The dietary antioxidant quercetin reduces hallmarks of bleomycin-induced lung fibrogenesis in mice

Abstract

Background Idiopathic pulmonary fibrosis (IPF) is a chronic, lethal disease of which the etiology is still not fully understood. Current treatment comprises two FDA-approved drugs that can slow down yet not stop or reverse the disease. As IPF pathology is associated with an altered redox balance, adding a redox modulating component to current therapy might exert beneficial effects. Quercetin is a dietary antioxidant with strong redox modulating capacities that is suggested to exert part of its antioxidative effects via activation of the redox-sensitive transcription factor Nrf2 that regulates endogenous antioxidant levels. Therefore, the aim of the present study was to investigate if the dietary antioxidant quercetin can exert anti-fibrotic effects in a mouse model of bleomycin-induced pulmonary fibrogenesis through Nrf2-dependent restoration of redox imbalance. Methods Homozygous Nrf2 deficient mice and their wildtype littermates were fed a control diet without or with 800 mg quercetin per kg diet from 7 days prior to a single 1 μg/2 μl per g BW bleomycin challenge until they were sacrificed 14 days afterwards. Lung tissue and plasma were collected to determine markers of fibrosis (expression of extracellular matrix genes and histopathology), inflammation (pulmonary gene expression and plasma levels of tumor necrosis factor-α (TNFα) and keratinocyte chemoattrachtant (KC)), and redox balance (pulmonary gene expression of antioxidants and malondialdehyde-dG (MDA)- DNA adducts). Results Mice fed the enriched diet for 7 days prior to the bleomycin challenge had significantly enhanced plasma and pulmonary quercetin levels (11.08 ± 0.73 μM versus 7.05 ± 0.2 μM) combined with increased expression of Nrf2 and Nrf2-responsive genes compared to mice fed the control diet in lung tissue. Upon bleomycin treatment, quercetin-fed mice displayed reduced expression of collagen (COL1A2) and fibronectin (FN1) and a tendency of reduced inflammatory lesions (2.8 ± 0.7 versus 1.9 ± 0.8). These beneficial effects were accompanied by reduced pulmonary gene expression of TNFα and KC, but not their plasma levels, and enhanced Nrf2-induced pulmonary antioxidant defences. In Nrf2 deficient mice, no effect of the dietary antioxidant on either histology or inflammatory lesions was observed. Conclusion Quercetin exerts anti-fibrogenic and anti-inflammatory effects on bleomycin-induced pulmonary damage in mice possibly through modulation of the redox balance by inducing Nrf2. However, quercetin could not rescue the bleomycin-induced pulmonary damage indicating that quercetin alone cannot ameliorate the progression of IPF.

A Potential Quorum-Sensing Inhibitor for Bronchiectasis Therapy: Quercetin–Chitosan Nanoparticle Complex Exhibiting Superior Inhibition of Biofilm Formation and Swimming Motility of Pseudomonas aeruginosa to the Native Quercetin

“…In this regard, to the best of our knowledge, the amount of QUE recovered in the lung after inhaled QUE delivery has not been experimentally investigated before. Therefore, we carried out the cytotoxicity test in the QUE concentration range that was roughly between two to twenty times higher than the QUE concentration recovered in the lung after oral QUE delivery (i.e., 1.5 µg/mL) [ 39 ], as we anticipated that the inhaled delivery route would lead to a higher QUE concentration in the lung owed to avoidance of the first-pass metabolism.…”

Antiviral, immunomodulatory, and anticoagulant effects of quercetin and its derivatives: Potential role in prevention and management of COVID-19

“…Quercetin treatment stabilizes NRF2 by modifying KEAP1, thereby inhibiting NRF2 ubiquitination and proteasomal degradation [ 18 ]. Dietary feeding of quercetin in mouse models activated the NRF2 pathway in the lungs, as indicated by the expression of NRF2 regulated genes [ 19 ], and protected from bleomycin-induced lung fibrosis. Quercetin supplementation also protected other organ injuries, such as kidney injury, in an NRF2-dependent manner [ 20 ].…”

The Restorative Effect of Red Guava (Psidium guajava L.) Fruit Extract on Pulmonary Tissue of Rats (Rattus norvegicus) Exposed to Cigarette Smoke

“…e labile iron accumulation and enhanced lipid peroxidation with concomitant nonapoptotic cell death occur during CSE [41]. Quercetin exerts anti-inflammatory effects on pulmonary damage by inducing cellular defense against oxidative stress through transcriptional upregulation of antioxidant proteins [42]. Vitamin C inhibited the TNF-α-induced activation of the mitogen-activated protein kinase (MAPKs) and nuclear factor-kappa B (NF-κB) signaling [43].…”

“…CSE in the rat model caused the alveolar septal thickening score to be 5.3-fold higher compared to those of normal rats. Quercetin exerts antifibrogenic effects on pulmonary damage by inducing Nrf2 for cellular defense against oxidative stress and transcriptional regulation of antioxidant proteins [42]. Vitamin C reduced the recruitment of inflammatory cells, the secretion of IL-17, a cytokine involved in neutrophils migration, TGF-β, a profibrotic mediator, and collagen deposition [24].…”