scholarly journals Mode of action of nintedanib in the treatment of idiopathic pulmonary fibrosis

2015 ◽  
Vol 45 (5) ◽  
pp. 1434-1445 ◽  
Author(s):  
Lutz Wollin ◽  
Eva Wex ◽  
Alexander Pautsch ◽  
Gisela Schnapp ◽  
Katrin E. Hostettler ◽  
...  
Keyword(s):  
Growth Factor ◽  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Tyrosine Kinases ◽  
Cell Injury ◽  
Transforming Growth Factor ◽  
Alveolar Epithelial Cell ◽  
Phase Iii ◽  
Lung Fibroblasts

Idiopathic pulmonary fibrosis (IPF) is a progressive and ultimately fatal disease characterised by fibrosis of the lung parenchyma and loss of lung function. Although the pathogenic pathways involved in IPF have not been fully elucidated, IPF is believed to be caused by repetitive alveolar epithelial cell injury and dysregulated repair, in which there is uncontrolled proliferation of lung fibroblasts and differentiation of fibroblasts into myofibroblasts, which excessively deposit extracellular matrix (ECM) proteins in the interstitial space. A number of profibrotic mediators including platelet-derived growth factor (PDGF), fibroblast growth factor (FGF) and transforming growth factor-β are believed to play important roles in the pathogenesis of IPF. Nintedanib is a potent small molecule inhibitor of the receptor tyrosine kinases PDGF receptor, FGF receptor and vascular endothelial growth factor receptor. Data from in vitro studies have shown that nintedanib interferes with processes active in fibrosis such as fibroblast proliferation, migration and differentiation, and the secretion of ECM. In addition, nintedanib has shown consistent anti-fibrotic and anti-inflammatory activity in animal models of lung fibrosis. These data provide a strong rationale for the clinical efficacy of nintedanib in patients with IPF, which has recently been demonstrated in phase III clinical trials.

scholarly journals The role of tyrosine kinases in the pathogenesis of idiopathic pulmonary fibrosis

2015 ◽  
Vol 45 (5) ◽  
pp. 1426-1433 ◽  
Author(s):  
Friedrich Grimminger ◽  
Andreas Günther ◽  
Carlo Vancheri
Keyword(s):  
Growth Factor ◽  
Animal Models ◽  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Tyrosine Kinase ◽  
Tyrosine Kinases ◽  
Receptor Tyrosine Kinases ◽  
Growth Factor Receptor ◽  
Phase Iii

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with a median survival time from diagnosis of 2–3 years. Although the pathogenic pathways have not been fully elucidated, IPF is believed to be caused by persistent epithelial injury in genetically susceptible individuals. Tyrosine kinases are involved in a range of signalling pathways that are essential for cellular homeostasis. However, there is substantial evidence from in vitro studies and animal models that receptor tyrosine kinases, such as the platelet-derived growth factor receptor, vascular endothelial growth factor receptor and fibroblast growth factor receptor, and non-receptor tyrosine kinases, such as the Src family, play critical roles in the pathogenesis of pulmonary fibrosis. For example, the expression and release of tyrosine kinases are altered in patients with IPF, while specific tyrosine kinases stimulate the proliferation of lung fibroblasts in vitro. Agents that inhibit tyrosine kinases have shown anti-fibrotic and anti-inflammatory effects in animal models of pulmonary fibrosis. Recently, the tyrosine kinase inhibitor nintedanib has shown positive results in two phase III trials in patients with IPF. Here, we summarise the evidence for involvement of specific tyrosine kinases in the pathogenesis of IPF and the development of tyrosine kinase inhibitors as treatments for IPF.

scholarly journals GED-0507 attenuates lung fibrosis by counteracting myofibroblast transdifferentiation in vivo and in vitro

