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

To study the mechanism of protection in chloroquine treatment in the early phase after reperfusion, we investigated its effect on proinflammatory cytokines expression. Chloroquine has been extensively used in the treatment of chronic inflammatory diseases. 27 We hypothesized that chloroquine may also possess anti-inflammatory abilities in liver I/R injury, which is also regarded as an inflammatory injury. To study the effects of chloroquine on proinflammatory cytokine gene expression, rats were preconditioned with chloroquine before the ischemic insult. We demonstrated that following 60 min of warm ischemia, chloroquine treatment reduced TNF-a, IL-6, IL-1b and iNOS gene expression at 0.5 and 6 h after reperfusion. These cytokines are known to have a pivotal role in the pathophysiology of hepatic I/R injury. 6, 7, 28 Recent studies suggest that extracellular HMGB1, released from damaged liver cells, causes a proinflammatory intra-hepatic micro-environment in the post-ischemic liver. Therefore, we investigated whether chloroquine treatment could modulate the release of HMGB1. Consistent with the findings in our previous studies and from other groups, HMGB1 was mainly present in the nucleus of hepatocytes in normal livers, and translocated from nucleus to cytoplasm on liver I/R injury. 8, 9, 29, 30 Chloroquine treatment reduced hepatic HMGB1 translocation and serum levels in the early phase. HMGB1 release induced the synthesis of proinflammatory cytokines and caused further liver damage in liver after I/R injury. 8, 9 Treatment with a neutralizing antibody to HMGB1 significantly decreased liver I/R injury. 9 These data suggest that the inhibition of hepatic HMGB1 translocation and subsequent release is involved in the hepatoprotective effect of chloroquine in the early phase of reperfusion.