scholarly journals Regulation of Cellular Senescence Is Independent from Profibrotic Fibroblast-Deposited ECM

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1628
Author(s):  
Kaj E. C. Blokland ◽  
Habibie Habibie ◽  
Theo Borghuis ◽  
Greta J. Teitsma ◽  
Michael Schuliga ◽  
...  
Keyword(s):  
Growth Factor ◽  
Cellular Senescence ◽  
Transforming Growth Factor ◽  
Cell Function ◽  
Smooth Muscle Actin ◽  
Transforming Growth Factor Β1 ◽  
Tissue Growth ◽  
Alveolar Epithelial Cells ◽  
Lung Fibroblasts ◽  
Alpha Smooth Muscle Actin

Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease with poor survival. Age is a major risk factor, and both alveolar epithelial cells and lung fibroblasts in this disease exhibit features of cellular senescence, a hallmark of ageing. Accumulation of fibrotic extracellular matrix (ECM) is a core feature of IPF and is likely to affect cell function. We hypothesize that aberrant ECM deposition augments fibroblast senescence, creating a perpetuating cycle favouring disease progression. In this study, primary lung fibroblasts were cultured on control and IPF-derived ECM from fibroblasts pretreated with or without profibrotic and prosenescent stimuli, and markers of senescence, fibrosis-associated gene expression and secretion of cytokines were measured. Untreated ECM derived from control or IPF fibroblasts had no effect on the main marker of senescence p16Ink4a and p21Waf1/Cip1. However, the expression of alpha smooth muscle actin (ACTA2) and proteoglycan decorin (DCN) increased in response to IPF-derived ECM. Production of the proinflammatory cytokines C-X-C Motif Chemokine Ligand 8 (CXCL8) by lung fibroblasts was upregulated in response to senescent and profibrotic-derived ECM. Finally, the profibrotic cytokines transforming growth factor β1 (TGF-β1) and connective tissue growth factor (CTGF) were upregulated in response to both senescent- and profibrotic-derived ECM. In summary, ECM deposited by IPF fibroblasts does not induce cellular senescence, while there is upregulation of proinflammatory and profibrotic cytokines and differentiation into a myofibroblast phenotype in response to senescent- and profibrotic-derived ECM, which may contribute to progression of fibrosis in IPF.

scholarly journals Platelet-Derived Growth Factor and Transforming Growth Factor β1 Regulate ARDS-Associated Lung Fibrosis Through Distinct Signaling Pathways

2015 ◽  
Vol 36 (3) ◽  
pp. 937-946 ◽  
Author(s):  
Xingqi Deng ◽  
Kun Jin ◽  
Yanyan Li ◽  
Wei Gu ◽  
Mei Liu ◽  
...  
Keyword(s):  
Growth Factor ◽  
P38 Mapk ◽  
Lung Fibrosis ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Specific Inhibitor ◽  
Transforming Growth Factor Β1 ◽  
Collagen I ◽  
Platelet Derived Growth Factor ◽  
Lung Fibroblasts

Background/Aims: Severe acute lung injury (ALI) often develops into acute respiratory distress syndrome (ARDS). Previous studies have shown that platelet-derived growth factor (PDGF) and transforming growth factor β1 (TGFβ1) participate in the pathogenesis of ARDS by stimulation of fibroblast proliferation, leading to the development of pulmonary fibrosis. However, the exact pathways downstream of PDGF and TGFβ receptor signaling have not been completely elucidated. Method: We treated human lung fibroblasts (HLF) with PDGF, or TGFβ1, or combined, and examined the activation of p38 MAPK, p42/p44 MAPK and SMAD3. We used a specific inhibitor PD98059 to antagonize phosphorylation of p42/p44 MAPK, or used a specific inhibitor SN203580 to antagonize phosphorylation of p38 MAPK, or used a specific inhibitor SIS3 to antagonize phosphorylation of SMAD3. We then examined the effects of these inhibitors on the activation of collagen I and α-smooth muscle actin (α-SMA) induced by PDGF or TGFβ1 stimulation. Results: PDGF activated p38 MAPK and p42/p44 MAPK, but not SMAD3 in HLF cells. TGFβ1 activated p38 MAPK and SMAD3, but not p42/p44 MAPK in HLF cells. Activation of p38 MAPK by either PDGF or TGFβ1 induced α-SMA but not collagen I in HLF cells, while activation of p42/p44 MAPK by PDGF induced collagen I but not α-SMA in HLF cells. Activation of SMAD3 by TGFβ1 did not affect either collagen I or α-SMA in HLF cells. Conclusion: PDGF and TGFβ1 regulate ARDS-associated lung fibrosis through distinct signaling pathway-mediated activation of fibrosis-related proteins. Treatments with both PDGF and TGFβ1 antagonists may result in a better anti-fibrotic outcome for ALI-induced lung fibrosis.

