Fedratinib Attenuates Bleomycin-Induced Pulmonary Fibrosis via the JAK2/STAT3 and TGF-β1 Signaling Pathway

Ruan, Hao; Luan, Jiaoyan; Gao, Shaoyan; Li, Shuangling; Jiang, Qiuyan; Liu, Rui; Liang, Qing; Zhang, Ruiqin; Zhang, Fangxia; Li, Xiaohe; Yang, Cheng

doi:10.3390/molecules26154491

Cited by 28 publications

(18 citation statements)

References 49 publications

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“…The process of PF involves the abnormal expression of multiple cytokines and the activation of many signaling pathways. Previous studies found that the Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathways are involved in idiopathic pulmonary fibrosis (IPF) [ 13 , 14 ]. The levels of activated JAK2 and STAT3 were elevated in alveolar type II epithelial cells (ATII) and lung fibroblasts from patients with IPF, in which JAK2 and STAT3 participate in lung fibrosis by dependent and independent mechanisms [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

Dihydroartemisinin attenuates pulmonary inflammation and fibrosis in rats by suppressing JAK2/STAT3 signaling

You

Jiang

Zhang

et al. 2022

Aging

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Coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2, has induced a worldwide pandemic since early 2020. COVID-19 causes pulmonary inflammation, secondary pulmonary fibrosis (PF); however, there are still no effective treatments for PF. The present study aimed to explore the inhibitory effect of dihydroartemisinin (DHA) on pulmonary inflammation and PF, and its molecular mechanism. Morphological changes and collagen deposition were analyzed using hematoxylin-eosin staining, Masson staining, and the hydroxyproline content. DHA attenuated early alveolar inflammation and later PF in a bleomycin-induced rat PF model, and inhibited the expression of interleukin (IL)-1β, IL-6, tumor necrosis factor α (TNFα), and chemokine (C-C Motif) Ligand 3 (CCL3) in model rat serum. Further molecular analysis revealed that both pulmonary inflammation and PF were associated with increased transforming growth factor-β1 (TGF-β1), Janus activated kinase 2 (JAK2), and signal transducer and activator 3(STAT3) expression in the lung tissues of model rats. DHA reduced the inflammatory response and PF in the lungs by suppressing TGF-β1, JAK2, phosphorylated (p)-JAK2, STAT3, and p-STAT3. Thus, DHA exerts therapeutic effects against bleomycin-induced pulmonary inflammation and PF by inhibiting JAK2-STAT3 activation. DHA inhibits alveolar inflammation, and attenuates lung injury and fibrosis, possibly representing a therapeutic candidate to treat PF associated with COVID-19.

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Section: Introductionmentioning

confidence: 99%

Dihydroartemisinin attenuates pulmonary inflammation and fibrosis in rats by suppressing JAK2/STAT3 signaling

You

Jiang

Zhang

et al. 2022

Aging

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“…JAK2 plays an important role in a variety of cytokine signaling pathways and participates in a variety of biological processes (7,8). Studies have shown that the levels of p-JAK2 are signi cantly increased in the lung tissue of patients with IPF( 9), and the expression of the JAK2 gene is signi cantly increased in the lung tissue of patients with RA-usual interstitial pneumonia (RA-UIP) (10).…”

Section: Discussionmentioning

confidence: 99%

Crosstalk between the JAK2 and TGF-β1 signaling pathways in scleroderma-related interstitial lung disease targeted by baricitinib

Wang

Wei

et al. 2023

Preprint

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Background and objective: Systemic sclerosis (SSc) is an immune-mediated rheumatic disease characterized by fibrosis and vascular lesions. Interstitial lung disease (ILD) is an early complication of SSc and the main cause of death from SSc. Although baricitinib shows good efficacy in a variety of connective tissue diseases, its role in systemic sclerosis-related interstitial lung disease (SSc-ILD) is unclear. The objectiveof our study was to explore the effect and mechanism of baricitinib in SSc-ILD. Methods: We explored crosstalk between the JAK2 and TGF-β1 pathways. In vivo experiments, SSc-ILD mice model were constructed by subcutaneous injection of PBS or bleomycin (7.5 mg/kg) and intragastric administration of 0.5% CMC-Na or baricitinib (5 mg/kg) once every two days. We used ELISA, qRT‒PCR, western blotand immunofluorescence staining to evaluate the degree of fibrosis. In vitro experiments, we used TGF-β1 and baricitinib to stimulate human fetal lung fibroblasts (HFLs) and assessed protein expression by western blot. Results: The vivo experiments showed that baricitinib notably alleviated skin and lung fibrosis, decreased the concentration of pro-inflammatory factors and increased those of the anti-inflammatory factors. Baricitinib affected the expression of TGF-β1 and TβRI/II inhibitiing JAK2. In the vitro experiments, following the culture of HFLs with baricitinib or a STAT3 inhibitor for 48 h, the expression levels of TβRI/II decreased. Conversely, with successful inhibition of TGF-β receptors in HFLs, JAK2 protein expression decreased. Conclusions: Baricitinib attenuated bleomycin-induced skin and lung fibrosis in SSc-ILD micemodel by targeting JAK2 and regulating of the crosstalk between the JAK2 and TGF-β1 signaling pathways.

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“…Hepatic hepcidin production also occurs in response to aberrant cytokine-driven signaling via activin receptor type 1, a member of the transforming growth factor-β (TGF-β1) superfamily of receptors [ 14 ]. Fedratinib has dual activity in inhibiting both JAK2/STAT3 signaling and TGF-β1/Smad and non-Smad pathways, and this dual pathway inhibition leads to decreased hepcidin production in patients with MF [ 15 , 16 ]. Additionally, inhibition of SMAD signaling enables erythroid maturation by means of late-stage erythroblast differentiation thereby improving anemia.…”

Section: Discussionmentioning

confidence: 99%

Transfusion Independence Achieved with Combination Fedratinib and Luspatercept in an Elderly Man with Heavily Pretreated Intermediate-2 Risk Primary Myelofibrosis

et al. 2022

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Myelofibrosis (MF)-associated anemia and transfusion dependency are associated with inferior quality of life and poor prognosis. JAK2 inhibitors and TGF-β superfamily ligand traps are being explored as treatment options for MF-associated anemia. Here, we present the case of a 66-year-old man with heavily pretreated intermediate-2 (INT-2) risk primary MF who had an exceptional response to combination fedratinib and luspatercept therapy. He achieved transfusion independence and experienced a reduction in spleen size from 20 cm to 12 cm, with remarkable improvement in performance status. Compared with other JAK inhibitors, the mechanism of action of fedratinib may explain its milder effect on anemia. It is possible that the addition of luspatercept may result in an additive or synergistic effect of one or both medications. Although the exact biological pathways have not yet been elucidated, combination fedratinib and luspatercept nevertheless is a promising therapy for anemia in patients with transfusion-dependent INT-2 risk MF.

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Fedratinib Attenuates Bleomycin-Induced Pulmonary Fibrosis via the JAK2/STAT3 and TGF-β1 Signaling Pathway

Cited by 28 publications

References 49 publications

Dihydroartemisinin attenuates pulmonary inflammation and fibrosis in rats by suppressing JAK2/STAT3 signaling

Dihydroartemisinin attenuates pulmonary inflammation and fibrosis in rats by suppressing JAK2/STAT3 signaling

Crosstalk between the JAK2 and TGF-β1 signaling pathways in scleroderma-related interstitial lung disease targeted by baricitinib

Transfusion Independence Achieved with Combination Fedratinib and Luspatercept in an Elderly Man with Heavily Pretreated Intermediate-2 Risk Primary Myelofibrosis

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