Abstract

BACKGROUND: This study aims to demonstrate the underlying correlation between the resolution of liver fibrosis induced by Gexia-Zhuyu decoction (GZD) treatment and myeloid cell-mediated angiogenesis.

MATERIAL AND METHODS: A liver fibrosis mouse model induced by carbon tetrachloride (CCl4) intervention was employed in this study. Dynamics of blood liver function parameters were followed. The liver pathology was detected by Sirius Red and Masson staining. Matrix metalloproteinase (MMP) 2/9, tissue inhibitors of metalloproteinase (TIMP)-1/2, and vascular endothelial growth factor (VEGF)-A expression levels were measured. Bone marrow chimera mice were generated by transfer of bone morrow cells from green fluorescent protein (GFP)-knockin mice into irradiated wild-type mice, and were used it to visualize the role of myeloid cells on the fibrosis resolution induced by GZD treatment.

RESULTS: The result of Sirius Red and Masson staining and the dynamics of blood liver function parameters showed that 5 weeks of GZD treatment attenuated the severity of liver fibrosis with continual CCl4 administration. GZD treatment promoted the expression of MMP2/9 and repressed the heightened level of TIMP-1/2 in the recovery phase. More notably, the increased VEGF-A and augmented endothelial progenitor cells were observed in the liver and blood in mice that received GZD, and contributed to the remodeling of hepatic vascular though the CXCL12/CXCR4 axis. Then, chimera mice with GFP-positive bone marrow cells were used to show angiogenesis driven by GZD-induced myeloid cell motivation. We found that GZD facilitated myeloid cells binding to the vascular CXCR4 and induced the resolution of fibrosis.

CONCLUSIONS: This study shows that activation of myeloid cells induced by GZD administration accelerates the functional angiogenesis, which benefits the resolution of CCl4-induced liver fibrosis.

Keywords: Fibrosis, Liver, Myeloid Cells, Angiogenesis Inducing Agents, Bone Marrow Cells, Carbon Tetrachloride, Drugs, Chinese Herbal, Liver Cirrhosis, Matrix Metalloproteinase 2, Matrix Metalloproteinase 9, Mice, Inbred C57BL, Neovascularization, Pathologic, Tissue Inhibitor of Metalloproteinase-1, Tissue Inhibitor of Metalloproteinase-2, Vascular Endothelial Growth Factor A