scholarly journals Glucosamine impedes transforming growth factor β1-mediated corneal fibroblast differentiation by targeting Krüppel-like factor 4

2019 ◽  
Vol 26 (1) ◽  
Author(s):  
Ying-Jen Chen ◽  
Shih-Ming Huang ◽  
Ming-Cheng Tai ◽  
Jiann-Torng Chen ◽  
Chang-Min Liang
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Disease Model ◽  
Immunoblot Analysis ◽  
Transforming Growth Factor Β1 ◽  
Myofibroblast Differentiation ◽  
Alpha Smooth Muscle Actin ◽  
Corneal Fibroblasts ◽  
Tgf Β1

Abstract Background Transforming growth factor (TGF) family members play important roles in the regulation of corneal integrity, and the pathogenesis of corneal fibrosis. Currently, there are no effective agents targeting TGF-β signaling to diminish corneal fibrosis. Glucosamine (GlcN), which is widely used in the treatment of osteoarthritis, abrogates the morphologic effects of TGF-β2 on retinal pigmented epithelial cells in a mouse disease model. Here, we sought to determine whether GlcN would exert beneficial effects against TGF-β1-induced corneal fibrosis. Methods In human corneal fibroblasts (HCFs) treated with GlcN, the expression of Krüppel-like factor 4 (KLF4) and its downstream signaling effects were determined in the presence and absence of TGF-β1 using immunoblot analysis. We further explored GlcN inhibition of fibroblast-to-myofibroblast differentiation via KLF4 siRNA. The effect of cycloheximide on KLF4 protein levels with or without GlcN administration was assessed to determine whether GlcN affects the stability of the KLF4 protein. Results In HCFs, GlcN induced the expression of KLF4, which regulated the maturation and maintenance of the ocular surface. GlcN partially suppressed the TGF-β1-induced expression of alpha-smooth muscle actin (α-SMA) and reduced the collagen contraction capacity in HCFs, suggesting a decrease in fibroblast-to-myofibroblast differentiation. This effect appeared to be mediated through suppression of Smad2 phosphorylation and ERK-dependent signaling. The levels of KLF4 mRNA were increased by GlcN and decreased by TGF-β1 and the TGF-β1-induced α-SMA mRNA expression was upregulated when the KLF4 gene was silenced. GlcN also appeared to stabilize the KLF4 protein, reducing its turnover in corneal fibroblasts. Conclusion These findings shed light on a novel mechanism by which GlcN suppresses TGF-β1-induced fibroblast-to-myofibroblast differentiation through the upregulation of KLF4 expression. Current strategies for treating corneal fibrosis were not effective. Elevating KLF4 levels through the use of GlcN might provide an effective alternative to alleviate the development and progression of corneal fibrosis.

α-Lipoic acid modulates liver fibrosis: A cross talk between TGF-β1, autophagy, and apoptosis

2019 ◽  
Vol 39 (4) ◽  
pp. 440-450 ◽  
Author(s):  
WH El-Maadawy ◽  
OA Hammam ◽  
SH Seif el-Din ◽  
NM El-Lakkany
Keyword(s):  
Growth Factor ◽  
Liver Fibrosis ◽  
Hepatic Fibrosis ◽  
Lipoic Acid ◽  
Messenger Rna ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Transforming Growth Factor Β1 ◽  
Alpha Smooth Muscle Actin ◽  
Tgf Β1

Autophagy and apoptosis are important players in the progression of hepatic fibrosis via activation of hepatic stellate cells (HSCs). Despite the recently depicted antifibrotic effects of alpha-lipoic acid (ALA), however, its modulatory effects on HSCs autophagy remain unverified. Our study aimed to elucidate the underlying antifibrotic mechanisms through which ALA mediates HSC autophagy and apoptosis. Liver fibrosis was induced via thioacetamide (TAA) intoxication in rats; TAA-intoxicated rats were treated with either silymarin or ALA. Effect of ALA on biochemical parameters and immunohistopathological examinations was measured and compared to silymarin. ALA restored normal hepatic architecture (S1 vs. S4), liver functions, hepatic glutathione, and transforming growth factor-β1 levels. ALA ameliorated hepatic levels of malondialdehyde, platelet-derived growth factor, tissue inhibitor metalloproteinases-1, hydroxyproline, and expression of alpha-smooth muscle actin. Moreover, ALA significantly reduced messenger RNA expression of LC3-II genes and triggered caspase-3 expression. Interestingly, ALA exhibited superior activities over silymarin regarding suppression of proliferation, activation and autophagy of HSCs, collagen deposition, and induction of HSCs apoptosis. In conclusion, treatment of TAA-intoxicated rats with ALA inhibited autophagy and induced apoptotic clearance of activated HSCs. Accordingly, this study provides mechanistic insights into the possible applicability of ALA in the treatment of hepatic fibrosis.

