovered at 24 hr after reperfusion following ischemia for 60 min, but not for 90min. In hepatocytes, immunohistochemical staining showed a shift in HMGB1 expression from the nuclear to the cytoplasmic compartment after reperfusion. Elimination of ^<125>I radio-labeled recombinant HMGB1 was significantly delayed in the hepatic ischemia group than in controls (p<0.001). Neutralizing anti-HMGB1 antibody improved animal survival following a lethal hepatic I/R injury (p<0.02), and an improvement in tissue injury score was evident. Furthermore, removal of excess HMGB1 by an adsorption column significantly (p<0.03) improved animal survival. In conclusion, HMGB1 might enhance hepatic I/R injury. Blockade or elimination of circulating HMGB1 is beneficial in lethal hepatic I/R injury. The liver might play a vital role in elimination of excessive HMGB1. Therapies targeting at removal of excessive HMGB1 might be beneficial in ischemia related liver injuries.
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