Increased production of TGF-β1 from sputum cells of COPD: Relationship with airway obstruction

Godinas, Laurent; Corhay, Jean-Louis; Henket, Monique; Guiot, Julien; Louis, Renaud; Moermans, Catherine

doi:10.1016/j.cyto.2017.06.018

Cited by 24 publications

(21 citation statements)

References 39 publications

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“…From the different levels of repression by TGF-β observed, we can also speculate that these stem cell maintenance transcription factors are regulated by a combination of Slug and other regulators that are specific for each of them. There is a higher level of TGF-β in COPD airways and it increases with disease progression [20]. Our results are in line with the airway basal stem/progenitor cell exhaustion described for this disease.…”

Section: Discussionsupporting

confidence: 88%

Transcription factors involved in stem cell maintenance are downstream of Slug/Snail2 and repressed by TGF-β in bronchial basal stem/progenitor cells from COPD

P¹,

Jolly²,

Courageux³

et al. 2020

Preprint

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22Objectives: Patients with Chronic Obstructive Pulmonary Disease (COPD) have a bronchial 23 epithelium with many anomalies and basal/progenitor cells showing a decrease of self-renewal 24 and differentiation potential. The objective of this study was to identify deregulations in the 25 genetic program of COPD bronchial progenitors that could account for their exhaustion. The 26 transcription factor Slug/Snail2 is highly expressed in bronchial progenitors and we aimed at 27 identifying genes downstream of Slug whose expression is deregulated in COPD progenitors. 28 Results:We knocked down Slug in primary basal cells from COPD subjects and, since COPD 29 subjects have higher levels of Transforming Growth Factor (TGF)-β and Slug is regulated by 30 TGF-β, we selected genes downstream of Slug involved in differentiation that respond to We identified transcription factors involved in stem cell maintenance downstream of Slug and 32 repressed by TGF-β in COPD but not normal progenitors. We found that the effect of TGF-β on 33 the expression of these genes is correlated to Slug knockdown effect. We also found a correlation 34 between the mRNA levels of Slug and these genes only in presence of TGF-β. These results 35 reveal that stem cell maintenance genes are deregulated in COPD bronchial progenitors, Slug and 36 TGF-β being involved in that deregulation. 37

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Section: Discussionsupporting

confidence: 88%

Transcription factors involved in stem cell maintenance are downstream of Slug/Snail2 and repressed by TGF-β in bronchial basal stem/progenitor cells from COPD

P¹,

Jolly²,

Courageux³

et al. 2020

Preprint

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“…In this study, we investigated whether there was an association between the level of circulating H3.1 containing nucleosomes and other biomarkers of interest in systemic sclerosis or lung fibrosis such as the serum growth factors IGFBP-1 and the MMP enzyme MMP9, as a suitable approach or the correct identification of SSc-ILD disease [14][15][16][17][18][19].…”

Section: Introductionmentioning

confidence: 99%

A new nucleosomic-based model to identify and diagnose SSc-ILD

et al. 2020

Self Cite

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Background: Systemic sclerosis (SSc) is a rare connective tissue disease associated with rapid evolving interstitial lung disease (SSc-ILD), driving its mortality. Specific biomarkers associated with the evolution of the lung disease are highly needed. We aimed to identify specific biomarkers of SSc-ILD to predict the evolution of the disease. Nucleosomes are stable DNA/protein complexes that are shed into the blood stream making them ideal candidates for biomarkers. Methods: We studied circulating cell-free nucleosomes (cf-nucleosomes) in SSc patients, 31 with ILD (SSc-ILD) and 67 without ILD. We analyzed plasma levels for cf-nucleosomes and investigated whether global circulating nucleosome levels in association with or without other biomarkers of interest for systemic sclerosis or lung fibrosis (e.g., serum growth factors: IGFBP-1 and the MMP enzyme: MMP-9), could be suitable potential biomarkers for the correct identification of SSc-ILD disease. Results: We found that H3.1 nucleosome levels were significantly higher in patients with SSc-ILD compared SSc patients without ILD (p < 0.05) and levels of MMP-9 were significantly increased in patients with SSc-ILD compared to SSc patients without ILD (p < 0.05). Conversely, IGFBP-1 was significantly reduced in patients with SSc-ILD compared to SSc without ILD (p < 0.001). The combination of cf-nucleosomes H3.1 coupled to MMP-9 and IGFBP-1 increased the sensitivity for the differential detection of SSc-ILD. High levels of accuracy were reached with this combined model: its performances are strong with 68.4% of positive predictive value and 77.2% of negative predictive value for 90% of specificity. With our model, we identified a significant negative correlation with FVC % pred (r = −0.22) and TLC % pred (r = −0.31). The value of our model at T1 (baseline) has a predictive power over the Rodnan score at T2 (after 6-18 months), showed by a significant linear regression with R 2 = 19% (p = 0.013). We identified in the sole group of SSc-ILD patients a significant linear regression with a R 2 = 54.4% with the variation of DLCO between T1 and T2 (p < 0.05). Conclusion: In our study, we identified a new blood-based model with nucleosomic biomarker in order to diagnose SSc-ILD in a SSc cohort. This model is correlated with TLC and FVC at baseline and predictive of the skin evolution and the DLCO. Further longitudinal exploration studies should be performed in order to evaluate the potential of such diagnostic and predictive model.

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“…TGF-β signaling has been implicated in the pathogenesis of human chronic airway diseases (14)(15)(16)(17). It participates in airway narrowing by increasing ASM cell size and contractile protein expression, resulting in hypercontractility and hyperresponsiveness (18)(19)(20)(21)(22)(23).…”

Section: Introductionmentioning

confidence: 99%

Retinoic acid signaling is essential for airway smooth muscle homeostasis

Chen¹,

Shao²,

Hinds³

et al. 2018

JCI Insight

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Airway smooth muscle (ASM) is a dynamic and complex tissue involved in regulation of bronchomotor tone, but the molecular events essential for the maintenance of ASM homeostasis are not well understood. Observational and genome-wide association studies in humans have linked airway function to the nutritional status of vitamin A and its bioactive metabolite retinoic acid (RA). Here, we provide evidence that ongoing RA signaling is critical for the regulation of adult ASM phenotype. By using dietary, pharmacologic, and genetic models in mice and humans, we show that (a) RA signaling is active in adult ASM in the normal lung, (b) RA-deficient ASM cells are hypertrophic, hypercontractile, profibrotic, but not hyperproliferative, (c) TGF-β signaling, known to cause ASM hypertrophy and airway fibrosis in human obstructive lung diseases, is hyperactivated in RA-deficient ASM, (d) pharmacologic and genetic inhibition of the TGF-β activity in ASM prevents the development of the aberrant phenotype induced by RA deficiency, and (e) the consequences of transient RA deficiency in ASM are long-lasting. These results indicate that RA signaling actively maintains adult ASM homeostasis, and disruption of RA signaling leads to aberrant ASM phenotypes similar to those seen in human chronic airway diseases such as asthma.

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Increased production of TGF-β1 from sputum cells of COPD: Relationship with airway obstruction

Cited by 24 publications

References 39 publications

Transcription factors involved in stem cell maintenance are downstream of Slug/Snail2 and repressed by TGF-β in bronchial basal stem/progenitor cells from COPD

Transcription factors involved in stem cell maintenance are downstream of Slug/Snail2 and repressed by TGF-β in bronchial basal stem/progenitor cells from COPD

A new nucleosomic-based model to identify and diagnose SSc-ILD

Retinoic acid signaling is essential for airway smooth muscle homeostasis

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