Hexokinase 2 couples glycolysis with the profibrotic actions of TGF-β

2019 ◽  
Vol 12 (612) ◽  
pp. eaax4067 ◽  
Author(s):  
Xueqian Yin ◽  
Malay Choudhury ◽  
Jeong-Han Kang ◽  
Kyle J. Schaefbauer ◽  
Mi-Yeon Jung ◽  
...  
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Tissue Growth ◽  
Blood Oxygenation ◽  
Lung Fibroblasts ◽  
Hexokinase 2 ◽  
Metabolic Dysregulation ◽  
Factor C

Metabolic dysregulation in fibroblasts is implicated in the profibrotic actions of transforming growth factor–β (TGF-β). Here, we present evidence that hexokinase 2 (HK2) is important for mediating the fibroproliferative activity of TGF-β both in vitro and in vivo. Both Smad-dependent and Smad-independent TGF-β signaling induced HK2 accumulation in murine and human lung fibroblasts through induction of the transcription factor c-Myc. Knockdown of HK2 or pharmacological inhibition of HK2 activity with Lonidamine decreased TGF-β–stimulated fibrogenic processes, including profibrotic gene expression, cell migration, colony formation, and activation of the transcription factors YAP and TAZ, with no apparent effect on cellular viability. Fibroblasts from patients with idiopathic pulmonary fibrosis (IPF) exhibited an increased abundance of HK2. In a mouse model of bleomycin-induced lung fibrosis, Lonidamine reduced the expression of genes encoding profibrotic markers (collagenΙα1, EDA-fibronectin, α smooth muscle actin, and connective tissue growth factor) and stabilized or improved lung function as assessed by measurement of peripheral blood oxygenation. These findings provide evidence of how metabolic dysregulation through HK2 can be integrated within the context of profibrotic TGF-β signaling.

scholarly journals JNK and p38 Inhibitors Prevent Transforming Growth Factor-β1-Induced Myofibroblasts Transdifferentiation in Graves' Orbital Fibroblasts

2021 ◽  
Author(s):  
Tzu-Yu Hou ◽  
Shi-Bei Wu ◽  
Hui-Chuan Kau ◽  
Chieh-Chih Tsai
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Transforming Growth Factor Β1 ◽  
Tissue Growth ◽  
Mitogen Activated Protein Kinase ◽  
Tissue Inhibitors Of Metalloproteinases ◽  
Mapk Pathways ◽  
Orbital Fibroblasts ◽  
Tgf Β1

Abstract Transforming growth factor-β1 (TGF-β1)-induced myofibroblasts transdifferentiation from orbital fibroblasts is known to dominate tissue remodeling and fibrosis in Graves’ ophthalmopathy (GO). However, the signaling pathway through which TGF-β1 activates Graves’ orbital fibroblasts is unclear. This study investigated the role of mitogen-activated protein kinase (MAPK) pathways in TGF-β1-induced myofibroblasts transdifferentiation of Graves’ orbital fibroblasts. MAPK pathways were assessed by measuring the phosphorylation levels of p38, c-Jun N-terminal kinase (JNK) and extracellular-signal-regulated kinase (ERK) using Western blot analysis. The expression levels of connective tissue growth factor (CTGF), α-smooth muscle actin (α-SMA), fibronectin, and tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-3) representing fibrogenesis processes were analysed. Specific pharmacologic kinase inhibitors were used to confirm the involvement of MAPK pathways. After treating Graves’ orbital fibroblasts with TGF-β1, the phosphorylation levels of p38 and JNK but not ERK were increased. Meanwhile, CTGF, α-SMA and fibronectin were overexpressed. After pre-incubation with p38, JNK and ERK inhibitors respectively, the TGF-β1-induced expression of CTGF, α-SMA, fibronectin, TIMP-1 and TIMP3 was abolished by p38 and JNK inhibitors but not ERK inhibitors. This study confirmed TGF-β1-induced myofibroblasts transdifferentiation in Graves' orbital fibroblasts via p38 and JNK signaling. Thus, MAPK pathways may be potential targets for the management of GO.

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