title: Elastase and matrix metalloproteinase activities are associated with pulmonary vascular disease in the nitrofen rat model of congenital diaphragmatic hernia.
abstract: OBJECTIVE
  Pulmonary vascular disease (PVD) is a leading cause of congenital diaphragmatic hernia (CDH) mortality. Progression of PVD involves extracellular matrix remodeling by elastases and matrix metalloproteinases (MMP), concomitant with proliferation of smooth muscle cells in a growth factor-enriched environment. Blockade of this pathway reversed primary pulmonary hypertension and improved survival. This study was designed to determine whether a similar pathway is induced in PVD secondary to CDH.
  
  
  METHODS
  Fetal rats exposed to nitrofen at gestational day 9 developed left-sided CDH and were compared at term to their non-CDH littermates by assessing histologic and biochemical features of PVD.
  
  
  RESULTS
  Rats with CDH displayed right ventricle hypertrophy, increased pulmonary artery medial wall thickness and muscularization, and decreased lumen size. As revealed by in situ zymography and immunohistochemistry, this was associated with an induction of elastolytic and MMP activities as well as an elevation of epidermal growth factor and osteopontin levels in the diseased lung vasculature.
  
  
  CONCLUSIONS
  CDH-associated PVD involves an induction of elastase and MMP activities and increased osteopontin deposition in an epidermal growth factor-rich environment. Inhibition of this pathway may thus represent a novel therapeutic approach for the treatment of CDH-associated PVD.
  
  
  METHODS
  Level I (Basic Science Study).
authors.affiliation: Molecular Biomedicine Program, Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Wild
authors.affiliation: Molecular Biomedicine Program, Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada.
authors.forename: Marie-Eve
authors.initials: ME
authors.lastname: St-Pierre
authors.affiliation: Department of Surgery, Division of Pediatric Surgery, University of Ottawa, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada; Molecular Biomedicine Program, Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Langlois
authors.affiliation: Department of Surgery, Division of Pediatric Surgery, University of Ottawa, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada; Molecular Biomedicine Program, Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada. Electronic address: kcowan@cheo.on.ca.
authors.forename: Kyle N
authors.initials: KN
authors.lastname: Cowan
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D005260:Female; D065630:Hernias, Diaphragmatic, Congenital / Q000139:chemically induced / Q000150:complications* / Q000201:enzymology; D006976:Hypertension, Pulmonary / Q000201:enzymology / Q000209:etiology*; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D053495:Osteopontin / Q000378:metabolism; D010196:Pancreatic Elastase / Q000378:metabolism*; D010647:Phenyl Ethers; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D015415:Biomarkers; D010647:Phenyl Ethers; C506897:Spp1 protein, rat; D053495:Osteopontin; D010196:Pancreatic Elastase; D020782:Matrix Metalloproteinases; C007350:nitrofen
keywords: Congenital diaphragmatic hernia; Elastase; Matrix metalloproteinase; Pulmonary vascular disease