PLoS ONE ◽  
2021 ◽  
Vol 16 (9) ◽  
pp. e0257281
Author(s):  
Silvia Speca ◽  
Caroline Dubuquoy ◽  
Christel Rousseaux ◽  
Philippe Chavatte ◽  
Pierre Desreumaux ◽  
...  
Keyword(s):  
Epithelial Cell ◽  
Pulmonary Fibrosis ◽  
Transforming Growth Factor ◽  
Alveolar Epithelial Cell ◽  
Lung Fibroblasts ◽  
Epithelial Cell Line ◽  
Mesenchymal Transition ◽  
Alveolar Epithelial ◽  
Ppar Γ

The development of more effective, better tolerated drug treatments for progressive pulmonary fibrosis (of which idiopathic pulmonary fibrosis is the most common and severe form) is a research priority. The peroxisome proliferator-activated receptor gamma (PPAR-γ) is a key regulator of inflammation and fibrosis and therefore represents a potential therapeutic target. However, the use of synthetic PPAR-γ agonists may be limited by their potentially severe adverse effects. In a mouse model of bleomycin (BLM)-induced pulmonary fibrosis, we have demonstrated that the non-racemic selective PPAR-γ modulator GED-0507 is able to reduce body weight loss, ameliorate clinical and histological features of pulmonary fibrosis, and increase survival rate without any safety concerns. Here, we focused on the biomolecular effects of GED-0507 on various inflammatory/fibrotic pathways. We demonstrated that preventive and therapeutic administration of GED-0507 reduced the BLM-induced mRNA expression of several markers of fibrosis, including transforming growth factor (TGF)-β, alpha-smooth muscle actin, collagen and fibronectin as well as epithelial-to-mesenchymal transition (EMT) and expression of mucin 5B. The beneficial effect of GED-0507 on pulmonary fibrosis was confirmed in vitro by its ability to control TGFβ-induced myofibroblast activation in the A549 human alveolar epithelial cell line, the MRC-5 lung fibroblast line, and primary human lung fibroblasts. Compared with the US Food and Drug Administration-approved antifibrotic drugs pirfenidone and nintedanib, GED-0507 displayed greater antifibrotic activity by controlling alveolar epithelial cell dysfunction, EMT, and extracellular matrix remodeling. In conclusion, GED-0507 demonstrated potent antifibrotic properties and might be a promising drug candidate for the treatment of pulmonary fibrosis.

FGF9 and FGF18 in idiopathic pulmonary fibrosis promote survival and migration and inhibit myofibroblast differentiation of human lung fibroblasts in vitro

2016 ◽  
Vol 310 (7) ◽  
pp. L615-L629 ◽  
Author(s):  
Audrey Joannes ◽  
Stéphanie Brayer ◽  
Valérie Besnard ◽  
Joëlle Marchal-Sommé ◽  
Madeleine Jaillet ◽  
...  
Keyword(s):  
Growth Factor ◽  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Human Lung ◽  
Lung Fibroblasts ◽  
Myofibroblast Differentiation ◽  
Human Lung Fibroblasts ◽  
And Migration ◽  
Fibroblast Foci

Idiopathic pulmonary fibrosis (IPF) is characterized by an accumulation of extracellular matrix proteins and fibroblasts in the distal airways. Key developmental lung signaling pathways are reactivated in IPF. For instance, fibroblast growth factor 9 (FGF9) and FGF18, involved in epithelial-mesenchymal interactions, are critical for lung development. We evaluated the expression of FGF9, FGF18, and FGF receptors (FGFRs) in lung tissue from controls and IPF patients and assessed their effect on proliferation, survival, migration, and differentiation of control and IPF human lung fibroblasts (HLFs). FGF9, FGF18, and all FGFRs were present in the remodeled alveolar epithelium close to the fibroblast foci in IPF lungs. FGFR3 was generally detected in fibroblast foci by immunohistochemistry. In vitro, HLFs mainly expressed mesenchyme-associated FGFR isoforms (FGFR1c and FGFR3c) and FGFR4. FGF9 did not affect fibroblast proliferation, whereas FGF18 inhibited cell growth in control fibroblasts. FGF9 and FGF18 decreased Fas-ligand-induced apoptosis in control but not in IPF fibroblasts. FGF9 prevented transforming growth factor β1-induced myofibroblast differentiation. FGF9 and FGF18 increased the migratory capacities of HLF, and FGF9 actively modulated matrix metalloproteinase activity. In addition, FGFR3 inhibition by small interfering RNA impacted p-ERK activation by FGF9 and FGF18 and their effects on differentiation and migration. These results identify FGF9 as an antiapoptotic and promigratory growth factor on HLF, maintaining fibroblasts in an undifferentiated state. The biological effects of FGF9 and FGF18 were partially driven by FGFR3. FGF18 was a less potent molecule. Both growth factors likely contribute to the fibrotic process in vivo.

