Role of JAK/STAT in Interstitial Lung Diseases; Molecular and Cellular Mechanisms

Abstract

Interstitial lung diseases (ILDs) comprise different fibrotic lung disorders characterized by cellular proliferation, interstitial inflammation, and fibrosis. The JAK/STAT molecular pathway is activated under the interaction of a broad number of profibrotic/pro-inflammatory cytokines, such as IL-6, IL-11, and IL-13, among others, which are increased in different ILDs. Similarly, several growth factors over-expressed in ILDs, such as platelet-derived growth factor (PDGF), transforming growth factor β1 (TGF-β1), and fibroblast growth factor (FGF) activate JAK/STAT by canonical or non-canonical pathways, which indicates a predominant role of JAK/STAT in ILDs. Between the different JAK/STAT isoforms, it appears that JAK2/STAT3 are predominant, initiating cellular changes observed in ILDs. This review analyzes the expression and distribution of different JAK/STAT isoforms in ILDs lung tissue and different cell types related to ILDs, such as lung fibroblasts and alveolar epithelial type II cells and analyzes JAK/STAT activation. The effect of JAK/STAT phosphorylation on cellular fibrotic processes, such as proliferation, senescence, autophagy, endoplasmic reticulum stress, or epithelial/fibroblast to mesenchymal transition will be described. The small molecules directed to inhibit JAK/STAT activation were assayed in vitro and in in vivo models of pulmonary fibrosis, and different JAK inhibitors are currently approved for myeloproliferative disorders. Recent evidence indicates that JAK inhibitors or monoclonal antibodies directed to block IL-6 are used as compassionate use to attenuate the excessive inflammation and lung fibrosis related to SARS-CoV-2 virus. These altogether indicate that JAK/STAT pathway is an attractive target to be proven in future clinical trials of lung fibrotic disorders.

Combined administration of inhaled DNase, baricitinib and tocilizumab as rescue treatment in COVID-19 patients with severe respiratory failure

“…Moreover, IL-6 triggers JAK/STAT signaling, driving the transcription of an extensive range of acute phase proteins such as CRP. Furthermore, IL-6 may activate and promote differentiation or proliferation of several non-immune cells, including fibroblasts [37,38]. The application of combined therapeutic regimens against COVID-19-related SRF is an emerging challenge against this complex and heterogeneous mechanistic basis of COVID-19 pathophysiology.…”

“…Moreover, IL-6 triggers JAK/STAT signaling, driving the transcription of an extensive range of acute phase proteins such as CRP. Furthermore, IL-6 may activate and promote differentiation or proliferation of several non-immune cells, including fibroblasts [37,38].…”

Magnolol Attenuates Right Ventricular Hypertrophy and Fibrosis in Hypoxia-Induced Pulmonary Arterial Hypertensive Rats Through Inhibition of the JAK2/STAT3 Signaling Pathway

“…Janus kinase 2 (JAK2) is an essential member of the non-receptor tyrosine kinase family, promoting the phosphorylation of signal transducer of activators of transcription 3 (STAT3). The activated STAT3 can enter the nucleus and participate in cell growth, differentiation, and apoptosis by regulating the expression of downstream target genes ( Montero et al, 2021 ). Growing evidence has shown that JAK2/STAT3 pathway plays a vital role in the pathogenesis of PAH.…”

Indole-Based Small Molecules as Potential Therapeutic Agents for the Treatment of Fibrosis

“…β-catenin enters the nucleus and polymerizes with T cell factors and lymphocyte enhancer factors (TCF/LEF) to form intranuclear complexes, which regulate transcription of target genes and ultimately accelerate the progression of fibrosis ( Wang et al, 2018 ; Schunk et al, 2021 ). In addition to the above-mentioned pathways, Raf/MEK/ERK, JAK/STAT and other pathways are also involved in the regulation of fibrosis ( Figure 2 ; Guo et al, 2018 ; Foglia et al, 2019 ; Liu et al, 2019a ; Pompili et al, 2019 ; Montero et al, 2021 ). Fibrous diseases reportedly cause up to 45% of deaths in the western developed country ( Oruqaj et al, 2015 ).…”