Interstitial lung disease associated with rheumatoid arthritis (RA-ILD) can lead to interstitial fibrosis and even lung failure as a complication of rheumatoid arthritis (RA), and there is currently no effective treatment and related basic research. Studies have found that resveratrol (Res) can improve the progression of RA by regulating autophagy, and increasing evidence supports the connection between autophagy and common interstitial lung disease (ILD). We explored changes in autophagy levels in fibrotic lungs in RA-ILD and found that the level of autophagy is enhanced in the early stage but inhibited in the late stage. However, resveratrol treatment improved the level of autophagy and reversed the inhibition of autophagy, and attenuated fibrosis. We created corresponding cell models that exhibited the same phenotypic changes as animal models; under the effect of resveratrol, the level of fibrosis changed accordingly, and the fusion process of lysosomes and autophagosomes in autophagy was liberated from the inhibition state. Resveratrol effects were reversed by the addition of the late autophagy inhibitor chloroquine. These results suggest that resveratrol attenuates pulmonary fibrosis, increases autophagic flux, and modulates the autophagy–lysosome pathway, and particularly it may work by improving the formation of autophagic lysosomes, which may be an effective treatment for induced RA-ILD.

Rheumatoid arthritis (RA) is a refractory systemic autoimmune disease associated with synovial inflammation. Previous studies postulate that paeonol has good anti-arthritis effects on RA. However, its systematic description remains unknown. Herein, we used bioinformatics tools to evaluate the mechanism of paeonol in arthritis systematically. A macrophage model was employed to study the differentially expressed genes between the inflammation and normal group, revealing 169 inflammation-related genes. Another 275 key genes affected by paeonol were identified in the same model. Three key genes, FPR2, Cd83, and Cfb, were obtained after combining the two data sets. Paeonol inhibited the release of inflammatory factors and the proliferation of synovial. However, its inhibitory effect was blocked by Fpr2 blocker WRW4. In summary, paeonol can inhibit the development of arthritis through FPR2. This provides new scope for the design and development of FPR2 ligands.