JAK2 mediates lung fibrosis, pulmonary vascular remodelling and hypertension in idiopathic pulmonary fibrosis: an experimental study

Milara, Javier; Ballester, Beatriz; Morell, Anatol G.; Ortiz, J.L.; Escrivá, Juan; Fernández, Estrella; Pérez‐Vizcaíno, Francisco; Cogolludo, Ángel; Pastor, Enrique Carbonell; Artigues, Enrique; Morcillo, Esteban J.; Cortijo, Julio

doi:10.1136/thoraxjnl-2017-210728

Cited by 66 publications

(76 citation statements)

References 50 publications

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“…This is consistent with reports by others showing involvement of protein kinase C␤/ Erk1/2/NF-B signaling pathway in IL-17 induced myocardial fibrosis, both in vitro and in vivo (30), as well as the observation that suppression of NF-B by antisense oligonucleotides inhibits transdifferentiation of fibroblast toward myofibroblast in a bleomycin-induced pulmonary fibrosis mice model (68). Recent studies have also implicated a role for JAK2 and STAT3-dependent signaling in lung fibrosis (2,38,44,47,49,50) and ECM regulation (44,67). A recent study using IPF tissues revealed the presence of phosphorylated JAK2 and STAT3 in lung cells, suggesting a potential role of both JAK2 and STAT3 in the pathogenesis of IPF (39).…”

Section: Discussionsupporting

confidence: 92%

Profibrotic effect of IL-17A and elevated IL-17RA in idiopathic pulmonary fibrosis and rheumatoid arthritis-associated lung disease support a direct role for IL-17A/IL-17RA in human fibrotic interstitial lung disease

Zhang

Wang

et al. 2019

American Journal of Physiology-Lung Cellular and Molecular Phys

135

101

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Interleukin (IL)-17 is a T helper 17 cytokine implicated in the pathogenesis of many autoimmune diseases, including rheumatoid arthritis (RA). Although IL-17A has a well-established role in murine pulmonary fibrosis models, its role in the tissue remodeling and fibrosis occurring in idiopathic pulmonary fibrosis (IPF) and RA-associated interstitial lung disease (RA-ILD) is not very well defined. To address this question, we utilized complimentary studies to determine responsiveness of human normal and pathogenic lung fibroblasts to IL-17A and used lung biopsies acquired from patients with IPF and RA-ILD to determine IL-17A receptor (IL-17RA) expression. Both normal and pathogenic IPF lung fibroblasts express functional IL-17RA and respond to IL-17A stimulation with cell proliferation, generation of extracellular matrix (ECM) proteins, and induction of myofibroblast transdifferentiation. Small interfering RNA (siRNA) silencing of IL-17RA attenuated this fibroblast response to IL-17A on ECM production. These fibroblast responses to IL-17A are dependent on NF-κB-mediated signaling. In addition, inhibiting Janus activated kinase (JAK) 2 by either siRNA or a selective pharmacological inhibitor, AZD1480—but not a JAK1/JAK3 selective inhibitor, tofacitinib—also significantly reduced this IL-17A-induced fibrogenic response. Lung biopsies of RA-ILD patients demonstrate significantly higher IL-17RA expression in areas of fibroblast accumulation and fibrosis, compared with either IPF or normal lung tissue. These observations support a direct role for IL-17A in lung fibrosis that may be particularly relevant in the context of RA-ILD.

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Section: Discussionsupporting

confidence: 92%

Profibrotic effect of IL-17A and elevated IL-17RA in idiopathic pulmonary fibrosis and rheumatoid arthritis-associated lung disease support a direct role for IL-17A/IL-17RA in human fibrotic interstitial lung disease

Zhang

Wang

et al. 2019

American Journal of Physiology-Lung Cellular and Molecular Phys

135

101

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“…Nevertheless, a recent study by Milara et al showed that lungs from patients with IPF expressed higher levels of STAT3 and JAK2, as well as phosphorylated STAT3 [32]. In another article they showed that this was also the case in pulmonary arteries in IPF [29]. As STAT3 possesses two phosphorylation sites that are known to be relevant to function: pSTAT3-Y705 and pSTAT3-S727 [37], it is important to distinguish between the two.…”

Section: Discussionmentioning

confidence: 99%

“…Transforming growth factor-β (TGF-β) is another well discussed pathway in fibrosis development [19]. Recent publications [9,29,30], suggested Smad3 as a possible target of the IL-6 trans-signaling. Therefore, STRING analysis was performed, with the inclusion of the aforementioned targets, as well as Smad3.…”

