Therapeutic Potential of Janus Kinase Inhibitors for the Management of Interstitial Lung Disease

Abstract

Interstitial lung disease (ILD) refers to a heterogeneous group of diseases characterized by lung fibroblast proliferation, interstitial inflammation, and fibrosis-induced lung damage. The Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway is known to be activated by pro-fibrotic/pro-inflammatory cytokines such as IL-6 and IL-13, whose levels are elevated in ILD. The overexpression of growth factors such as transforming growth factor β1 in ILD activates the JAK/STAT pathway through classical or non-classical pathways, promotes macrophage activation, increases the release of pro-inflammatory and pro-fibrosis factors, and facilitates fibroblast differentiation into myofibroblasts. These findings implicate that the JAK/STAT pathway plays an important role in the course of ILD. Recent evidence also suggests that JAK inhibition alleviates excessive inflammation and pulmonary fibrosis. Accordingly, the JAK inhibitors may serve as promising drugs for the treatment of JAK/STAT-induced ILD.

Down-regulation of KLF2 in lung fibroblasts is linked with COVID-19 immunofibrosis and restored by combined inhibition of NETs, JAK-1/2 and IL-6 signaling

“…Previously, we and others demonstrated the pre-fibrotic role of neutrophils/NETs by promoting myofibroblast differentiation and activation in several disease models [ 34 , [53] , [54] , [55] , [56] , [57] ]. In addition, several studies indicated that TF/thrombin and JAK/STAT/cytokines pathways are involved in fibroblast activation and the immunofibrotic process constituting candidate therapeutic targets [ 35 , 39 , [58] , [59] , [60] , [61] , [62] , [63] ]. Recently, results of our group highlighted the importance of inhibiting multiple immune-mediated pathways, to improve survival in severe COVID-19.…”

“…Similarly, to COVID-19 lung disease, ILDs are characterized by lung fibroblast activation, interstitial inflammation, and fibrotic lung damage [ 67 ]. Over the last years, multiple mechanism-based immunomodulatory therapies, including tocilizumab or JAK inhibitors, have been used as salvage treatment in refractory and progressive ILDs [ 61 , 68 , 69 ]. Of note, it has been proposed that immunomodulation might be effective particularly in early disease with higher levels of inflammatory activity [ 68 ].…”

Potential of resveratrol in the treatment of interstitial lung disease

“…The management and treatment of ILD remains challenging for clinicians. Currently, common therapeutic strategies include glucocorticoids and immunosuppressants (such as cyclophosphamide) ( Shao et al, 2021 ), but sometimes they are resistant to the above-mentioned drugs and have serious adverse reactions ( Huo et al, 2022 ). Therefore, it is urgent to find a drug with significant efficacy and few side effects.…”

Targeting intracellular pathways in idiopathic inflammatory myopathies: A narrative review

“…The principal role in ILD patients seems to be played by the JAK2/STAT3 axis. STAT 3 is overexpressed in lung macrophages, endothelial cells, myofibroblasts and neutrophils in idiopathic pulmonary fibrosis (IPF) and systemic sclerosis patients, allowing the deposition of extracellular matrix leading to fibrosis ( 33 ). Finally, transforming growth factor β (TGFβ) is recognized by JAK2-coupled receptors that are highly expressed in fibroblasts, hyperplastic alveolar epithelial type II cells, and in the small pulmonary arteries of IPF patients ( 34 ).…”

“…The JAK2/STAT3 pathway therefore mediates TGFβ and IL6 induced pro-fibrotic and pro-inflammatory effects leading to ILD in connective tissue diseases ( 33 ). In a recent in vitro assay, Baricitinib was able to inhibit JAK2/STAT3 and therefore prevent IL6 induced epithelial-mesenchymal transition ( 35 ).…”