scholarly journals Role of fibroblast growth factor 23 and klotho cross talk in idiopathic pulmonary fibrosis

2019 ◽  
Vol 317 (1) ◽  
pp. L141-L154 ◽  
Author(s):  
Jarrod W. Barnes ◽  
Dawn Duncan ◽  
Scott Helton ◽  
Samuel Hutcheson ◽  
Deepali Kurundkar ◽  
...  
Keyword(s):  
Growth Factor ◽  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Fibroblast Growth Factor ◽  
Transforming Growth Factor ◽  
Inflammatory Marker ◽  
Fibroblast Growth Factor 23 ◽  
Lung Fibroblasts ◽  
Fibroblast Growth ◽  
Anti Inflammatory

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrosing interstitial pneumonia that mainly affects the elderly. Several reports have demonstrated that aging is involved in the underlying pathogenic mechanisms of IPF. α-Klotho (KL) has been well characterized as an “age-suppressing” hormone and can provide protection against cellular senescence and oxidative stress. In this study, KL levels were assessed in human plasma and primary lung fibroblasts from patients with idiopathic pulmonary fibrosis (IPF-FB) and in lung tissue from mice exposed to bleomycin, which showed significant downregulation when compared with controls. Conversely, transgenic mice overexpressing KL were protected against bleomycin-induced lung fibrosis. Treatment of human lung fibroblasts with recombinant KL alone was not sufficient to inhibit transforming growth factor-β (TGF-β)-induced collagen deposition and inflammatory marker expression. Interestingly, fibroblast growth factor 23 (FGF23), a proinflammatory circulating protein for which KL is a coreceptor, was upregulated in IPF and bleomycin lungs. To our surprise, FGF23 and KL coadministration led to a significant reduction in fibrosis and inflammation in IPF-FB; FGF23 administration alone or in combination with KL stimulated KL upregulation. We conclude that in IPF downregulation of KL may contribute to fibrosis and inflammation and FGF23 may act as a compensatory antifibrotic and anti-inflammatory mediator via inhibition of TGF-β signaling. Upon restoration of KL levels, the combination of FGF23 and KL leads to resolution of inflammation and fibrosis. Altogether, these data provide novel insight into the FGF23/KL axis and its antifibrotic/anti-inflammatory properties, which opens new avenues for potential therapies in aging-related diseases like IPF.

scholarly journals Extracellular HSP90α Interacts With ER Stress to Promote Fibroblasts Activation Through PI3K/AKT Pathway in Pulmonary Fibrosis

2021 ◽  
Vol 12 ◽  
Author(s):  
Jinming Zhang ◽  
Wenshan Zhong ◽  
Yuanyuan Liu ◽  
Weimou Chen ◽  
Ye Lu ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Er Stress ◽  
Signaling Pathway ◽  
Cell Injury ◽  
Alveolar Epithelial Cell ◽  
Mapk Signaling ◽  
Lung Fibroblast ◽  
Lung Fibroblasts ◽  
Akt Inhibitor

