Modifiers of TGF-β1 effector function as novel therapeutic targets of pulmonary fibrosis

Lee, Chang-Min; Park, Jin Wook; Cho, Won‐Kyung; Zhou, Yang; Han, Boram; Yoon, Pyoung Oh; Chae, Jeiwook; Elias, Jack A.

doi:10.3904/kjim.2014.29.3.281

Cited by 66 publications

(50 citation statements)

References 76 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…TGF-␤ 1 is a primary driver of tissue fibrogenesis in the lung (2,33), heart (49,59), kidney (4,54), and liver (8). TGF-␤ 1 also inhibits starvation-induced autophagy in HAFs and cells of the annulus fibrosus of intervertebral disks (42,43).…”

Section: Discussionmentioning

confidence: 99%

Autophagy and the unfolded protein response promote profibrotic effects of TGF-β₁ in human lung fibroblasts

Ghavami

Yeganeh

Zeki

et al. 2018

American Journal of Physiology-Lung Cellular and Molecular Phys

114

102

View full text Add to dashboard Cite

Idiopathic pulmonary fibrosis (IPF) is a lethal fibrotic lung disease in adults with limited treatment options. Autophagy and the unfolded protein response (UPR), fundamental processes induced by cell stress, are dysregulated in lung fibroblasts and epithelial cells from humans with IPF. Human primary cultured lung parenchymal and airway fibroblasts from non-IPF and IPF donors were stimulated with transforming growth factor-β (TGF-β) with or without inhibitors of autophagy or UPR (IRE1 inhibitor). Using immunoblotting, we monitored temporal changes in abundance of protein markers of autophagy (LC3βII and Atg5-12), UPR (BIP, IRE1α, and cleaved XBP1), and fibrosis (collagen 1α2 and fibronectin). Using fluorescent immunohistochemistry, we profiled autophagy (LC3βII) and UPR (BIP and XBP1) markers in human non-IPF and IPF lung tissue. TGF-β-induced collagen 1α2 and fibronectin protein production was significantly higher in IPF lung fibroblasts compared with lung and airway fibroblasts from non-IPF donors. TGF-β induced the accumulation of LC3βII in parallel with collagen 1α2 and fibronectin, but autophagy marker content was significantly lower in lung fibroblasts from IPF subjects. TGF-β-induced collagen and fibronectin biosynthesis was significantly reduced by inhibiting autophagy flux in fibroblasts from the lungs of non-IPF and IPF donors. Conversely, only in lung fibroblasts from IPF donors did TGF-β induce UPR markers. Treatment with an IRE1 inhibitor decreased TGF-β1-induced collagen 1α2 and fibronectin biosynthesis in IPF lung fibroblasts but not those from non-IPF donors. The IRE1 arm of the UPR response is uniquely induced by TGF-β in lung fibroblasts from human IPF donors and is required for excessive biosynthesis of collagen and fibronectin in these cells.

show abstract

Section: Discussionmentioning

confidence: 99%

Autophagy and the unfolded protein response promote profibrotic effects of TGF-β₁ in human lung fibroblasts

Ghavami

Yeganeh

Zeki

et al. 2018

American Journal of Physiology-Lung Cellular and Molecular Phys

114

102

View full text Add to dashboard Cite

show abstract

“…A previous study found markedly increased levels of TGF-β1 and IL-6 in both bronchoalveolar lavage fluid (BALF) and in the serum of mice following exposure to BLM (23). TGF-β1 has been identified as a key mediator of lung fibrosis, and it induces the proliferation and migration of lung fibroblasts, as well as the remodeling of the extracellular matrix (ECM) (24,25). In this context, TGF-β1 and IL-6 are considered to be useful parameters for observing the progression of PF.…”

Section: Introductionmentioning

confidence: 99%

Bach1 siRNA attenuates bleomycin-induced pulmonary fibrosis by modulating oxidative stress in mice

