scholarly journals Identification of TGF-β receptor-1 as a key regulator of carbon nanotube-induced fibrogenesis

2015 ◽  
Vol 309 (8) ◽  
pp. L821-L833 ◽  
Author(s):  
Anurag Mishra ◽  
Todd A. Stueckle ◽  
Robert R. Mercer ◽  
Raymond Derk ◽  
Yon Rojanasakul ◽  
...  
Keyword(s):  
Lung Fibrosis ◽  
Human Lung ◽  
Lung Fibroblasts ◽  
Screening Tests ◽  
Rapid Screening ◽  
Interstitial Tissue ◽  
Collagen Production ◽  
Human Lung Fibroblasts ◽  
Β Receptor ◽  
Tgf Β1

Carbon nanotubes (CNTs) induce rapid interstitial lung fibrosis, but the underlying mechanisms are unclear. Previous studies indicated that the ability of CNTs to penetrate lung epithelium, enter interstitial tissue, and stimulate fibroblasts to produce collagen matrix is important to lung fibrosis. In this study, we investigated the activation of transforming growth factor-β receptor-1 [TGF-β R1; i.e., activin receptor-like kinase 5 (ALK5) receptor] and TGF-β/Smad signaling pathway in CNT-induced collagen production in human lung fibroblasts. Human lung fibroblasts and epithelial cells were exposed to low, physiologically relevant concentrations (0.02–0.6 μg/cm2) of single-walled CNTs (SWCNT) and multiwalled CNTs (MWCNT) in culture and analyzed for collagen, TGF-β1, TGF-β R1, and SMAD proteins by Western blotting and immunofluorescence. Chemical inhibition of ALK5 and short-hairpin (sh) RNA targeting of TGF-β R1 and Smad2 were used to probe the fibrogenic mechanism of CNTs. Both SWCNT and MWCNT induced an overexpression of TGF-β1, TGF-β R1 and Smad2/3 proteins in lung fibroblasts compared with vehicle or ultrafine carbon black-exposed controls. SWCNT- and MWCNT-induced collagen production was blocked by ALK5 inhibitor or shRNA knockdown of TGF-β R1 and Smad2. Our results indicate the critical role of TGF-β R1/Smad2/3 signaling in CNT-induced fibrogenesis by upregulating collagen production in lung fibroblasts. This novel finding may aid in the design of mechanism-based risk assessment and development of rapid screening tests for nanomaterial fibrogenicity.

scholarly journals Tropomyosin 2.1 collaborates with fibronectin to promote TGF-β1-induced contraction of human lung fibroblasts

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Peta Bradbury ◽  
Cassandra P. Nader ◽  
Aylin Cidem ◽  
Sandra Rutting ◽  
Dianne Sylvester ◽  
...  
Keyword(s):  
Lung Fibrosis ◽  
Human Lung ◽  
Collagen Gel ◽  
Protein Profiling ◽  
Lung Fibroblasts ◽  
Human Lung Fibroblasts ◽  
Collagen Gel Contraction ◽  
The Matrix ◽  
Cytokine Stimulation ◽  
Tgf Β1

AbstractMany lung diseases are characterized by fibrosis, leading to impaired tissue patency and reduced lung function. Development of fibrotic tissue depends on two-way interaction between the cells and the extra-cellular matrix (ECM). Concentration-dependent increased stiffening of the ECM is sensed by the cells, which in turn increases intracellular contraction and pulling on the matrix causing matrix reorganization and further stiffening. It is generally accepted that the inflammatory cytokine growth factor β1 (TGF-β1) is a major driver of lung fibrosis through the stimulation of ECM production. However, TGF-β1 also regulates the expression of members of the tropomyosin (Tm) family of actin associating proteins that mediate ECM reorganization through intracellular-generated forces. Thus, TGF-β1 may mediate the bi-directional signaling between cells and the ECM that promotes tissue fibrosis. Using combinations of cytokine stimulation, mRNA, protein profiling and cellular contractility assays with human lung fibroblasts, we show that concomitant induction of key Tm isoforms and ECM by TGF-β1, significantly accelerates fibrotic phenotypes. Knocking down Tpm2.1 reduces fibroblast-mediated collagen gel contraction. Collectively, the data suggest combined ECM secretion and actin cytoskeleton contractility primes the tissue for enhanced fibrosis. Our study suggests that Tms are at the nexus of inflammation and tissue stiffening. Small molecules targeting specific Tm isoforms have recently been designed; thus targeting Tpm2.1 may represent a novel therapeutic target in lung fibrosis.

scholarly journals Inhibition of Raf1 ameliorates bleomycin-induced pulmonary fibrosis through attenuation of TGF-β1 signaling

2018 ◽  
Vol 315 (2) ◽  
pp. L241-L247 ◽  
Author(s):  
Shuang Li ◽  
Jia Liu ◽  
Jiangning Tan ◽  
Lian Li ◽  
Mary J. Kaltreider ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Lung Fibrosis ◽  
Molecular Mechanisms ◽  
Human Lung ◽  
Smooth Muscle Actin ◽  
Lung Fibroblasts ◽  
Human Lung Fibroblasts ◽  
And Migration ◽  
Fibrotic Lung Disease ◽  
Tgf Β1

