title: Prostaglandin E2 as an inhibitory modulator of fibrogenesis in human lung allografts.
abstract: BACKGROUND
  Donor mesenchymal stromal/stem cell (MSC) expansion and fibrotic differentiation is associated with development of bronchiolitis obliterans syndrome (BOS) in human lung allografts. However, the regulators of fibrotic differentiation of these resident mesenchymal cells are not well understood.
  
  
  OBJECTIVE
  This study examines the role of endogenous and exogenous prostaglandin (PG)E2 as a modulator of fibrotic differentiation of human lung allograft-derived MSCs.
  
  
  METHODS
  Effect of PGE2 on proliferation, collagen secretion, and α-smooth muscle actin (α-SMA) expression was assessed in lung-resident MSCs (LR-MSCs) derived from patients with and without BOS. The response pathway involved was elucidated by use of specific agonists and antagonists.
  
  
  RESULTS
  PGE2 treatment of LR-MSCs derived from normal lung allografts significantly inhibited their proliferation, collagen secretion, and α-SMA expression. On the basis of pharmacologic and small-interfering RNA approaches, a PGE2/E prostanoid (EP)2/adenylate cyclase pathway was implicated in these suppressive effects. Stimulation of endogenous PGE2 secretion by IL-1β was associated with amelioration of their myofibroblast differentiation in vitro, whereas its inhibition by indomethacin augmented α-SMA expression. LR-MSCs from patients with BOS secreted significantly less PGE2 than non-BOS LR-MSCs. Furthermore, BOS LR-MSCs were found to be defective in their ability to induce cyclooxygenase-2, and therefore unable to up-regulate PGE2 synthesis in response to IL-1β. BOS LR-MSCs also demonstrated resistance to the inhibitory actions of PGE2 in association with a reduction in the EP2/EP1 ratio.
  
  
  CONCLUSIONS
  These data identify the PGE2 axis as an important autocrine-paracrine brake on fibrotic differentiation of LR-MSCs, a failure of which is associated with BOS.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, 1500 East Medical Center Drive, 3916 Taubman Center, Ann Arbor, MI 48109-0360, USA.
authors.forename: Natalie M
authors.initials: NM
authors.lastname: Walker
authors.forename: Linda N
authors.initials: LN
authors.lastname: Badri
authors.forename: Anish
authors.initials: A
authors.lastname: Wadhwa
authors.forename: Scott
authors.initials: S
authors.lastname: Wettlaufer
authors.forename: Marc
authors.initials: M
authors.lastname: Peters-Golden
authors.forename: Vibha N
authors.initials: VN
authors.lastname: Lama
mesh_terms: D000199:Actins / Q000378:metabolism; D000262:Adenylyl Cyclases / Q000378:metabolism; D015153:Blotting, Western; D001989:Bronchiolitis Obliterans / Q000378:metabolism* / Q000473:pathology*; D001992:Bronchoalveolar Lavage Fluid; D002454:Cell Differentiation; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism*; D005355:Fibrosis; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism; D008168:Lung / Q000378:metabolism* / Q000473:pathology*; D016040:Lung Transplantation; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000473:pathology; D058628:Myofibroblasts / Q000378:metabolism / Q000473:pathology; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D000199:Actins; D053583:Interleukin-1beta; D003094:Collagen; D051546:Cyclooxygenase 2; D000262:Adenylyl Cyclases; D015232:Dinoprostone