Columbianadin Ameliorates Bleomycin-Induced Pulmonary Fibrosis by Inhibiting Cellular Senescence via the AMPK-Sirt1/3 Signaling Pathway.

Abstract

Idiopathic pulmonary fibrosis is a chronic, progressive disease in older adults with unclear pathogenesis and a lack of effective drugs. Columbianadin, a natural coumarin analog isolated from Angelicae pubescentis Radix, has a wide range of pharmacological effects; however, its effects on pulmonary fibrosis are unknown. This study investigates the anti-pulmonary fibrosis effects of columbianadin and their underlying mechanisms of action. An in vivo model of mouse lung fibrosis was established, and mice were randomly assigned to different doses of columbianadin. The effects of 5'-adenosine monophosphate-activated protein kinase (AMPK) on the anti-pulmonary fibrosis and anti-cellular senescence effects of columbianadin was observed by combining AMPK inhibitor and columbianadin. Cellular senescence was induced in vitro by hydrogen peroxide and treated with different concentrations of columbianadin, and we observed the effect of AMPK on the anti-cellular senescence effect of columbianadin by specifically silencing the AMPK gene. Columbianadin reduced the expression levels of collagen type I alpha 1 (col1-a1), alpha-smooth muscle actin (a-SMA), p21, and p16 in lung tissues of mice with pulmonary fibrosis, and these effects were inhibited by AMPK inhibitors. Similarly, Columbianadin reduced the expression levels of p21 and p16 in senescent cells. In addition, we found that columbianadin promoted Sirt1 and Sirt3 expression as well as AMPK phosphorylation, whereas the anti-cellular senescence effect of columbianadin and the effect of promoting the expression of Sirt1 and Sirt3 were suppressed by specific silencing of the AMPK gene. Columbianadin exerts its anti-pulmonary fibrosis effect by inhibiting cellular senescence via the AMPK-Sirt1/3 pathway. The present study provided new insight into a novel treatment of pulmonary fibrosis.