Dataset Information

Inhibiting Sialidase-Induced TGF-β1 Activation Attenuates Pulmonary Fibrosis in Mice.

ABSTRACT: The active form of transforming growth factor-β1 (TGF-β1) plays a key role in potentiating fibrosis. TGF-β1 is sequestered in an inactive state by a latency-associated glycopeptide (LAP). Sialidases (also called neuraminidases (NEU)) cleave terminal sialic acids from glycoconjugates. The sialidase NEU3 is upregulated in fibrosis, and mice lacking Neu3 show attenuated bleomycin-induced increases in active TGF-β1 in the lungs and attenuated pulmonary fibrosis. Here we observe that recombinant human NEU3 upregulates active human TGF-β1 by releasing active TGF-β1 from its latent inactive form by desialylating LAP. Based on the proposed mechanism of action of NEU3, we hypothesized that compounds with a ring structure resembling picolinic acid might be transition state analogs and thus possible NEU3 inhibitors. Some compounds in this class showed nanomolar IC₅₀ for recombinant human NEU3 releasing active human TGF-β1 from the latent inactive form. The compounds given as daily 0.1-1-mg/kg injections starting at day 10 strongly attenuated lung inflammation, lung TGF-β1 upregulation, and pulmonary fibrosis at day 21 in a mouse bleomycin model of pulmonary fibrosis. These results suggest that NEU3 participates in fibrosis by desialylating LAP and releasing TGF-β1 and that the new class of NEU3 inhibitors are potential therapeutics for fibrosis. SIGNIFICANCE STATEMENT: The extracellular sialidase NEU3 appears to be a key driver of pulmonary fibrosis. The significance of this report is that 1) we show the mechanism (NEU3 desialylates the latency-associated glycopeptide protein that keeps the profibrotic cytokine transforming growth factor-β1 (TGF-β1) in an inactive state, causing active TGF-β1 release), 2) we then use the predicted NEU3 mechanism to identify nM IC₅₀ NEU3 inhibitors, and 3) these new NEU3 inhibitors are potent therapeutics in a mouse model of pulmonary fibrosis.

SUBMITTER: Karhadkar TR

PROVIDER: S-EPMC7788355 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:Silicosis is a fatal occupational lung disease which currently has no effective treatment. Dihydroquercetin (DHQ) is a flavonoid compound known for its anti-inflammatory, anti-oxidant and anti-cancer bioactivity. However, whether DHQ protects against silica-induced lung fibrosis remains unknown. Therefore, we aimed to investigate the effect of DHQ on silica-induced lung fibrosis and the underlying molecular mechanism in vivo and in vitro. Our results demonstrated that DHQ treatment markedly attenuated SiO2-induced inflammation and fibrosis degree of lung tissues in the C57BL/6 mice. Additionally, experiments in vitro also confirmed that conditioned medium from DHQ-treated human bronchial epithelial (HBE) cells significantly decreased expression of fibrosis markers of human fetal lung fibroblast cells (MRC-5), such as α-SMA, collagen1 and fibronectin. Interestingly, HBE cells treated by DHQ showed few morphological features of ferroptosis compared with SiO2-treated cells. Furthermore, DHQ treatment remarkably inhibited ferroptosis in activated HBE cells by decreasing the accumulation of iron and lipid peroxidation products, and increasing levels of glutathione (GSH) and glutathione peroxidase 4 (GPX4), whereas stimulation of ferroptosis by specific inducer erastin deeply impaired anti-fibrosis effect of DHQ in vitro. More importantly, our results showed that DHQ also evidently suppressed ferritinophagy by down-regulation of microtubule-associated protein 1A/1B-light chain 3 (LC3), and up-regulation of ferritin heavy chain 1 (FTH1), nuclear receptor co-activator 4 (NCOA4) in activated HBE cells. Nevertheless, activation of ferritinophagy by specific inducer rapamycin (Rapa) evidently blocked DHQ-inhibited HBE cells ferritinophagy and anti-fibrosis effect of DHQ. Overall, our research revealed that inhibition of ferritinophagy-mediated HBE cells ferroptosis was responsible for DHQ to ameliorate SiO2-induced lung fibrosis, which provided a preliminary theoretical basis for the clinical application of DHQ in the treatment of silicosis.

Dataset Information

Inhibiting Sialidase-Induced TGF-β1 Activation Attenuates Pulmonary Fibrosis in Mice.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets