Quercetin Enhances Ligand-induced Apoptosis in Senescent Idiopathic Pulmonary Fibrosis Fibroblasts and Reduces Lung Fibrosis In Vivo.
Miriam S N HohmannDavid M HabielAna L CoelhoWaldiceu A VerriCory M HogaboamPublished in: American journal of respiratory cell and molecular biology (2019)
Although cellular senescence may be a protective mechanism in modulating proliferative capacity, fibroblast senescence is now recognized as a key pathogenic mechanism in idiopathic pulmonary fibrosis (IPF). In aged mice, abundance and persistence of apoptosis-resistant senescent fibroblasts play a central role in nonresolving lung fibrosis after bleomycin challenge. Therefore, we investigated whether quercetin can restore the susceptibility of senescent IPF fibroblasts to proapoptotic stimuli and mitigate bleomycin-induced pulmonary fibrosis in aged mice. Unlike senescent normal lung fibroblasts, IPF lung fibroblasts from patients with stable and rapidly progressing disease were highly resistant to Fas ligand (FasL)-induced and TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis. Senescent IPF fibroblasts exhibited decreased expression of FasL and TRAIL receptors and caveolin-1, as well as increased AKT activation, compared with senescent normal lung fibroblasts. Although quercetin alone was not proapoptotic, it abolished the resistance to FasL- or TRAIL-induced apoptosis in IPF fibroblasts. Mechanistically, quercetin upregulated FasL receptor and caveolin-1 expression and modulated AKT activation. In vivo quercetin reversed bleomycin-induced pulmonary fibrosis and attenuated lethality, weight loss, and the expression of pulmonary senescence markers p21 and p19-ARF and senescence-associated secretory phenotype in aged mice. Collectively, these data indicate that quercetin reverses the resistance to death ligand-induced apoptosis by promoting FasL receptor and caveolin-1 expression and inhibiting AKT activation, thus mitigating the progression of established pulmonary fibrosis in aged mice. Therefore, quercetin may be a viable therapeutic option for IPF and other age-related diseases that progress with the accumulation of senescent fibroblasts.
Keyphrases
- idiopathic pulmonary fibrosis
- induced apoptosis
- pulmonary fibrosis
- endoplasmic reticulum stress
- signaling pathway
- oxidative stress
- extracellular matrix
- poor prognosis
- interstitial lung disease
- diabetic rats
- dna damage
- weight loss
- endothelial cells
- high fat diet induced
- pi k akt
- high glucose
- binding protein
- cell proliferation
- pulmonary hypertension
- long non coding rna
- drug induced
- microbial community
- type diabetes
- wastewater treatment
- body mass index
- bariatric surgery
- data analysis
- rheumatoid arthritis
- wild type
- high resolution
- metabolic syndrome
- big data
- roux en y gastric bypass
- weight gain