Novel CXCR2-dependent liver regenerative qualities of ELR-containing CXC chemokines

Severe acute liver injury due to accidental or intentional acetaminophen ov erdose presents a major clinical dilemma often requiring liver transplantat ion. In the present study, liver regeneration after profound liver injury i n mice challenged with acetaminophen was facilitated by the exogenous addit ion of ELR-containing CXC chemokines such as macrophage inflammatory protei n-a (MIP-2), epithelial neutrophil-actavating protein-78 (ENA-78), or inter leukin 8, Intravenous administration of ELR-CXC chemokines or N-acetyl-cyst eine (NAC) immediately after acetaminophen challenge in mice significantly reduced histological and biochemical markers of hepatic injury. However, wh en the intervention was delayed until 10 h after acetaminophen challenge, o nly ELR-CXC chemokines significantly reduced liver injury and mouse mortali ty. The delayed addition of ELR-CXC chemokines to cultured hepatocytes main tained the proliferation of these cells in a CXCR2-dependent fashion after acetaminophen challenge whereas delayed NAC treatment did not. These observ ations demonstrate that ELR-CXC chemokines represent novel hepatic regenera tive factors that exhibit prolonged therapeutic effects after acetaminophen -induced hepatotoxicity.