Aging decreases reversibility of pulmonary fibrosis by regulating PRDM16-related fatty acid metabolism in lung fibroblasts

Abstract

<b>Background:</b> Aging decreases reversibility of pulmonary fibrosis. Activated lung fibroblasts (aLF) transforming into inactivated form (iLF) and LF-mediated clearance of collagen are necessary for fibrosis resolution. Reprogramming of fatty acid (FA) metabolism is related with fibrosis&nbsp;and aging. However, whether and how aging regulates FA metabolism of LF to inhibit fibrosis resolution is unclear. <b>Aims:</b> We hypothesized that aging may decrease the reversibility of lung fibrosis by inhibiting the transformation of aLF to iLF and collagen clearance in an FA metabolism-related pathway. <b>Methods:</b><i>In vivo</i>, fibrotic degree was evaluated in bleomycin (BLM)-treated 6 weeks and 8 months old mice. <i>In vitro</i>, LF&nbsp;of both mice&nbsp;were treated with TGF-β for 24 hours. Then, TGF-β in conditioned media was depleted. Collagen I, α-SMA, collagen&nbsp;uptaking and FA metabolism were examined. Effects of FA&nbsp;metabolism&nbsp;on&nbsp;above were evaluated. Then, we analyzed database to search the molecular that related with fibrosis, aging and FA metabolism. <b>Results:</b><i>In vivo</i>, fibrosis reversibility and CPT1, key enzyme of FAO, was decreased and collagen crosslinking was increased with aging. FAO inhibitor blocked fibrosis resolution. <i>In vitro</i>, aging decreased transformation of aLF to iLF and collagen I uptaking by inhibiting FAO and increasing FAS. We found PRDM16 was related with aging, fibrosis and FA metabolism. It had full length (fPRDM16) and short terms (sPRDM16). We proved fPRDM16 promoted the transformation of aLF to iLF by inducing FAO and decreasing FAS. While sPRDM16 had adverse effect. <b>Conclusion:</b> Aging inhibited lung fibrosis resolution by reprogramming FA metabolism which was regulated by PRDM16.