Fenofibrate Reduces the Asthma-Related Fibroblast-To-Myofibroblast Transition by TGF-Β/Smad2/3 Signaling Attenuation and Connexin 43-Dependent Phenotype Destabilization

Paw, Milena; Wnuk, Dawid; Kądziołka, Dominika; Sęk, Aleksandra; Lasota, Sławomir; Czyż, Jarosław; Madeja, Zbigniew; Michalik, Marta

doi:10.3390/ijms19092571

Cited by 26 publications

(55 citation statements)

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“…Close associations of GC with the growth factor‐producing activity of organ‐specific fibroblasts have already been reported . Numerous reports indicate that this kind of reactions is common for cancer‐predisposed fibroblasts . Notably, in our experimental model the expression of Snail mRNA was upregulated in Hp ‐infected fibroblasts.…”

Section: Discussionsupporting

confidence: 64%

Helicobacter pylori‐activated gastric fibroblasts induce epithelial‐mesenchymal transition of gastric epithelial cells in vitro in a TGF‐β‐dependent manner

et al. 2019

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Background: Colonization of the gastric mucosa with Helicobacter pylori (Hp) leads to the cascade of pathologic events including local inflammation, gastric ulceration, and adenocarcinoma formation. Paracrine loops between tissue cells and Hp contribute to the formation of gastric cancerous loci; however, the specific mechanisms underlying existence of these loops remain unknown. We determined the phenotypic properties of gastric fibroblasts exposed to Hp (cagA+vacA+) infection and their influence on normal epithelial RGM-1 cells. Materials and Methods: RGM-1 cells were cultured in the media conditioned with Hpactivated gastric fibroblasts. Their morphology and phenotypical changes associated with epithelial-mesenchymal transition (EMT) were assessed by Nomarski and fluorescence microscopy and Western blot analysis. Motility pattern of RGM-1 cells was examined by time-lapse video microscopy and transwell migration assay. The content of TGF-β in Hp-activated fibroblast-conditioned media was determined by ELISA. Results: The supernatant from Hp-activated gastric fibroblasts caused the EMT-like phenotypic diversification of RGM-1 cells. The formation of fibroblastoid cell sub-populations, the disappearance of their collective migration, an increase in transmigration potential with downregulation of E-cadherin and upregulation of N-cadherin proteins, prominent stress fibers, and decreased proliferation were observed. The fibroblast (CAF)-like transition was manifested by increased secretome TGF-β level, α-SMA protein expression, and its incorporation into stress fibers, and the TGF-βR1 kinase inhibitor reduced the rise in Snail, Twist, and E-cadherin mRNA and increased E-cadherin expression induced by CAFs. Conclusion: Gastric fibroblasts which are one of the main targets for Hp infection contribute to the paracrine interactions between Hp, gastric fibroblasts, and epithelial cells. TGF-β secreted by Hp-activated gastric fibroblasts prompting their differentiation toward CAF-like phenotype promotes the EMT-related phenotypic shifts in normal gastric epithelial cell populations. This mechanism may serve as the prerequisite for GC development. K E Y W O R D S cadherin, epithelial-mesenchymal transition, fibroblasts, Helicobacter pylori, transforming growth factor beta | 3 of 14 KRZYSIEK-MACZKA Et Al. | Isolation of conditioned mediaGastric fibroblasts were co-cultured with Hp (cagA+vacA+) strain for 72 hours. Then, the Hp was washed out from fibroblasts and the medium was changed into DMEM with 10% FBS and antibiotics. The culture dishes were maintained in a humidified atmosphere of 5% CO 2 at 37°C for 4 hours, and then, the incubatory fluid was again replaced with fresh portion of the medium. Fibroblasts were then left in fresh medium for 96 hours. After 96 hours, the supernatant was collected. The same procedure was applied to the control, noninfected fibroblast culture.

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Section: Discussionsupporting

confidence: 64%

Helicobacter pylori‐activated gastric fibroblasts induce epithelial‐mesenchymal transition of gastric epithelial cells in vitro in a TGF‐β‐dependent manner

et al. 2019

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“…Therefore, substances that act downstream in the TGF-β/Smad2/3 pathway, such as inhibitors of Smad2/3 phosphorylation or nuclear translocation inhibitors (SIS3, statins, fenofibrate, etc. ), are continually being assessed 16,37,38 .…”

Section: Discussionmentioning

confidence: 99%

“…The Smad1/5/9-regulated pathway is activated mainly by bone morphogenic protein receptors (R-BMPs) 24 . Although our recent reports indicated the involvement of TGF-β/Smad2/3 signalling in FMT efficiency, whether the enhanced TGF-β 1 -induced FMT potential in human bronchial fibroblast (HBF) populations derived from asthmatic donors compared to that of non-asthmatic donors may be the result of differential regulation of Smad signalling is still unclear 16,[36][37][38] . Thus, elucidation of the cellular/molecular mechanisms by which TGF-β 1 favours myofibroblast accumulation during subepithelial fibrosis in asthma remodelling progression remains the aim of many research groups.…”

