title: Normal Human Lung Epithelial Cells Inhibit Transforming Growth Factor-β Induced Myofibroblast Differentiation via Prostaglandin E2.
abstract: BACKGROUND
  Idiopathic pulmonary fibrosis (IPF) is a chronic progressive disease with very few effective treatments. The key effector cells in fibrosis are believed to be fibroblasts, which differentiate to a contractile myofibroblast phenotype with enhanced capacity to proliferate and produce extracellular matrix. The role of the lung epithelium in fibrosis is unclear. While there is evidence that the epithelium is disrupted in IPF, it is not known whether this is a cause or a result of the fibroblast pathology. We hypothesized that healthy epithelial cells are required to maintain normal lung homeostasis and can inhibit the activation and differentiation of lung fibroblasts to the myofibroblast phenotype. To investigate this hypothesis, we employed a novel co-culture model with primary human lung epithelial cells and fibroblasts to investigate whether epithelial cells inhibit myofibroblast differentiation.
  
  
  RESULTS
  In the presence of transforming growth factor (TGF)-β, fibroblasts co-cultured with epithelial cells expressed significantly less α-smooth muscle actin and collagen and showed marked reduction in cell migration, collagen gel contraction, and cell proliferation compared to fibroblasts grown without epithelial cells. Epithelial cells from non-matching tissue origins were capable of inhibiting TGF-β induced myofibroblast differentiation in lung, keloid and Graves' orbital fibroblasts. TGF-β promoted production of prostaglandin (PG) E2 in lung epithelial cells, and a PGE2 neutralizing antibody blocked the protective effect of epithelial cell co-culture.
  
  
  CONCLUSIONS
  We provide the first direct experimental evidence that lung epithelial cells inhibit TGF-β induced myofibroblast differentiation and pro-fibrotic phenotypes in fibroblasts. This effect is not restricted by tissue origin, and is mediated, at least in part, by PGE2. Our data support the hypothesis that the epithelium plays a crucial role in maintaining lung homeostasis, and that damaged and/ or dysfunctional epithelium contributes to the development of fibrosis.
authors.affiliation: Department of Pathology, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Rochester, NY 14642, United States of America; Lung Biology and Disease Program, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Rochester, NY 14642, United States of America; Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Rochester, 601 Elmwood Avenue, Rochester, NY 14642, United States of America.
authors.forename: Amali P
authors.initials: AP
authors.lastname: Epa
authors.affiliation: Lung Biology and Disease Program, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Rochester, NY 14642, United States of America; Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Rochester, 601 Elmwood Avenue, Rochester, NY 14642, United States of America.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Thatcher
authors.affiliation: Lung Biology and Disease Program, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Rochester, NY 14642, United States of America; Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Rochester, NY 14642, United States of America.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Pollock
authors.affiliation: Lung Biology and Disease Program, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Rochester, NY 14642, United States of America; Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Rochester, 601 Elmwood Avenue, Rochester, NY 14642, United States of America.
authors.forename: Lindsay A
authors.initials: LA
authors.lastname: Wahl
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Rochester, 601 Elmwood Avenue, Rochester, NY 14642, United States of America.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Lyda
authors.affiliation: Lung Biology and Disease Program, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Rochester, NY 14642, United States of America; Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Rochester, 601 Elmwood Avenue, Rochester, NY 14642, United States of America.
authors.forename: R M
authors.initials: RM
authors.lastname: Kottmann
authors.affiliation: Department of Pathology, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Rochester, NY 14642, United States of America; Lung Biology and Disease Program, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Rochester, NY 14642, United States of America; Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Rochester, NY 14642, United States of America; Department of Environmental Medicine, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Rochester NY, 14642, United States of America.
authors.forename: Richard P
authors.initials: RP
authors.lastname: Phipps
authors.affiliation: Lung Biology and Disease Program, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Rochester, NY 14642, United States of America; Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Rochester, 601 Elmwood Avenue, Rochester, NY 14642, United States of America; Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Rochester, NY 14642, United States of America; Department of Environmental Medicine, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Rochester NY, 14642, United States of America.
authors.forename: Patricia J
authors.initials: PJ
authors.lastname: Sime
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation; D018920:Coculture Techniques; D015232:Dinoprostone / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D058628:Myofibroblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D061251:Primary Cell Culture; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
chemical_list: C541116:ACTA2 protein, human; D000199:Actins; D057134:Antibodies, Neutralizing; D016212:Transforming Growth Factor beta; D015232:Dinoprostone