title: Matrix metalloproteinase-19 is a key regulator of lung fibrosis in mice and humans.
abstract: BACKGROUND
  Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by epithelial phenotypic changes and fibroblast activation. Based on the temporal heterogeneity of IPF, we hypothesized that hyperplastic alveolar epithelial cells regulate the fibrotic response.
  
  
  OBJECTIVE
  To identify novel mediators of fibrosis comparing the transcriptional signature of hyperplastic epithelial cells and conserved epithelial cells in the same lung.
  
  
  METHODS
  Laser capture microscope and microarrays analysis were used to identify differentially expressed genes in IPF lungs. Bleomycin-induced lung fibrosis was evaluated in Mmp19-deficient and wild-type (WT) mice. The role of matrix metalloproteinase (MMP)-19 was additionally studied by transfecting the human MMP19 in alveolar epithelial cells.
  
  
  RESULTS
  Laser capture microscope followed by microarray analysis revealed a novel mediator, MMP-19, in hyperplastic epithelial cells adjacent to fibrotic regions. Mmp19(-/-) mice showed a significantly increased lung fibrotic response to bleomycin compared with WT mice. A549 epithelial cells transfected with human MMP19 stimulated wound healing and cell migration, whereas silencing MMP19 had the opposite effect. Gene expression microarray of transfected A549 cells showed that PTGS2 (prostaglandin-endoperoxide synthase 2) was one of the highly induced genes. PTGS2 was overexpressed in IPF lungs and colocalized with MMP-19 in hyperplastic epithelial cells. In WT mice, PTGS2 was significantly increased in bronchoalveolar lavage and lung tissues after bleomycin-induced fibrosis, but not in Mmp19(-/-) mice. Inhibition of Mmp-19 by siRNA resulted in inhibition of Ptgs2 at mRNA and protein levels.
  
  
  CONCLUSIONS
  Up-regulation of MMP19 induced by lung injury may play a protective role in the development of fibrosis through the induction of PTGS2.
authors.affiliation: Facultad de Ciencias, Universidad Nacional Autónoma de México, Mexico DF, Mexico. apardos@unam.mx
authors.forename: Guoying
authors.initials: G
authors.lastname: Yu
authors.forename: Elisabetha
authors.initials: E
authors.lastname: Kovkarova-Naumovski
authors.forename: Paul
authors.initials: P
authors.lastname: Jara
authors.forename: Anil
authors.initials: A
authors.lastname: Parwani
authors.forename: Daniel
authors.initials: D
authors.lastname: Kass
authors.forename: Victor
authors.initials: V
authors.lastname: Ruiz
authors.forename: Carlos
authors.initials: C
authors.lastname: Lopez-Otín
authors.forename: Ivan O
authors.initials: IO
authors.lastname: Rosas
authors.forename: Kevin F
authors.initials: KF
authors.lastname: Gibson
authors.forename: Sandra
authors.initials: S
authors.lastname: Cabrera
authors.forename: Remedios
authors.initials: R
authors.lastname: Ramírez
authors.forename: Samuel A
authors.initials: SA
authors.lastname: Yousem
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Richards
authors.forename: Lara J
authors.initials: LJ
authors.lastname: Chensny
authors.forename: Moisés
authors.initials: M
authors.lastname: Selman
authors.forename: Naftali
authors.initials: N
authors.lastname: Kaminski
authors.forename: Annie
authors.initials: A
authors.lastname: Pardo
mesh_terms: D000818:Animals; D001761:Bleomycin; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D061346:Laser Capture Microdissection; D053505:Matrix Metalloproteinases, Secreted / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D011650:Pulmonary Alveoli / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D001761:Bleomycin; D051546:Cyclooxygenase 2; D053505:Matrix Metalloproteinases, Secreted; C108362:matrix metalloproteinase 19