Limiting ischemic liver injury by interfering with lysosomal autophagy

Two regimens designed to ameliorate hepatic injury from complete liver dearterialization (LD) by interfering with lysosome-mediated proteolysis were studied in 200-g Buffalo rats. Five rats received a lysosome membrane-stabilizing flavenoid, catechin, 200 mg/kg/day for 5 days pre-LD. Five others were infused with lysosome protease inhibitors (LPI), leupeptin and pepstatin, delivered in 0.22-micron multilamellar liposomes at 500 micrograms each per hour for 2 hr, beginning 20 min before LD. Control groups (n = 4 or 5) were untreated LD, and treated and untreated sham LD rats. Blood from an arterial catheter pre-LD and 2 hr (peak enzyme release), 2 days, and 4 days post-LD yielded beta-glucuronidase (BG), aspartate transaminase (AST), and alkaline phosphatase values for each rat. Liver histology was not different between groups at 4 days post-LD. Untreated controls and the catechin LD group had similar enzyme levels at all points. LPI treatment values were statistically similar to sham LD values and had peak values significantly lower (P less than 0.05) than untreated LD controls at 2 hr. BG, 75 +/- 10 (SD) units per liter versus 185 +/- 32 units per liter; AST, 134 +/- 47 units per liter versus 459 +/- 175 units per liter. The BG lowering persisted to day 2 (55 +/- 25 units per liter versus 93 +/- 40 units per liter). Other values remained normal or normalized by Day 2. Hepatic damage as measured by enzyme release was not diminished by the membrane stabilizer catechin but was diminished after ischemic injury by specific targeted lysosomal protease inhibitors.