Abstract
Background: Reversibility of bleomycin (BLM) induced pulmonary fibrosis decreases with aging, while its mechanism is unclear.
Aims: To explore whether aging can affect dedifferentiation of activated lung fibroblasts (aLF) into inactive (iLF) and fibrosis resolution by remodeling fatty acid metabolism via PRDM16.
Methods: In vivo, 6-week-old (6w) and 8-month-old (8m) c57 mice were treated with BLM. 4 weeks later, 6w BLM mice were treated with etomoxir (ETO), inhibitor of fatty acid oxidation (FAO). 4 and 6 weeks after BLM, fibrosis degree, collagen-I, α-SMA, fatty acid metabolism related genes, fPRDM16 and sPRDM16 were examined. In vitro, LFs isolated from 6w and 8m mice was activated by TGF-β, after which culture supernatant was replaced by fresh culture with or without ETO or oleic acid (OA). Above indicators were detected.
Results: In vivo, 4 weeks after BLM, fibrosis degree showed no difference, while 6 weeks later, fibrosis was mitigated in 6w but not in 8m mice. 4 and 6 weeks after BLM stimulation, FAO, fPRDM16 and fPRDM16/sPRDM16 ratio decreased with aging. ETO inhibited fibrosis resolution. In vitro, 6w and 8m aLF transformed into iLF 12h and 24h after TGF-β removing, respectively. Moreover, 8m aLF and iLF showed decreased FAO, fPRDM16 and fPRDM16/sPRDM16 ratio. ETO, OA, fPRDM16 knocking down and sPRDM16 overexpression delayed dedifferentiation of 6w LF. Conversely, fPRDM16 overexpression promoted transformation of aLF, and this effect was eliminated by ETO or OA.
Conclusion: Decreased pulmonary fibrosis reversibility and fibroblast dedifferentiation during aging were cause by fatty acid metabolism remodeling resulting from imbalance of fPRDM16 and sPRDM16.
Footnotes
Cite this article as: European Respiratory Journal 2020; 56: Suppl. 64, 3384.
This abstract was presented at the 2020 ERS International Congress, in session “Respiratory viruses in the "pre COVID-19" era”.
This is an ERS International Congress abstract. No full-text version is available. Further material to accompany this abstract may be available at www.ers-education.org (ERS member access only).
- Copyright ©the authors 2020