Dual role of chloroquine in liver ischemia reperfusion injury: reduction of liver damage in early phase, but aggravation in late phase

Fang, H; Liu, A; Dahmen, U; Dirsch, O

Chloroquine reduces liver injury in the early reperfusion phase, but worsens liver injury during the late reperfusion phase after hepatic ischemic injury. To determine whether chloroquine treatment could affect liver I/R injury, chloroquine was administrated to rats 1 h before warm ischemia followed by a daily injection for up to 2 days. Liver warm I/R resulted in significant increase in serum levels of alanine transaminase (ALT) and aspartate aminotransferase (AST). As shown in Figure 1a , following 60 min of warm ischemia, chloroquine treatment decreased I/R injury at 0.5 and 6 h as indicated by lower liver enzymes (Po0.05). However, the serum levels of ALT and AST were much higher following 24-and 48-h reperfusion when compared Figure 1 Chloroquine treatment prevented liver I/R injury at early phase, but worsened at late phase following I/R injury. Rats were pre-treated with either chloroquine (60 mg/kg) or vehicle (saline) 1 h before warm ischemia, followed by an additional chloroquine injections at 24 h after reperfusion. Following 60 min (a) or 90 min (b) of warm ischemia, liver injury was assessed at various time points following reperfusion by determination of serum AST and ALT levels. Data are shown as mean ± S.D. *Po0.05 compared with vehicle-treated I/R group. (c) Routine histopathology was performed on formalin-fixed liver sections obtained from rats that had undergone 60 min of ischemia followed by 6-and 24-h reperfusion, respectively (original magnification  400). Representative images from six rats per group were selected with vehicle-injected rats (Po0.05). To further confirm the dual effects of chloroquine on liver I/R injury, additional rats were subjected to 90 min of warm I/R. Chloroquine treatment caused a similar dual effect in terms of liver injury when rats were subjected to prolonged warm ischemic insult ( Figure 1b ). Liver histology confirmed the findings regarding liver injury described above. Moderate hepatocellular necrosis, cytoplasmic vacuolization of hepatocytes and sinusoidal dilation were observed 6 h after reperfusion in vehicle-treated rats. In contrast, minor hepatocellular necrosis and slight sinusoidal dilation were observed in chloroquine treatment group. However, chloroquine-treated rats showed more severe cytoplasmic vacuolization and hepatocellular necrosis 24 h after reperfusion when compared with vehicle-treated rats ( Figure 1c ; Table 1 ).