scholarly journals Toll-like receptor 4 activation attenuates profibrotic response in control lung fibroblasts but not in fibroblasts from patients with IPF

2017 ◽  
Vol 312 (1) ◽  
pp. L42-L55 ◽  
Author(s):  
Simone Ebener ◽  
Sandra Barnowski ◽  
Carlos Wotzkow ◽  
Thomas M. Marti ◽  
Elena Lopez-Rodriguez ◽  
...  
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Tissue Growth ◽  
Lung Fibroblasts ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Vitro Model ◽  
Fibroblast Foci

Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease with a median survival of 3 yr. IPF deteriorates upon viral or bacterial lung infection although pulmonary infection (pneumonia) in healthy lungs rarely induces fibrosis. Bacterial lipopolysaccharide (LPS) activates Toll-like receptor 4 (TLR4), initiating proinflammatory pathways. As TLR4 has already been linked to hepatic fibrosis and scleroderma, we now investigated the role of TLR4 in IPF fibroblasts. Lung tissue sections from patients with IPF were analyzed for TLR4 expression. Isolated normal human lung fibroblasts (NL-FB) and IPF fibroblasts (IPF-FB) were exposed to LPS and transforming growth factor-β (TGF-β) before expression analysis of receptors, profibrotic mediators, and cytokines. TLR4 is expressed in fibroblast foci of IPF lungs as well as in primary NL-FB and IPF-FB. As a model for a gram-negative pneumonia in the nonfibrotic lung, NL-FB and IPF-FB were coexposed to LPS and TGF-β. Whereas NL-FB produced significantly less connective tissue growth factor upon costimulation compared with TGF-β stimulation alone, IPF-FB showed significantly increased profibrotic markers compared with control fibroblasts after costimulation. Although levels of antifibrotic prostaglandin E2 were elevated after costimulation, they were not responsible for this effect. However, significant downregulation of TGF-β receptor type 1 in control fibroblasts seems to contribute to the reduced profibrotic response in our in vitro model. Normal and IPF fibroblasts thus differ in their profibrotic response upon LPS-induced TLR4 stimulation.

scholarly journals Age-dependent shifts in renal response to injury relate to altered BMP6/CTGF expression and signaling

2016 ◽  
Vol 311 (5) ◽  
pp. F926-F934 ◽  
Author(s):  
Lucas L. Falke ◽  
Hiroshi Kinashi ◽  
Amelie Dendooven ◽  
Roel Broekhuizen ◽  
Reinout Stoop ◽  
...  
Keyword(s):  
Growth Factor ◽  
Tissue Damage ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Renal Tissue ◽  
Tissue Growth ◽  
Bmp Signaling ◽  
Obstructive Nephropathy ◽  
Young Mice

Age is associated with an increased prevalence of chronic kidney disease (CKD), which, through progressive tissue damage and fibrosis, ultimately leads to loss of kidney function. Although much effort is put into studying CKD development experimentally, age has rarely been taken into account. Therefore, we investigated the effect of age on the development of renal tissue damage and fibrosis in a mouse model of obstructive nephropathy (i.e., unilateral ureter obstruction; UUO). We observed that after 14 days, obstructed kidneys of old mice had more tubulointerstitial atrophic damage but less fibrosis than those of young mice. This was associated with reduced connective tissue growth factor (CTGF), and higher bone morphogenetic protein 6 (BMP6) expression and pSMAD1/5/8 signaling, while transforming growth factor-β expression and transcriptional activity were no different in obstructed kidneys of old and young mice. In vitro, CTGF bound to and inhibited BMP6 activity. In summary, our data suggest that in obstructive nephropathy atrophy increases and fibrosis decreases with age and that this relates to increased BMP signaling, most likely due to higher BMP6 and lower CTGF expression.

Profibrogenic phenotype in caveolin-1 deficiency via differential regulation of STAT-1/3 proteins

2014 ◽  
Vol 92 (5) ◽  
pp. 370-378 ◽  
Author(s):  
Stefan W. Ryter ◽  
Augustine M.K. Choi ◽  
Hong Pyo Kim
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Tyrosine Phosphatase ◽  
Transforming Growth Factor Β ◽  
Lung Fibroblasts ◽  
Caveolin 1 ◽  
Expression Of Genes ◽  
Liver And Kidney

Fibrosis underlies the pathogenesis of several human diseases, which can lead to severe injury of vital organs. We previously demonstrated that caveolin-1 expression is reduced in experimental fibrosis and that caveolin-1 exerts antiproliferative and antifibrotic effects in lung fibrosis models. The signal transducers and activators of transcription (STAT) proteins, STAT1 and STAT3, can be activated simultaneously. STAT1 can inhibit cell growth and promote apoptosis while STAT3 inhibits apoptosis. Here, we show that caveolin-1-deficient (cav-1−/−) lung fibroblasts display dramatically upregulated STAT3 activation in response to platelet-derived growth factor-BB and transforming growth factor-β stimuli, whereas STAT1 activation is undetectable. Downregulation of protein tyrosine phosphatase-1B played a role in the preferential activation of STAT3 in cav-1−/− fibroblasts. Genetic deletion of STAT3 by siRNA modulated the expression of genes involved in cell proliferation and fibrogenesis. Basal expression of α-smooth muscle actin was prominent in cav-1−/− liver and kidney, consistent with deposition of collagen in these organs. Collectively, we demonstrate that the antiproliferative and antifibrogenic properties of caveolin-1 in vitro are mediated by the balance between STAT1 and STAT3 activation. Deregulated STAT signaling associated with caveolin-1 deficiency may be relevant to proliferative disorders such as tissue fibrosis.

Characterization of a putative intrarenal serotonergic system

2007 ◽  
Vol 293 (5) ◽  
pp. F1468-F1475 ◽  
Author(s):  
Jie Xu ◽  
Bing Yao ◽  
Xiaofeng Fan ◽  
Melissa M. Langworthy ◽  
Ming-Zhi Zhang ◽  
...  
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Mesangial Cells ◽  
Transforming Growth Factor Β ◽  
Cell Types ◽  
Tissue Growth ◽  
Serotonergic System ◽  
Rt Pcr

Serotonin [5-hydroxytryptamine (5HT)] acts through multiple G protein-coupled 5-HT receptors, and its activity is also regulated by the 5-HT transporter. The current studies report the expression and localization of the 5-HT receptors and transporter in the kidney. In addition, the enzymatic pathway mediating 5-HT synthesis is present in renal cortex, especially in the proximal tubules and glomerular epithelial cells and mesangial cells. Expression of the 5-HT receptors and 5-HT transporter was detected by RT-PCR in cell lines of these cell types. In cultured proximal tubule cells and podocytes, 5-HT activated ERK1/2 and increased the expression of connective tissue growth factor and transforming growth factor-β, two key mediators of extracellular matrix accumulation. Immunohistochemistry and real-time RT-PCR studies also indicated that 5-HT stimulated expression of vascular endothelial growth factor in podocytes in vitro and in vivo. Therefore, these results indicate the presence of an integrated intrarenal serotonergic system and suggest a possible role for 5-HT as a mediator of renal fibrosis in the kidney.

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