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

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.

Download Full-text

TNF-± Induces TSLP Expression By Human Lung Fibroblasts In An AP-1 / JNK Dependent Manner

10.1164/ajrccm-conference.2010.181.1_meetingabstracts.a5718 ◽

2010 ◽

Author(s):

Arnab Datta ◽

Chris J. Scotton ◽

Alejandro Ortiz-Stern ◽

Robin J. McAnulty ◽

Rachel C. Chambers

Keyword(s):

Human Lung ◽

Lung Fibroblasts ◽

Dependent Manner ◽

Human Lung Fibroblasts

Download Full-text

Mycobacterium tuberculosis induces connective tissue growth factor expression through the TLR2‐JNK‐AP‐1 pathway in human lung fibroblasts

The FASEB Journal ◽

10.1096/fj.201900487r ◽

2019 ◽

Vol 33 (11) ◽

pp. 12554-12564 ◽

Cited By ~ 3

Author(s):

Hong‐Sheng Lee ◽

Hung‐Sheng Hua ◽

Cheng‐Hui Wang ◽

Ming‐Chih Yu ◽

Bing‐Chang Chen ◽

...

Keyword(s):

Mycobacterium Tuberculosis ◽

Growth Factor ◽

Connective Tissue ◽

Connective Tissue Growth Factor ◽

Human Lung ◽

Tissue Growth ◽

Lung Fibroblasts ◽

Human Lung Fibroblasts ◽

Factor Expression ◽

Growth Factor Expression

Download Full-text

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

Pharmacological Research ◽

10.1016/j.phrs.2008.02.001 ◽

2008 ◽

Vol 57 (4) ◽

pp. 274-282 ◽

Cited By ~ 123

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

Download Full-text

Upregulated Expression of Fibroblast Growth Factor (FGF) Receptors by Transforming Growth Factor-β1 (TGF-β1) Mediates Enhanced Mitogenic Responses to FGFs in Cultured Human Lung Fibroblasts

Biochemical and Biophysical Research Communications ◽

10.1006/bbrc.1998.9443 ◽

1998 ◽

Vol 251 (2) ◽

pp. 437-441 ◽

Cited By ~ 45

Author(s):

Victor J. Thannickal ◽

Kristen D.L. Aldweib ◽

Thomas Rajan ◽

Barry L. Fanburg

Keyword(s):

Growth Factor ◽

Fibroblast Growth Factor ◽

Transforming Growth Factor ◽

Human Lung ◽

Transforming Growth Factor Β1 ◽

Lung Fibroblasts ◽

Fibroblast Growth ◽

Human Lung Fibroblasts ◽

Tgf Β1

Download Full-text

Activated protein C suppresses tissue factor expression on U937 cells in the endothelial protein C receptor-dependent manner

FEBS Letters ◽

10.1016/s0014-5793(00)01740-3 ◽

2000 ◽

Vol 477 (3) ◽

pp. 208-212 ◽

Cited By ~ 50

Author(s):

Fang Shu ◽

Hiroshi Kobayashi ◽

Kenji Fukudome ◽

Naoko Tsuneyoshi ◽

Masao Kimoto ◽

...

Keyword(s):

Tissue Factor ◽

Protein C ◽

Activated Protein C ◽

Dependent Manner ◽

U937 Cells ◽

Tissue Factor Expression ◽

Endothelial Protein C Receptor ◽

Factor Expression

Download Full-text

Platelet-activating factor exerts mitogenic activity and stimulates expression of interleukin 6 and interleukin 8 in human lung fibroblasts via binding to its functional receptor.

Journal of Experimental Medicine ◽

10.1084/jem.184.1.191 ◽

1996 ◽

Vol 184 (1) ◽

pp. 191-201 ◽

Cited By ~ 65

Author(s):

M Roth ◽

M Nauck ◽

S Yousefi ◽

M Tamm ◽

K Blaser ◽

...

Keyword(s):

Pertussis Toxin ◽

Tyrosine Kinases ◽

Human Lung ◽

Human Fibroblasts ◽

Platelet Activating Factor ◽

Lung Fibroblasts ◽

Dependent Manner ◽

Concentration Dependent Manner ◽

Human Lung Fibroblasts ◽

Paf Receptor

Platelet-activating factor (PAF) is a potent proinflammatory phospholipid mediator of the lung. In this study, we demonstrate that PAF receptor mRNA and protein is expressed by human lung fibroblasts. Interaction of PAF with its specific receptor resulted in increases of tyrosine phosphorylation of several intracellular proteins, indicating that the PAF-receptor might be functionally active. PAF-induced transcription of protooncogenes c-fos and c-jun as well as of interleukin (IL)-6 and IL-8 genes in human fibroblasts. Transcription of the interleukins was followed by secretion of the respective proteins. Moreover, PAF enhanced proliferation of fibroblasts in a concentration-dependent manner. Using signaling inhibitors, we demonstrate that PAF-induced transcription of the c-fos, IL-6, and IL-8 genes, as well as proliferation, require activation of pertussis toxin-sensitive G proteins, tyrosine kinases, and protein kinase C (PKC). In contrast, transcription of c-jun was blocked by pertussis toxin, but not by inhibitors for tyrosine kinases or PKC. These data suggest that PAF stimulates distinct signaling pathways in human lung fibroblasts. In addition, the activation of human fibroblasts by PAF leads to enhanced proliferation and to the expression of proinflammatory cytokines, which may contribute to the pathophysiological changes in pulmonary inflammation.

Download Full-text

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

10.21203/rs.3.rs-238806/v1 ◽

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.

Download Full-text