Idiopathic pulmonary fibrosis (IPF) is a fatal fibrotic lung disease associated with aberrant activation and differentiation of fibroblasts, leading to abnormal extracellular matrix production. Currently, it is still an untreatable disease (except for lung transplantation). Here, we demonstrate that the Raf1 inhibitor GW5074 ameliorates lung fibrosis in bleomycin-induced pulmonary fibrosis. Posttreatment with GW5074 reduced fibronectin (FN) expression, collagen deposition, and inflammatory cell infiltration in bleomycin-challenged mice, suggesting an antifibrotic property of GW5074. To determine the molecular mechanisms by which inhibition of Raf1 ameliorates lung fibrosis, we investigated the role of Raf1 in TGF-β1 signaling in human lung fibroblasts. GW5074 or downregulation of Raf1 by siRNAs significantly attenuated TGF-β1-induced smooth muscle actin, FN, and collagen I expression, whereas overexpression of Raf1 promoted the effects of TGF-β1 in lung fibroblasts. Furthermore, we found that Raf1-promoted TGF-β1 signaling was through the Raf1/ERK/Smad pathway and contributed to the cell proliferation and migration in human lung fibroblasts. This study provides preclinical and mechanistic evidence for development of Raf1 inhibitors as potential antifibrotic drugs for the treatment of IPF.

Phenylbutyrate decreases type I collagen production in human lung fibroblasts

2004 ◽  
Vol 91 (4) ◽  
pp. 740-748 ◽  
Author(s):  
David C. Rishikof ◽  
Dennis A. Ricupero ◽  
Hanqiao Liu ◽  
Ronald H. Goldstein
Keyword(s):  
Type I Collagen ◽  
Human Lung ◽  
Lung Fibroblasts ◽  
Type I ◽  
Collagen Production ◽  
Human Lung Fibroblasts

TGF-β1 Induces Tissue Factor Expression in Human Lung Fibroblasts in a PI3K/JNK/Akt-Dependent and AP-1–Dependent Manner

2012 ◽  
Vol 47 (5) ◽  
pp. 614-627 ◽  
Author(s):  
Malgorzata Wygrecka ◽  
Dariusz Zakrzewicz ◽  
Brigitte Taborski ◽  
Miroslava Didiasova ◽  
Grazyna Kwapiszewska ◽  
...  
Keyword(s):  
Tissue Factor ◽  
Human Lung ◽  
Lung Fibroblasts ◽  
Dependent Manner ◽  
Tissue Factor Expression ◽  
Human Lung Fibroblasts ◽  
Factor Expression ◽  
Tgf Β1

TGF-β1 targets the GSK-3β/β-catenin pathway via ERK activation in the transition of human lung fibroblasts into myofibroblasts

2008 ◽  
Vol 57 (4) ◽  
pp. 274-282 ◽  
Author(s):  
F CARACI ◽  
E GILI ◽  
M CALAFIORE ◽  
M FAILLA ◽  
C LAROSA ◽  
...  
Keyword(s):  
Human Lung ◽  
Lung Fibroblasts ◽  
Erk Activation ◽  
Human Lung Fibroblasts ◽  
Gsk 3Β ◽  
Tgf Β1

scholarly journals 5-Aminosalicylic acid Attenuates Paraquat-induced Lung Fibroblasts Activation and Pulmonary Fibrosis of Rats

2021 ◽  
Author(s):  
Hui Chen ◽  
Jinfeng Cui ◽  
Juan Wang ◽  
Yuan Wang ◽  
Fei Tong ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Signaling Pathway ◽  
Human Lung ◽  
Lung Fibroblasts ◽  
Control Group ◽  
Peroxisome Proliferator ◽  
Aminosalicylic Acid ◽  
Human Lung Fibroblasts ◽  
Group 5 ◽  
Tgf Β1

Abstract Pulmonary fibrosis is one of the most common complications of paraquat (PQ) poisoning, which becomes the focus of treatment. More and more studies have found that 5-Aminosalicylic acid (5-ASA) may be a prospective therapy against fibrotic diseases. In the present study, we observed whether 5-ASA could attenuate the pulmonary fibrosis in PQ-treated rats and human lung fibroblasts (WI38VA13) cells, and subsequently explored the possible underlying mechanisms. Wistar rats were divided into control group, 5-ASA group, PQ group and PQ + 5-ASA group. Rats were sacrificed on 3, 7, 14, and 28 days after PQ treatment. We observed pulmonary histopathological changes and fibrosis formation among different groups through hematoxylin and eosin (H&E) and Masson staining and TGF-β1, p-Smad3 and the peroxisome proliferator activated receptor γ (PPARγ) pulmonary content via immunohistochemical staining and Western blot. In addition, human lung fibroblasts WI38VA13 were also divided into control group, PQ group, 5-ASA group and PQ + 5-ASA group. And the role of TGF-β1 signaling pathway regulated factors (TGF-β1, p-Smad3 and PPARγ) were explored. Treatment with 5-ASA significantly inhibited the PQ-induced activation of TGF-β1 signaling pathway in human lung fibroblasts WI38VA13 cells. In conclusion, the results of this study suggested that 5-ASA has potential value in the treatment of PQ-induced pulmonary fibrosis via suppressing the activation of TGF-β1 signaling pathway.

Smad3 mediates TGF-β1-induced collagen gel contraction by human lung fibroblasts

2006 ◽  
Vol 339 (1) ◽  
pp. 290-295 ◽  
Author(s):  
Tetsu Kobayashi ◽  
Xiangde Liu ◽  
Fu-Qiang Wen ◽  
Tadashi Kohyama ◽  
Lei Shen ◽  
...  
Keyword(s):  
Human Lung ◽  
Collagen Gel ◽  
Lung Fibroblasts ◽  
Human Lung Fibroblasts ◽  
Collagen Gel Contraction ◽  
Tgf Β1
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