Blockade of CCN4 attenuates CCl4-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 (CCl4). Mice received vehicle (saline/olive oil) by subcutaneous injection, CCl4 by subcutaneous injection or CCl4 (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)-kappa B activity were also assessed. Results: Chronic CCl4 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-kappa B were markedly increased. Treatment with CCN4mAb significantly inhibited CCl4-induced CCN4 expression, leading to attenuated CCl4-induced liver injury and the inflammatory response. CCN4 blockade also significantly reduced the formation of collagen in the liver and the expression of alpha-smooth muscle actin and transforming growth factor beta 1. Conclusions: CCN4 inhibition by CCN4mAb in vivo significantly attenuated the CCl4 -induced liver injury and the progression of liver fibrosis. CCN4 may represent a novel therapeutic target for liver injury and fibrosis.