Liu

Zheng

2016

International Journal of Molecular Medicine

View full text Add to dashboard Cite

Oxidative stress plays an essential role in inflammation and fibrosis. Bach1 is an important transcriptional repressor that acts by modulating oxidative stress and represents a potential target in the treatment of pulmonary fibrosis (PF). In this study, we knocked down Bach1 using adenovirus-mediated small interfering RNA (siRNA) to determine whether the use of Bach1 siRNA is an effective therapeutic strategy in mice with bleomycin (BLM)-induced PF. Mouse lung fibroblasts (MLFs) were incubated with transforming growth factor (TGF)-β1 (5 ng/ml) and subsequently infected with recombined adenovirus-like Bach1 siRNA1 and Bach1 siRNA2, while an empty adenovirus vector was used as the negative control. The selected Bach1 siRNA with higher interference efficiency was used for the animal experiments. A mouse model of BLM-induced PF was established, and Bach1 siRNA (1×109 PFU) was administered to the mice via the tail vein. The results revealed that the Bach1 mRNA and protein levels were significantly downregulated by Bach1 siRNA. Furthermore, the MLFs infected with Bach1 siRNA exhibited increased mRNA and protein expression levels of heme oxygenase-1 and glutathione peroxidase 1, but decreased levels of TGF-β1 and interleukin-6 in the cell supernatants compared with the cells exposed to TGF-β1 alone. Bach1 knockdown by siRNA also enhanced the expression of antioxidant factors, but suppressed that of fibrosis-related cytokines in mice compared with the BLM group. Finally, the inflammatory infiltration of alveolar and interstitial cells and the destruction of lung structure were significantly attenuated in the mide administered Bach1 siRNA compared with those in the BLM group. On the whole, our findings demonstrate that Bach1 siRNA exerts protective effects against BLM-induced PF in mice. Our data may provide the basis for the development of novel targeted therapeutic strategies for PF.

show abstract

“…Both fibroblasts and myofibroblasts predominantly secrete Types I and III collagen, the major components of the ECM (Wolters et al 2014). TGF-β1-Smad signaling pathway is considered to be the most important regulation pathway for proliferation, differentiation and collagen synthesis of pulmonary fibroblasts (Lee et al 2014).…”

mentioning

confidence: 99%

TGF-β1-Induced Pulmonary Fibroblasts Proliferation and Differentiation Are Inhibited by Antisense Oligodeoxynucleotide of Basic Fibroblast Growth Factor

Tan

Wang

et al. 2015

CYTOLOGIA

View full text Add to dashboard Cite

SummaryThe objective of this study is to investigate the role of antisense oligodeoxynucleotide (ASODN) of basic fibroblast growth factor (bFGF) in the proliferation, differentiation and collagen synthesis of pulmonary fibroblasts (PFs) and the possible mechanism. PFs were isolated from male Wistar Rat and transfected with antisense oligodeoxynucleotide or sense oligodeoxynucleotide (SODN) of bFGF for four experimental conditions: (1) control group: PFs without TGF-β1; (2) TGF-β1 group: PFs with TGF-β1; (3) TGF-β1+ASODN group: ASODN transfected PFs with TGF-β1; and (4) TGF-β1+SODN group: SODN transfected PFs with TGF-β1. Proliferation of PFs was monitored by growth curves and MTT assays, expression of α-smooth muscle actin (α-SMA) was evaluated by immunocytochemistry, concentrations of bFGF, CTGF, and Type I collagen in culture supernatants were determined by ELISA, and mRNA expression of Smad3, Smad7 and Type I collagen in pulmonary fibroblasts was detected by RT-PCR. We found that SODN of bFGF increased cell proliferation of PFs, enhanced the expression level of bFGF, CTGF, α-SMA, type I collagen and Smad3. However, ASODN of bFGF had the opposite effects. However, Smad7 was increased in TGF-β1+SODN group but decreased in TGF-β1+ASODN group. The proliferation, differentiation, and collagen synthesis of PFs could be promoted by bFGF and inhibited by ASODN of bFGF which may be related to the regulation of TGF-β1-Smad signaling pathway.

show abstract

Modifiers of TGF-β1 effector function as novel therapeutic targets of pulmonary fibrosis

Cited by 66 publications

References 76 publications

Autophagy and the unfolded protein response promote profibrotic effects of TGF-β₁ in human lung fibroblasts

Autophagy and the unfolded protein response promote profibrotic effects of TGF-β₁ in human lung fibroblasts

Bach1 siRNA attenuates bleomycin-induced pulmonary fibrosis by modulating oxidative stress in mice

TGF-β1-Induced Pulmonary Fibroblasts Proliferation and Differentiation Are Inhibited by Antisense Oligodeoxynucleotide of Basic Fibroblast Growth Factor

Contact Info

Product

Resources

About

Modifiers of TGF-β1 effector function as novel therapeutic targets of pulmonary fibrosis

Cited by 66 publications

References 76 publications

Autophagy and the unfolded protein response promote profibrotic effects of TGF-β1 in human lung fibroblasts

Autophagy and the unfolded protein response promote profibrotic effects of TGF-β1 in human lung fibroblasts

Bach1 siRNA attenuates bleomycin-induced pulmonary fibrosis by modulating oxidative stress in mice

TGF-β1-Induced Pulmonary Fibroblasts Proliferation and Differentiation Are Inhibited by Antisense Oligodeoxynucleotide of Basic Fibroblast Growth Factor

Contact Info

Product

Resources

About

Autophagy and the unfolded protein response promote profibrotic effects of TGF-β₁ in human lung fibroblasts

Autophagy and the unfolded protein response promote profibrotic effects of TGF-β₁ in human lung fibroblasts