Abstract
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease with multiple causes, characterized by excessive myofibrocyte aggregation and extracellular matrix deposition. Related studies have shown that transforming growth factor-β1 (TGF-β1) is a key cytokine causing fibrosis, promoting abnormal epithelial–mesenchymal communication and fibroblast-to-myofibroblast transition. Fedratinib (Fed) is a marketed drug for the treatment of primary and secondary myelofibrosis, targeting selective JAK2 tyrosine kinase inhibitors. However, its role in pulmonary fibrosis remains unclear. In this study, we investigated the potential effects and mechanisms of Fed on pulmonary fibrosis in vitro and in vivo. In vitro studies have shown that Fed attenuates TGF-β1- and IL-6-induced myofibroblast activation and inflammatory response by regulating the JAK2/STAT3 signaling pathway. In vivo studies have shown that Fed can reduce bleomycin-induced inflammation and collagen deposition and improve lung function. In conclusion, Fed inhibited inflammation and fibrosis processes induced by TGF-β1 and IL-6 by targeting the JAK2 receptor.
Highlights
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease with a poor prognosis with unknown etiology
We demonstrated the anti-pulmonary-fibrosis and anti-inflammatory effects of Fed through suppressing both JAK2/STAT3 and transforming growth factor-β1 (TGF-β1) signaling
JAK2 is a novel regulator of TGF-β1, and JAK2/STAT3 signaling is widely considered to be necessary in TGF-β1-induced abnormal wound healing of epithelial cells and fibroblastto-myofibroblast transition
Summary
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease with a poor prognosis with unknown etiology. Clinical outcomes reveal them to mitigate symptoms or retard progression and to fail to prolong survival Given this situation, more pharmacotherapy strategies are needed for patients to improve their health status. Injured AECs secret numerous mediators that induce the migration of mesenchymal cells of different origins (such as local fibroblasts or fibrocytes), as well as their differentiation to myofibroblasts [2] These myofibroblasts in turn contribute to excessive extracellular matrix (ECM) deposition and eventually destroy the lung architecture. Studies revealed that JAK2/STAT3 signaling undergoes a hyperactivation in IPF patients [12]. We demonstrate that Fed can inhibit the progression of pulmonary inflammation and fibrosis by inhibiting both JAK2/STAT3 and TGF-β1 signaling. These findings together demonstrate the antifibrotic effects of Fed and might have direct translational implications
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