Effect of polarized bone marrow-derived macrophage transplantation on the progression of CCl / 临床肝胆病杂志

ABSTRACT

Objective To investigate the effect of polarized bone marrow-derived macrophage (BMDM) transplantation on the progression of CCl 4 -induced liver fibrosis in rats. Methods Rat BMDMs were isolated and induced to differentiate into M1 phenotype (M1-BMDM) by lipopolysaccharide (5 ng/mL) or M2 phenotype (M2-BMDM) by the supernatant of L929 cells. A rat model of liver fibrosis was established by subcutaneous injection of 30% CCl 4 for 6 weeks, and at week 7, the model rats were randomly divided into model control group (M group), M1-BMDM group, and M2-BMDM group and were given a single injection of normal saline, M1-BMDM, and M2-BMDM, respectively, via the caudal vein, and subcutaneous injection of 30% CCl 4 was given until the end of week 9. Related indices were observed, including liver function, liver histopathology, hydroxyproline (Hyp) content in liver tissue, hepatic stellate cell activation, liver fibrosis, and expression of inflammatory cytokines. The continuous data were expressed as mean±standard deviation; an analysis of variance was used for comparison between multiple groups, and the SNK- q test was used for further comparison between two groups. Results Compared with the M group, both M1-BMDM and M2-BMDM significantly inhibited liver inflammation and liver fibrosis progression and significantly reduced serum alanine aminotransferase and aspartate aminotransferase activities ( P < 0.01) and Hyp content in liver tissue ( P < 0.05). M1-BMDM and M2-BMDM significantly inhibited the activation of hepatic stellate cells and significantly reduced the mRNA expression levels of TGF-β, Col1A1, and Col4 (all P < 0.05). Both M1-BMDM and M2-BMDM significantly increased the expression level of CD163 protein in liver tissue ( P < 0.01), and the M2-BMDM group had a significantly higher level than the M1-BMDM group ( P < 0.05); both M1-BMDM and M2-BMDM significantly reduced the mRNA expression levels of MMP-2 and TIMP-1 in liver tissue ( P < 0.05) and significantly increased the mRNA expression level of MMP-13 ( P < 0.01); in addition, M2-BMDM significantly reduced the expression level of CD68 protein in liver tissue ( P < 0.01). Both M1-BMDM and M2-BMDM significantly increased the mRNA expression levels of IL-6 and IL-10 and the protein expression level of albumin in liver tissue (all P < 0.05), and the above indices in the M2-BMDM group were significantly higher than those in the M1-BMDM group (all P < 0.05). Conclusion Both M1-BMDM and M2-BMDM can effectively inhibit the progression of CCl 4 -induced liver fibrosis in rats, possibly by inhibiting the activation of hepatic stellate cells and promoting the activation of anti-inflammatory macrophages. Moreover, M2-BMDM can also inhibit the activation of pro-inflammatory macrophages and thus has a better comprehensive intervention effect than M1-BMDM.