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confidence: 99%

Enhanced asthma-related fibroblast to myofibroblast transition is the result of profibrotic TGF-β/Smad2/3 pathway intensification and antifibrotic TGF-β/Smad1/5/(8)9 pathway impairment

Wnuk

Paw

Ryczek

et al. 2020

Sci Rep

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Airway remodelling with subepithelial fibrosis, which abolishes the physiological functions of the bronchial wall, is a major issue in bronchial asthma. Human bronchial fibroblasts (HBFs) derived from patients diagnosed with asthma display in vitro predestination towards TGF-β1-induced fibroblast-to-myofibroblast transition (FMT), a key event in subepithelial fibrosis. As commonly used anti-asthmatic drugs do not reverse the structural changes of the airways, and the molecular mechanism of enhanced asthma-related TGF-β1-induced FMT is poorly understood, we investigated the balance between the profibrotic TGF-β/Smad2/3 and the antifibrotic TGF-β/Smad1/5/9 signalling pathways and its role in the myofibroblast formation of HBF populations derived from asthmatic and non-asthmatic donors. Our findings showed for the first time that TGF-β-induced activation of the profibrotic Smad2/3 signalling pathway was enhanced, but the activation of the antifibrotic Smad1/5/(8)9 pathway by TGF-β1 was significantly diminished in fibroblasts from asthmatic donors compared to those from their healthy counterparts. The impairment of the antifibrotic TGF-β/Smad1/5/(8)9 pathway in HBFs derived from asthmatic donors was correlated with enhanced FMT. Furthermore, we showed that Smad1 silencing in HBFs from non-asthmatic donors increased the FMT potential in these cells. Additionally, we demonstrated that activation of antifibrotic Smad signalling via BMP7 or isoliquiritigenin [a small-molecule activator of the TGF-β/Smad1/5/(8)9 pathway] administration prevents FMT in HBFs from asthmatic donors through downregulation of profibrotic genes, e.g., α-SMA and fibronectin. Our data suggest that influencing the balance between the antifibrotic and profibrotic TGF-β/Smad signalling pathways using BMP7-mimetic compounds presents an unprecedented opportunity to inhibit subepithelial fibrosis during airway remodelling in asthma.

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“…This is evidence of the effectiveness of the combined therapeutic regimens in asthma [12]. The opportunity of using fenofibrate both in therapy and the prevention of bronchial remodeling in asthma has been shown [147]. Fibrates as therapeutic agents in asthma are currently being studied.…”

Section: Syntheticmentioning

confidence: 99%

Peroxisome Proliferator-Activated Receptors as a Therapeutic Target in Asthma

et al. 2020

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The complexity of the pathogenetic mechanisms of the development of chronic inflammation in asthma determines its heterogeneity and insufficient treatment effectiveness. Nuclear transcription factors, which include peroxisome proliferatoractivated receptors, that is, PPARs, play an important role in the regulation of initiation and resolution of the inflammatory process. The ability of PPARs to modulate not only lipid homeostasis but also the activity of the inflammatory response makes them an important pathogenetic target in asthma therapy. At present, special attention is focused on natural (polyunsaturated fatty acids (PUFAs), endocannabinoids, and eicosanoids) and synthetic (fibrates, thiazolidinediones) PPAR ligands and the study of signaling mechanisms involved in the implementation of their anti-inflammatory effects in asthma. This review summarizes current views on the structure and function of PPARs, as well as their participation in the pathogenesis of chronic inflammation in asthma. The potential use of PPAR ligands as therapeutic agents for treating asthma is under discussion.

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Fenofibrate Reduces the Asthma-Related Fibroblast-To-Myofibroblast Transition by TGF-Β/Smad2/3 Signaling Attenuation and Connexin 43-Dependent Phenotype Destabilization

Cited by 26 publications

References 57 publications

Helicobacter pylori‐activated gastric fibroblasts induce epithelial‐mesenchymal transition of gastric epithelial cells in vitro in a TGF‐β‐dependent manner

Helicobacter pylori‐activated gastric fibroblasts induce epithelial‐mesenchymal transition of gastric epithelial cells in vitro in a TGF‐β‐dependent manner

Enhanced asthma-related fibroblast to myofibroblast transition is the result of profibrotic TGF-β/Smad2/3 pathway intensification and antifibrotic TGF-β/Smad1/5/(8)9 pathway impairment

Peroxisome Proliferator-Activated Receptors as a Therapeutic Target in Asthma

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