title: Reversal of myofibroblast differentiation by prostaglandin E(2).
abstract: Differentiation of fibroblasts into α-smooth muscle actin (SMA)-expressing myofibroblasts represents a critical step in the pathogenesis of fibrotic disorders, and is generally regarded as irreversible. Prostaglandin E2 (PGE2) has been shown to prevent multiple aspects of fibroblast activation, including the differentiation of fibroblasts to myofibroblasts. Here, we investigated its ability to reverse this differentiated phenotype. Fetal and adult lung fibroblasts were induced to differentiate into myofibroblasts by 24-hour culture with transforming growth factor (TGF)-β1 or endothelin-1. Cells were then treated without or with PGE2 for various intervals and assessed for α-SMA expression. In the absence of PGE2 treatment, α-SMA expression induced by TGF-β1 was persistent and stable for up to 8 days. By contrast, PGE2 treatment effected a dose-dependent decrease in α-SMA and collagen I expression that was observed 2 days after PGE2 addition, peaked at 3 days, and persisted through 8 days in culture. This effect was not explained by an increase in myofibroblast apoptosis, and indeed, reintroduction of TGF-β1 2 days after addition of PGE2 prompted dedifferentiated fibroblasts to re-express α-SMA, indicating redifferentiation to myofibroblasts. This effect of PGE2 was associated with inhibition of focal adhesion kinase signaling, and a focal adhesion kinase inhibitor was also capable of reversing myofibroblast phenotype. These data unambiguously demonstrate reversal of established myofibroblast differentiation. Because many patients have established or even advanced fibrosis by the time they seek medical attention, this capacity of PGE2 has the potential to be harnessed for therapy of late-stage fibrotic disorders.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Garth
authors.initials: G
authors.lastname: Garrison
authors.forename: Steven K
authors.initials: SK
authors.lastname: Huang
authors.forename: Katsuhide
authors.initials: K
authors.lastname: Okunishi
authors.forename: Jacob P
authors.initials: JP
authors.lastname: Scott
authors.forename: Loka Raghu
authors.initials: LR
authors.lastname: Kumar Penke
authors.forename: Anne M
authors.initials: AM
authors.lastname: Scruggs
authors.forename: Marc
authors.initials: M
authors.lastname: Peters-Golden
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D000943:Antigens, Differentiation / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis; D002454:Cell Differentiation; D002460:Cell Line; D024042:Collagen Type I / Q000378:metabolism; D015232:Dinoprostone / Q000494:pharmacology* / Q000502:physiology; D019332:Endothelin-1 / Q000502:physiology; D005355:Fibrosis; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D008168:Lung / Q000473:pathology; D008171:Lung Diseases / Q000188:drug therapy; D058628:Myofibroblasts / Q000187:drug effects / Q000502:physiology*; D010641:Phenotype; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000502:physiology
chemical_list: D000199:Actins; D000943:Antigens, Differentiation; D024042:Collagen Type I; D019332:Endothelin-1; D053773:Transforming Growth Factor beta1; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D051416:Focal Adhesion Protein-Tyrosine Kinases; D015232:Dinoprostone