Blockade of CCN4 attenuates CCl(4)-induced liver fibrosis

INTRODUCTION: CCN4, also termed WNT-inducible signaling pathway protein-1 (WISP-1), has important roles in inflammation and tissue injury. This study aimed to investigate the effect of CCN4 inhibition using monoclonal anti-CCN4 antibody (CCN4mAb) on the liver injury and fibrosis in a mouse model of liver fibrosis. MATERIAL AND METHODS: The mouse liver fibrosis model was induced by carbon tetrachloride (CCl(4)). Mice received vehicle (saline/olive oil) by subcutaneous injection, CCl(4) by subcutaneous injection or CCl(4) (subcutaneous) plus CCN4mAb by subcutaneous injection. The pro-inflammatory and pro-fibrotic factors were determined by Western blot. The biochemistry and histopathology, collagen deposition and nuclear factor (NF)-κB activity were also assessed. RESULTS: Chronic CCl(4) treatment caused liver injury and collagen accumulation. The expression levels of CCN4, pro-inflammatory and pro-fibrotic mediators as well as the activity of NF-κB were markedly increased. Treatment with CCN4mAb significantly inhibited CCl(4)-induced CCN4 expression, leading to attenuated CCl(4)-induced liver injury and the inflammatory response. CCN4 blockade also significantly reduced the formation of collagen in the liver and the expression of α-smooth muscle actin and transforming growth factor β1. CONCLUSIONS: CCN4 inhibition by CCN4mAb in vivo significantly attenuated the CCl(4)-induced liver injury and the progression of liver fibrosis. CCN4 may represent a novel therapeutic target for liver injury and fibrosis.