A plant-based medicine called quercetin reversed pulmonary fibrosis in a mouse model likely by reducing the burden of growth-arrested and fibrosis-promoting cells, called senescent cells, in the animals’ lungs, researchers report.
Findings were published in the study, “Quercetin enhances ligand-induced apoptosis in senescent IPF fibroblasts and reduces lung fibrosis in vivo,” in the journal American Journal of Respiratory Cell and Molecular Biology.
The progression of idiopathic pulmonary fibrosis (IPF) is highly variable, with the disease progressing rapidly in some patients (rapid IPF), while in other patients, the disease remains stable for years (stable IPF). The mechanisms underlying IPF progression remain poorly known.
Cellular senescence occurs when cells permanently stop dividing, and happens more frequently as cells grow older.
Accumulating evidence suggests that senescent cells may play a role in age-related diseases, including IPF and chronic obstructive pulmonary disease (COPD). In fact, fibroblastic foci — places where fibrotic (scarring) processes start — are mainly composed of senescent myofibroblasts, which are cells involved in wound healing and fibrosis.
Senescent cells secrete a series of signaling molecules — pro-inflammatory cytokines, chemokines, and other molecules — a phenomenon collectively known as senescence-associated secretory phenotype (SASP) that is believed to promote fibrosis.
A plant pigment (flavonoid) called quercetin administered together with the chemotherapy dasatinib (sold under the brand name Sprycel by Bristol-Myers Squibb), used in chronic myeloid leukemia treatment, were shown to decrease senescence and lessen the fibrotic burden in the lungs of the bleomycin-induced pulmonary fibrosis mouse model.
These results prompted researchers to test the therapy’s potential in senescent lung fibroblasts from IPF patients. The team also tested quercetin’s effectiveness when administered alone to senescent human lung fibroblasts or in senescent mice with pulmonary fibrosis.
Researchers first confirmed that lung fibroblasts derived from both stable and rapid IPF lung biopsies grown in culture were more senescent than normal, healthy fibroblasts.
They then found that IPF senescent lung fibroblasts were resistant to cues triggering their death.
Quercetin was previously shown to selectively kill senescent cells by inducing apoptosis, a form of programmed cell death.
To assess the ability of quercetin to induce apoptosis, researchers treated normal, stable IPF and rapid IPF fibroblasts with quercetin for 24 hours. Results showed that quercetin led to increased expression of the FAS receptor, which induces apoptosis when bound to its ligand, FasL, and two other death receptors called death receptor (DR) 4 and 5. No differences were observed in normal fibroblasts.
While quercetin alone was not sufficient to induce apoptosis in senescent lung fibroblasts, it increased the cells’ susceptibility to pro-apoptotic stimuli, such as FasL and TRAIL, short for tumor necrosis factor (TNF)-related apoptosis-inducing ligand.
The team then tested the in vivo effectiveness of quercetin in resolving fibrosis in an aged (older than 12 months) bleomycin-induced lung injury mouse model. Seven days after bleomycin administration (the inflammatory phase), mice received quercetin (30 mg/kg) every other day over a period of one or three weeks, until day 14 or 28 after bleomycin administration.
Quercetin was found to reverse the established bleomycin-induced pulmonary fibrosis in these animals. Moreover, the therapy restored the animals’ body weight loss and increased their survival, compared with bleomycin-treated control mice.
Administration of quercetin in these animals also led to a decrease in senescence markers, namely of p21 and p19-ARF, suggesting “that the therapeutic effect of quercetin in aged mice with bleomycin-induced pulmonary fibrosis was due to the reduction of the senescent cell burden in the lungs,” the researchers wrote.
“In conclusion, we demonstrate that the flavonoid quercetin renders senescent IPF fibroblasts susceptible to apoptosis induced by FasL and TRAIL,” they said.
These results support the potential therapeutic benefits of quercetin in the treatment of IPF and other fibrotic disorders.