Pulmonary fibrosis is characterized by alveolar epithelial cell injury, lung fibroblast proliferation, differentiation, and extracellular matrix (ECM) deposition. Our previous study indicated that extracellular HSP90α (eHSP90α) promotes pulmonary fibrosis by activating the MAPK signaling pathway. Thus, treatment with 1G6-D7 (a selective HSP90α monoclonal antibody) to antagonize eHSP90α could effectively ameliorate fibrosis. This study aimed to elucidate the mechanism underlying the effects of eHSP90α in pulmonary fibrosis by focusing on its link with endoplasmic reticulum (ER) stress. Our results showed that eHSP90α promoted lung fibroblast differentiation by activating ER stress. Treatment with the ER stress inhibitor tauroursodeoxycholate (TUDCA) or glucose-regulated protein 78 kDa (GRP78) depletion significantly abrogated the effect of eHSP90α on ER stress and fibroblast activation. In addition, eHSP90α induced ER stress in fibroblasts via the phosphoinositide-4,5-bisphosphate 3-kinase (PI3K)-protein kinase B (AKT) signaling pathway, which could be blocked by the PI3K/AKT inhibitor LY294002, and blockade of eHSP90α by 1G6-D7 markedly inhibited ER stress in the model, indicating preventive and therapeutic applications. Intriguingly, we observed that TUDCA effectively reduced the secretion of eHSP90α in vitro and in vivo. In conclusion, this study shows that the interaction between eHSP90α and ER stress plays a crucial role in pulmonary fibrosis, indicating a positive feedback in lung fibroblasts. Targeting eHSP90α and alleviating fibroblast ER stress may be promising therapeutic approaches for pulmonary fibrosis.

scholarly journals Latent Transforming Growth Factor-β Binding Protein-2 Regulates Lung Fibroblast-to-Myofibroblast Differentiation in Pulmonary Fibrosis via NF-κB Signaling

2021 ◽  
Vol 12 ◽  
Author(s):  
Menglin Zou ◽  
Jingfeng Zou ◽  
Xingxing Hu ◽  
Weishuai Zheng ◽  
Mingyang Zhang ◽  
...  
Keyword(s):  
Growth Factor ◽  
Pulmonary Fibrosis ◽  
Transforming Growth Factor ◽  
Nuclear Translocation ◽  
Binding Protein ◽  
Critical Role ◽  
Transforming Growth Factor Β ◽  
Lung Fibroblasts ◽  
Myofibroblast Differentiation

Despite past extensive studies, the mechanisms underlying pulmonary fibrosis (PF) still remain poorly understood. The aberrantly activated lung myofibroblasts, predominantly emerging through fibroblast-to-myofibroblast differentiation, are considered to be the key cells in PF, resulting in excessive accumulation of extracellular matrix (ECM). Latent transforming growth factor-β (TGFβ) binding protein-2 (LTBP2) has been suggested as playing a critical role in modulating the structural integrity of the ECM. However, its function in PF remains unclear. Here, we demonstrated that lungs originating from different types of patients with PF, including idiopathic PF and rheumatoid arthritis-associated interstitial lung disease, and from mice following bleomycin (BLM)-induced PF were characterized by increased LTBP2 expression in activated lung fibroblasts/myofibroblasts. Moreover, serum LTBP2 was also elevated in patients with COVID-19-related PF. LTBP2 silencing by lentiviral shRNA transfection protected against BLM-induced PF and suppressed fibroblast-to-myofibroblast differentiation in vivo and in vitro. More importantly, LTBP2 overexpression was able to induce differentiation of lung fibroblasts to myofibroblasts in vitro, even in the absence of TGFβ1. By further mechanistic analysis, we demonstrated that LTBP2 silencing prevented fibroblast-to-myofibroblast differentiation and subsequent PF by suppressing the phosphorylation and nuclear translocation of NF-κB signaling. LTBP2 overexpression-induced fibroblast-to-myofibroblast differentiation depended on the activation of NF-κB signaling in vitro. Therefore, our data indicate that intervention to silence LTBP2 may represent a promising therapy for PF.