Section: Phosphorylated and Total Smad3 Are Overexpressed In Ipf-hlfsmentioning

confidence: 99%

TGF-β pathway activation by idiopathic pulmonary fibrosis (IPF) fibroblast derived soluble factors is mediated by IL-6 trans-signaling

et al. 2020

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Background: Idiopathic pulmonary fibrosis (IPF) is a chronic and ultimately fatal disease characterized by a progressive decline in lung function. Fibrotic diseases, such as IPF, are characterized by uncontrolled activation of fibroblasts. Since the microenvironment is known to affect cell behavior, activated fibroblasts can in turn activate healthy neighboring cells. Thus, we investigated IPF paracrine signaling in human lung fibroblasts (HLFs) derived from patients with IPF. Methods: Primary human fibroblast cultures from IPF (IPF-HLF) and control donor (N-HLF) lung tissues were established and their supernatants were collected. These supernatants were then added to N-HLFs for further culture. Protein and RNA were extracted from IPF/ N-HLFs at baseline. Interleukin-6 (IL-6) and TGF-β-related signaling factors (e.g. STAT3, Smad3) were evaluated by western blot and qPCR. IL-6 levels were measured by ELISA. IL-6 signaling was blocked by Tocilizumab (TCZ) (10 ng/ml).Results: IPF-HLFs were found to significantly overexpress IL-6 receptor (IL-6R), suppressor of cytokine signaling 3 (SOCS3), phospho-STAT3-Y705 and phospho-Smad3 in comparison to N-HLFs (p < 0.05). In addition, they were found to proliferate faster, secrete more IL-6 and express higher levels of the soluble IL-6R. IPF-HLF increased proliferation was inhibited by TCZ. Moreover, IPF-HLF derived supernatants induced both direct and indirect STAT3 activation that resulted in Smad3 phosphorylation and elevated Gremlin levels in N-HLFs. These effects were also successfully blocked by TCZ.Conclusions: IPF-HLF paracrine signaling leads to IL-6R overexpression, which in turn, affects N-HLF survival. The IL-6/STAT3/ Smad3 axis facilitates cellular responses that could potentially promote fibrotic disease. This interplay was successfully blocked by TCZ.

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“…At present, lung diseases, including pulmonary hypertension, pulmonary fibrosis, chronic obstructive pulmonary disease, and even lung cancer, are a type of disease with extremely high mortality [1][2][3] . Although different diseases have different characteristics and pathogenesis, PASMC dysfunction plays an important role in the pathogenesis of various lung diseases [4][5][6] . Therefore, it is extremely important to further study the functions and regulation mechanisms of PASMCs, and the need to find new therapeutic targets is urgent.…”

Section: Introductionmentioning

confidence: 99%

BCAT1 binds the RNA-binding protein ZNF423 to activate autophagy via the IRE1-XBP-1-RIDD axis in hypoxic PASMCs

Wei

Zhang

et al. 2020

Cell Death Dis

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Abnormal functional changes in pulmonary artery smooth muscle cells are the main causes of many lung diseases. Among, autophagy plays a crucial role. However, the specific molecular regulatory mechanism of autophagy in PASMCs remains unclear. Here, we first demonstrate that BCAT1 played a key role in the autophagy of hypoxic PASMCs and hypoxic model rats. BCAT1-induced activation and accumulation of the autophagy signaling proteins BECN1 and Atg5 by the endoplasmic reticulum (ER) stress pathway. Interestingly, we discovered that BCAT1 bound IRE1 on the ER to activate expression of its downstream pathway XBP-1-RIDD axis to activate autophagy. More importantly, we identified an RNA-binding protein, zinc finger protein 423, which promoted autophagy by binding adenylate/uridylate (AU)-rich elements in the BCAT1 mRNA 3′-untranslated region. Overall, our results identify BCAT1 as a potential therapeutic target for the clinical treatment of lung diseases and reveal a novel posttranscriptional regulatory mechanism and signaling pathway in hypoxia-induced PASMC autophagy.

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JAK2 mediates lung fibrosis, pulmonary vascular remodelling and hypertension in idiopathic pulmonary fibrosis: an experimental study

Abstract: JAK2 participates in PA remodelling and tension and may be an attractive target to treat IPF associated to PH.

Cited by 66 publications

References 50 publications

Profibrotic effect of IL-17A and elevated IL-17RA in idiopathic pulmonary fibrosis and rheumatoid arthritis-associated lung disease support a direct role for IL-17A/IL-17RA in human fibrotic interstitial lung disease

Profibrotic effect of IL-17A and elevated IL-17RA in idiopathic pulmonary fibrosis and rheumatoid arthritis-associated lung disease support a direct role for IL-17A/IL-17RA in human fibrotic interstitial lung disease

TGF-β pathway activation by idiopathic pulmonary fibrosis (IPF) fibroblast derived soluble factors is mediated by IL-6 trans-signaling

BCAT1 binds the RNA-binding protein ZNF423 to activate autophagy via the IRE1-XBP-1-RIDD axis in hypoxic PASMCs

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