Resveratrol Ameliorates Fibrosis in Rheumatoid Arthritis-Associated Interstitial Lung Disease via the Autophagy–Lysosome Pathway

Abstract

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.

Potential Role of Dietary Phenolic Compounds in the Prevention and Treatment of Rheumatoid Arthritis: Current Reports

“…aqueous ethanolic extract (30:70) showed potential to reduce paw volume/diameter and PGE2, COX-2, IL-1β, IL-6, NF-κB, and TNF-α levels and enhance IL-4 and IL-10 contents in Sprague Dawley rats with induced RA [229]. Additionally, 80 mg/kg daily of chebulanin for 3 weeks significantly suppressed the progression and development of RA in a collagen-induced arthritis mouse model by decreasing the arthritis severity score, attenuating paw swelling and joint destruction, and reducing IL-6 and TNF-α amounts, excised phosphorylated (p)-p38 and p-p65, phosphorylated-c-JUN N-terminal kinase, and phosphorylated NF-κB inhibitor alpha, but without effects on extracellular-signal-regulated kinase levels [231].…”

“…Hydrogen peroxide is also released, owing to the activation of nuclear factor kappa-lightchain-enhancer of activated B cells (NF-κB) kinases and oxidation, hence stopping reactive species accumulation [228,229]. However, although inflammatory processes are directly linked to individual development, when these responses are exaggerated, carbohydrate damage, lipid peroxidation protein, and nucleic acid oxidation happen, contributing to the onset of many disorders, including AR [230][231][232]. Once again, given that phenolics can counteract oxidative stress and normalize immune responses, it is not surprising that phenolics are a target of extensive research.…”

“…On the other hand, 25, 50, and 100 µM chebulanim, a natural polyphenol acid isolated from Terminalia chebula Retz inhibited the nuclear translocation of p38 and p65 in liposaccharide-stimulated macrophages in a dose-dependent manner [231]. Additionally, aqueous birch leaf extract of Betula pendula Roth inhibits the growth and cell division of inflammatory lymphocytes in a dose-dependent manner because of apoptosis induction [265].…”

Resveratrol attenuates inflammation and fibrosis in rheumatoid arthritis-associated interstitial lung disease via the AKT/TMEM175 pathway

“…Furthermore, autophagy plays a significant role in the development of pulmonary fibrosis [18][19][20]. Research has demonstrated that resveratrol can suppress fibrosis in RA-ILD by reinstating autophagy [21].…”

Potential of resveratrol in the treatment of interstitial lung disease

“…At the same time, the autophagy process and the nucleotide-binding domain and leucine-rich repeat protein 3 inflammasome activities are inhibited, and the production of pro-inflammatory factors is reduced, thus improving lung inflammation and fibrosis ( Ding et al, 2019 ). In addition, in the fusion process of autophagosome and lysosome, RSV can relieve their inhibitory state and reverse the destruction of autophagosome—lysosome fusion, thus improving ILD ( Bao et al, 2022 ). These findings suggest that RSV can be used as a potential treatment for ILD ( Figure 1 ).…”