Fisetin Alleviated Bleomycin-Induced Pulmonary Fibrosis Partly by Rescuing Alveolar Epithelial Cells From Senescence

Abstract

Idiopathic pulmonary fibrosis is an aging-associated disease, satisfactory therapies are not yet available. Accelerated senescence of alveolar epithelial cells plays an important part in Idiopathic pulmonary fibrosis pathogenesis. Fisetin (FIS) is a natural non-toxic flavonoid, which has many pharmacological functions. However, the role of FIS in pulmonary fibrosis has not been established. In this study, we found that FIS treatment apparently alleviated BLM-induced weight loss, inflammatory cells infiltration, inflammatory factors expression, collagen deposition and alveolar epithelial cell senescence, along with AMPK activation and the down regulation of NF-κB and TGF-β/Smad3 in vivo. In vitro, FIS administration significantly inhibited the senescence of alveolar epithelial cells and senescence-associated secretory phenotype, followed by reduced transdifferentiation of fibroblasts to myofibroblasts as well as collagen deposition in fibroblasts, which was blocked by an AMPK inhibitor, Compound C. Together, these results suggest that FIS can alleviate the development of BLM-induced pulmonary fibrosis, which is related to the inhibition of TGF-β/Smad3 signaling and the reduction of alveolar epithelium cell senescence by regulating AMPK/NF-κB signaling pathway. FIS may be a promising candidate for patients with pulmonary fibrosis.

Protective Effects of Sacubitril/Valsartan on Cardiac Fibrosis and Function in Rats With Experimental Myocardial Infarction Involves Inhibition of Collagen Synthesis by Myocardial Fibroblasts Through Downregulating TGF-β1/Smads Pathway

“…Our in vivo experiment showed that both sacubitril/valsartan and valsartan could effectively inhibit the expression of TGF-β1 and p-Smads in the infarcted area. Our results have been further confirmed by a recent study by Zhang W et al, who found in rats with heart failure with preserved ejection fraction induced by high-salt diet that, sacubitril/valsartan effectively alleviated the symptoms probably by inhibiting fibrosis via the TGF-β1/Smad3 signaling pathway (Zhang et al, 2020).…”

Accumulation of Senescent Neural Cells in Murine Lupus With Depression-Like Behavior

“…In this study, fisetin administration reduced the high transcription level of IL-6 in the hippocampus of MRL/lpr mice. Fisetin treatment causes a reduction of the transcription level of IL-6 in senescent cells in pulmonary fibrosis and aging-related pathology ( 40 , 66 ). Although the varied and complex pathogenic pathways complicate the development of NPSLE therapies, our data indicate that fisetin treatment targeted specifically to NPSLE senescent neural cells results in inhibition of SASP factors such as type-I interferon and IL-6, suggesting that fisetin is a candidate NPSLE therapeutic.…”

Cellular Senescence: Mechanisms and Therapeutic Potential

“…The administration of Fisetin on aged wild-type mice reduced senescence markers in the fat, spleen, kidney, liver, and a subset of cell types in the adipose tissue, and its long-term administration on wild-type mice late in life improved tissue homeostasis, suppressed ageing-associated diseases like osteoporosis, and extended their median and maximum lifespan [ 152 ]. Fisetin has also been demonstrated to rescue bleomycin-induced pulmonary fibrosis in mice by relieving senescence in alveolar epithelial cells [ 153 ].…”