title: Dehydroepiandrosterone has strong antifibrotic effects and is decreased in idiopathic pulmonary fibrosis.
abstract: Idiopathic pulmonary fibrosis (IPF) is an ageing-related lung disorder characterised by expansion of the myofibroblast population and aberrant lung remodelling. Dehydroepiandrosterone (DHEA), a steroid pro-hormone, decreases with age but an exaggerated decline has been associated with chronic degenerative diseases. We quantified the plasma levels of DHEA and its sulfated form (DHEA-S) in 137 IPF patients and 58 controls and examined the effects of DHEA on human lung fibroblasts. Plasma DHEA/DHEA-S was significantly decreased in male IPF patients (median (range) DHEA: 4.4 (0.2-29.2) versus 6.7 (2.1-15.2) ng · mL(-1), p<0.01; DHEA-S: 47 (15.0-211) versus 85.2 (37.6-247.0) μg · dL(-1), p<0.001), while in females only DHEA-S was significantly decreased (32.6 (15.0-303.0) versus 68.3 (16.4-171) μg · dL(-1), p<0.001). DHEA caused a decrease in fibroblast proliferation and an approximately two-fold increase in fibroblast apoptosis, probably through the intrinsic pathway with activation of caspase-9. This effect was accompanied by upregulation of several pro-apoptotic proteins (Bax and cyclin-dependent kinase-inhibitor CDNK1A) and downregulation of anti-apoptotic proteins, such as cellular inhibitor of apoptosis (c-IAP)1 and c-IAP2. DHEA also caused a significant decrease of transforming growth factor-β1-induced collagen production and fibroblast to myofibroblast differentiation, and inhibited platelet-derived growth factor-induced fibroblast migration. These findings demonstrate a disproportionate decrease of DHEA/DHEA-S in IPF patients and indicate that this molecule has multiple antifibrotic properties.
authors.affiliation: Mexico City.
authors.forename: Criselda
authors.initials: C
authors.lastname: Mendoza-Milla
authors.forename: Ana
authors.initials: A
authors.lastname: Valero Jiménez
authors.forename: Claudia
authors.initials: C
authors.lastname: Rangel
authors.forename: Alfredo
authors.initials: A
authors.lastname: Lozano
authors.forename: Violeta
authors.initials: V
authors.lastname: Morales
authors.forename: Carina
authors.initials: C
authors.lastname: Becerril
authors.forename: Roberto
authors.initials: R
authors.lastname: Chavira
authors.forename: Víctor
authors.initials: V
authors.lastname: Ruiz
authors.forename: Lourdes
authors.initials: L
authors.lastname: Barrera
authors.forename: Martha
authors.initials: M
authors.lastname: Montaño
authors.forename: Annie
authors.initials: A
authors.lastname: Pardo
authors.forename: Moisés
authors.initials: M
authors.lastname: Selman
mesh_terms: D000368:Aged; D017209:Apoptosis; D018893:Bronchoalveolar Lavage; D016022:Case-Control Studies; D053453:Caspase 9 / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D003687:Dehydroepiandrosterone / Q000097:blood* / Q000494:pharmacology*; D019314:Dehydroepiandrosterone Sulfate / Q000494:pharmacology; D005260:Female; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D010982:Platelet-Derived Growth Factor; D053773:Transforming Growth Factor beta1; D003687:Dehydroepiandrosterone; D019314:Dehydroepiandrosterone Sulfate; D003094:Collagen; C506433:CASP9 protein, human; D053453:Caspase 9