PMID- 35676709 OWN - NLM STAT- MEDLINE DCOM- 20220610 LR - 20220716 IS - 1465-993X (Electronic) IS - 1465-9921 (Print) IS - 1465-9921 (Linking) VI - 23 IP - 1 DP - 2022 Jun 8 TI - Dehydroepiandrosterone in fibrotic interstitial lung disease: a translational study. PG - 149 LID - 10.1186/s12931-022-02076-9 [doi] LID - 149 AB - BACKGROUND: Dehydroepiandrosterone (DHEA) is a precursor sex hormone with antifibrotic properties. The aims of this study were to investigate antifibrotic mechanisms of DHEA, and to determine the relationship between DHEA-sulfate (DHEAS) plasma levels, disease severity and survival in patients with fibrotic interstitial lung diseases (ILDs). METHODS: Human precision cut lung slices (PCLS) and normal human lung fibroblasts were treated with DHEA and/or transforming growth factor (TGF)-beta1 before analysis of pro-fibrotic genes and signal proteins. Cell proliferation, cytotoxicity, cell cycle and glucose-6-phosphate dehydrogenase (G6PD) activity were assessed. DHEAS plasma levels were correlated with pulmonary function, the composite physiologic index (CPI), and time to death or lung transplantation in a derivation cohort of 31 men with idiopathic pulmonary fibrosis (IPF) and in an independent validation cohort of 238 men and women with fibrotic ILDs. RESULTS: DHEA decreased the expression of pro-fibrotic markers in-vitro and ex-vivo. There was no cytotoxic effect for the applied concentrations, but DHEA interfered in proliferation by modulating the cell cycle through reduction of G6PD activity. In men with IPF (derivation cohort) DHEAS plasma levels in the lowest quartile were associated with poor lung function and higher CPI (adjusted OR 1.15 [95% CI 1.03-1.38], p = 0.04), which was confirmed in the fibrotic ILD validation cohort (adjusted OR 1.03 [95% CI 1.00-1.06], p = 0.01). In both cohorts the risk of early mortality was higher in patients with low DHEAS levels, after accounting for potential confounding by age in men with IPF (HR 3.84, 95% CI 1.25-11.7, p = 0.02), and for age, sex, IPF diagnosis and prednisone treatment in men and women with fibrotic ILDs (HR 3.17, 95% CI 1.35-7.44, p = 0.008). CONCLUSIONS: DHEA reduces lung fibrosis and cell proliferation by inducing cell cycle arrest and inhibition of G6PD activity. The association between low DHEAS levels and disease severity suggests a potential prognostic and therapeutic role of DHEAS in fibrotic ILD. CI - (c) 2022. The Author(s). FAU - Guler, Sabina A AU - Guler SA AD - Department of Pulmonary Medicine, Inselspital, Bern University Hospital, University of Bern, Freiburgstrasse 18, 3010, Bern, Switzerland. sabina.guler@insel.ch. AD - Department for BioMedical Research DBMR, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland. sabina.guler@insel.ch. FAU - Machahua, Carlos AU - Machahua C AD - Department of Pulmonary Medicine, Inselspital, Bern University Hospital, University of Bern, Freiburgstrasse 18, 3010, Bern, Switzerland. AD - Department for BioMedical Research DBMR, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland. FAU - Geiser, Thomas K AU - Geiser TK AD - Department of Pulmonary Medicine, Inselspital, Bern University Hospital, University of Bern, Freiburgstrasse 18, 3010, Bern, Switzerland. AD - Department for BioMedical Research DBMR, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland. FAU - Kocher, Gregor AU - Kocher G AD - Department for BioMedical Research DBMR, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland. AD - Division of General Thoracic Surgery, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland. FAU - Marti, Thomas M AU - Marti TM AD - Department for BioMedical Research DBMR, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland. AD - Division of General Thoracic Surgery, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland. FAU - Tan, Benjamin AU - Tan B AD - Department of Medicine, University of British Columbia, Vancouver, Canada. FAU - Trappetti, Verdiana AU - Trappetti V AD - Institute of Anatomy, University of Bern, Bern, Switzerland. FAU - Ryerson, Christopher J AU - Ryerson CJ AD - Department of Medicine, University of British Columbia, Vancouver, Canada. AD - Centre for Heart Lung Innovation, University of British Columbia, Vancouver, Canada. FAU - Funke-Chambour, Manuela AU - Funke-Chambour M AD - Department of Pulmonary Medicine, Inselspital, Bern University Hospital, University of Bern, Freiburgstrasse 18, 3010, Bern, Switzerland. AD - Department for BioMedical Research DBMR, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland. LA - eng PT - Journal Article DEP - 20220608 PL - England TA - Respir Res JT - Respiratory research JID - 101090633 RN - 57B09Q7FJR (Dehydroepiandrosterone Sulfate) SB - IM MH - Dehydroepiandrosterone Sulfate MH - Female MH - Fibrosis MH - Humans MH - *Idiopathic Pulmonary Fibrosis/diagnosis/drug therapy/pathology MH - Lung MH - *Lung Diseases, Interstitial/diagnosis/drug therapy/pathology MH - Male PMC - PMC9178848 COIS- The authors declare that they have no conflicts of interest related to this work. EDAT- 2022/06/09 06:00 MHDA- 2022/06/11 06:00 PMCR- 2022/06/08 CRDT- 2022/06/08 23:42 PHST- 2022/01/17 00:00 [received] PHST- 2022/05/31 00:00 [accepted] PHST- 2022/06/08 23:42 [entrez] PHST- 2022/06/09 06:00 [pubmed] PHST- 2022/06/11 06:00 [medline] PHST- 2022/06/08 00:00 [pmc-release] AID - 10.1186/s12931-022-02076-9 [pii] AID - 2076 [pii] AID - 10.1186/s12931-022-02076-9 [doi] PST - epublish SO - Respir Res. 2022 Jun 8;23(1):149. doi: 10.1186/s12931-022-02076-9.