Pneumologie 2019; 73(02): 112
DOI: 10.1055/s-0039-1678392
Abstracts
Georg Thieme Verlag KG Stuttgart · New York

Transciptomic Profile TGF-β Inhibitor Treatment in BAL Cells from IPF Patients

Alfonso Carleo
1   Medizinische Hochschule Hannover (MHH) – Hannover (DE)
,
Oliver Terwolbeck
2   Fraunhofer-Institut fur Toxikologie und Experimentelle Medizin, Clinical Research Center – Hannover (DE)
,
Antje Prasse
1   Medizinische Hochschule Hannover (MHH) – Hannover (DE)
› Author Affiliations
Further Information

Publication History

Publication Date:
15 February 2019 (online)

Also available at
 

Introduction Transforming Growth Factor β (TGF-β) is considered as a key player in multiple fibrotic diseases, including Idiopathic Pulmonary Fibrosis (IPF). Previous data suggested that unstimulated alveolar macrophages from IPF patients show already high levels of TGF-β signaling and that inhibition of TGF-β signaling can be tested on native BAL cells.
Objective In this study we evaluate the effect of SB-431542, an inhibitor of TGFBR1 and thereby TGF-β signaling, on the transcriptome of ex vivo BAL cells from 9 IPF patients.
Workflow Culture was treated with 10 µM of SB-431542 for 24 hours. After RNA purification, microarray transcriptomics analysis was carried out using mRNA array (TempoSeq Technologie). Statistical analysis was performed using BRB-ArrayTools comparing SB-431542-treated culture against the respective unstimulated control by paired t-test. Further statistical analysis and plots (principal component analysis, heatmap, and partial least square regression discriminant analysis) were obtained using RStudio. The genes modulated by TGF-β inhibition were also tested for their clinical significance using a previously published dataset.
Results TGFBR1 Inhibition by SB-431542 lead to a robust change in the gene expression profile of BAL cells. We observed 507 differentially expressed genes (DEGs) with FDR<0.05. In detail, 273 of them were up- and 234 genes were down-regulated after treatment with SB-431542. Pathway analysis by David showed that the DEGs are related to connective tissue disorders and involved in cellular movement, wound healing, iron homeostasis, inflammatory, and immune response. SB-431542 seems also to influence the Wnt, MAPK, Notch, and chemokine-mediated signaling pathways of BAL cells. In addition, we found that 51 of the downregulated DEGs by SB-431542 were enriched in our recently published BAL cell signature prognostic of mortality in IPF.
Conclusions This study on the effects of TGFBR1 inhibition confirmed that TGF-β signaling is an important target for IPF and that BAL cell profiles can be used as a readout to test pharmacomodulation of this pathway.

 

  • References

  • 1 Mu et al., J Cell Biol (2002); Prasse et al., Am J Respir Crit Care Med (2018).
    PubMedGoogle Scholar