Carrimycin alleviates fibrogenesis in Bile Duct Ligated rats and human fibroblasts by suppressing inflammation

Corresponding author: Wei-qing He, heweiqing@imb.pumc.edu.cn; Hong-wei He, hehwei@imb.pumc.edu.cn

DOI: 10.12201/bmr.202004.00024

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  Abstract: Aims: Fibrosis is a tissue repair compensatory response that is majorly characterized by excess accumulation of fibrous connective tissue resulting in progressive architectural remodeling in nearly all tissues and organs, such as liver, kidney, lung, heart and skin. Liver fibrosis is a vital cause of morbidity of patients with liver diseases, ultimately leading to liver cirrhosis, liver failure and even hepatocellular carcinoma, it is imperative to develop novel antifibrotic drugs for prevention or reversal of liver fibrosis. Carrimycin (CAM), a new genetic engineering 16-membered macrolide antibiotic, has been applied to upper respiratory infections, little is known about its ability to prevent hepatic injury and fibrosis. The aim of the present study is to evaluate the functional roles and mechanism of CAM in protecting against liver injury and fibrosis in bile duct ligated (BDL) rats and human fibroblasts. Result: CAM reduced the mRNA and protein levels of TGFβ1, COL1A1 and α-SMA induced by TGFβ1 in human hepatic stellate cells LX-2, human lung fibroblasts MRC5 and human skin fibroblasts CCC-ESF-1. In BDL rats, biochemical result showed that CAM treatment reduced indicators levels of γ-GT, HDL in the serum and TBA, TBiL in urine. The pathological H&E stained sections showed that CAM significantly reduced the bile duct proliferation and inflammation infiltration induced by BDL, area and density of collagen fibers in Sirius red stained sections decreased markedly as well. Furthermore, CAM also inhibited the mRNA expression of Col1a1, Acta2, Tgfb1, Mmp2 and Mmp9 in rat liver tissue. The mRNA expression of Tnfα and Il-1b, and protein levels of IL-1β and NF-κB in the inflammatory pathway were significantly suppressed by CAM treatment, and immunohistochemistry of liver tissue showed a significant decrease in the levels of NF-κB and F4/80. Conclusion: These results demonstrate that CAM ameliorates BDL-induced liver damage and fibrosis in rats by suppressing inflammation, and reduces fibrogenesis induced by TGFβ1 in human fibroblast cells LX-2, MRC5 and CCC-ESF-1, which suggests that CAM might be a novel antifibrotic candidate that protect against fibrosis in liver and in other tissue.

  Key words: liver fibrosis; Carrimycin (CAM); BDL; NF-κB

  Submit time: 20 April 2020

  Copyright: The copyright holder for this preprint is the author/funder, who has granted biomedRxiv a license to display the preprint in perpetuity.
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