Clevudine attenuates bleomycin-induced early pulmonary fibrosis via regulating M2 macrophage polarization

• DOI: 10.1016/j.intimp.2021.108271
• Publication Date: 2021-10-25T18:18:10Z
• Authors: Shuangling Li; Shaoyan Gao; Qiuyan Jiang; Qing Liang; Jiaoyan Luan; Ruiqin Zhang; Fangxia Zhang; Hao Ruan; Xiaohe Li; Xiaoping Li; Honggang Zhou; Cheng Yang
• Keywords: Male; 0303 health sciences; Macrophages; Pulmonary Fibrosis; Arabinofuranosyluracil; Cell Differentiation; Respiratory Mucosa; Antiviral Agents; 3. Good health; Mice, Inbred C57BL; Bleomycin; Disease Models, Animal; Mice; 03 medical and health sciences; RAW 264.7 Cells; Th2 Cells; Animals; Cytokines; Humans

Pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease. It is a growing clinical problem which can result in breathlessness or respiratory failure and has an average life expectancy of 3 years from diagnosis. Predominantly accumulation of M2 macrophages accelerates fibrosis progression by secreting multiple cytokines that promote fibroblast to myofibroblast transition and aberrant wound healing of epithelial cells. Targeting activated macrophages to inhibit the pro-fibrotic phenotype is considered as an approach for the potential treatment of PF. Clevudine is s a purine nucleoside analogue which in an oral formulation is approved for treatment of patients with hepatitis B virus (HBV). Here, we found that clevudine is capable of suppressing pro-fibrotic phenotype (i.e., CD206, Arg1 and YM1) of M2 macrophages while enhancing anti-fibrotic phenotype (i.e., CD86, IL-6 and IL-10) by inhibiting PI3K/Akt signaling pathway. This effect further alleviates M2-induced myofibroblast activation and epithelial-to-mesenchymal transition (EMT), thus resulting in a decline of collagen deposition, pro-fibrotic cytokines secretion, with a concomitant recover ofpulmonary functions in vivo. Less infiltration of M2 macrophages between α-SMA + cells was also found in clevudine treated mice. Our findings indicate a potential anti-fibrotic effect of clevudine by regulating macrophage polarization and might be meaningful in clinical settings.