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

Apoptotic cell death has a prominent role in the evolution of organ damage following liver I/R. 43 It has been shown that inhibition of autophagy triggers apoptosis. 20 Apoptosis is defined as suicidal cell death with a particular morphology involving nuclear chromatin condensation, and triggered by activation of either extrinsic (death receptor-mediated) or intrinsic (mitochondrial-associated) death pathways. Recent studies have suggested possible molecular mechanisms for crosstalk between autophagy and apoptosis. [44] [45] [46] Bcl-2 family proteins, the well-characterized apoptosis regulators, has recently become clear that they reduce Beclin 1-mediated autophagy by inhibiting the formation of the Beclin 1-hVps34 PI3K complex and Beclin 1-associated class III PI3K activity. 44 It has been demonstrated that inhibition of autophagy by chloroquine prevents the fusion of autophagosomes with lysosomes via a disruption in the pH of acidic vesicles. Thus, the increased cellular burden of autophagosomes has been shown to precede and possibly induce Bax-and mitochondrial-dependent apoptosis. [17] [18] [19] [20] These previous results led us to investigate whether chloroquine could also increase hepatic apoptosis after I/R injury. Our results showed that chloroquine treatment increased apoptotic cell death as indicated by increased I/Rinduced caspase protein cleavage. Together, these data suggest that chloroquine-mediated hepatic harmful effects may involve induction of apoptosis.