Transforming growth factor-alpha enhances alveolar epithelial cell repair in a new in vitro model

1994 ◽  
Vol 267 (6) ◽  
pp. L728-L738 ◽  
Author(s):  
F. Kheradmand ◽  
H. G. Folkesson ◽  
L. Shum ◽  
R. Derynk ◽  
R. Pytela ◽  
...  
Keyword(s):  
Growth Factor ◽  
Epithelial Cell ◽  
Wound Repair ◽  
Wound Closure ◽  
Transforming Growth Factor ◽  
Alveolar Epithelial Cell ◽  
Alveolar Epithelial ◽  
Factor Alpha ◽  
Vitro Model

Alveolar epithelial type II cells are essential for regenerating an intact alveolar barrier after destruction of type I cells in vivo. The first objective of these experimental studies was to develop an in vitro model to quantify alveolar epithelial cell wound repair. The second objective was to investigate mechanisms of alveolar epithelial cell wound healing by studying the effects of serum and transforming growth factor-alpha (TGF-alpha) on wound closure. Primary cultures of rat alveolar type II cells were prepared by standard methods and grown to form confluent monolayers in 48 h. Then a wound was made by denuding an area (mean initial area of 2.1 +/- 0.6 mm2) of the monolayer. Re-epithelialization of the denuded area over time in the presence or absence of serum was measured using quantitative measurements from time-lapse video microscopy. The half time of wound healing was significantly enhanced in the presence of serum compared with serum-free conditions (2.4 +/- 0.2 vs. 17.4 +/- 0.8 h, P < 0.001). We then tested the hypothesis that TGF-alpha is an important growth factor for stimulating wound repair of alveolar epithelial cells. Exogenous addition of TGF-alpha in serum-free medium resulted in a significantly more rapid wound closure, and, furthermore, the addition of a monoclonal antibody to TGF-alpha in the presence of serum significantly decreased fourfold the rate of wound closure. Measurement of internuclear cell distance confirmed that both cell motility and cell spreading were responsible for closure of the wound. These data demonstrate that 1) the mechanisms of alveolar cell repair can be studied in vitro and that 2) TGF-alpha is a potent growth factor that enhances in vitro alveolar epithelial cell wound closure.

scholarly journals Amplified canonical transforming growth factor-β signalling via heat shock protein 90 in pulmonary fibrosis

2016 ◽  
Vol 49 (2) ◽  
pp. 1501941 ◽  
Author(s):  
Zaneta Sibinska ◽  
Xia Tian ◽  
Martina Korfei ◽  
Baktybek Kojonazarov ◽  
Janina Susanne Kolb ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Growth Factor ◽  
Pulmonary Fibrosis ◽  
Transforming Growth Factor ◽  
A549 Cells ◽  
Lung Fibroblasts ◽  
Hsp90 Inhibition ◽  
Extracellular Matrix Production ◽  
Matrix Production ◽  
Β Receptor

Interstitial lung fibroblast activation coupled with extracellular matrix production is a pathological signature of idiopathic pulmonary fibrosis (IPF), and is governed by transforming growth factor (TGF)-β/Smad signalling. We sought to define the role of heat shock protein (HSP)90 in profibrotic responses in IPF and to determine the therapeutic effects of HSP90 inhibition in a murine model of pulmonary fibrosis.We investigated the effects of HSP90 inhibition in vitro by applying 17-AAG (17-allylamino-17-demethoxygeldanamycin) to lung fibroblasts and A549 cells and in vivo by administering 17-DMAG (17-dimethylaminoethylamino-17-demethoxygeldanamycin) to mice with bleomycin-induced pulmonary fibrosis.HSP90 expression was increased in (myo)fibroblasts from fibrotic human and mouse lungs compared with controls. 17-AAG inhibited TGF-β1-induced extracellular matrix production and transdifferentiation of lung fibroblasts and epithelial–mesenchymal transition of A549 cells. The antifibrotic effects were associated with TGF-β receptor disruption and inhibition of Smad2/3 activation. Co-immunoprecipitation revealed that HSP90β interacted with TGF-β receptor II and stabilised TGF-β receptors. Furthermore, 17-DMAG improved lung function and decreased fibrosis and matrix metalloproteinase activity in the lungs of bleomycin-challenged mice.In conclusion, this is the first study to demonstrate that HSP90 inhibition blocks pulmonary fibroblast activation and ameliorates bleomycin-induced pulmonary fibrosis in mice.

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