title: Transforming growth factor beta 1 activation, storage, and signaling pathways in idiopathic pulmonary fibrosis in dogs.
abstract: BACKGROUND
  The pathogenesis of idiopathic pulmonary fibrosis (IPF) in dogs is poorly understood. In human, transforming growth factor β1 (TGF-β1) is considered central in the pathogenesis.
  
  
  OBJECTIVE
  To investigate TGF-β1 pathway in IPF.
  
  
  METHODS
  Lung tissues from 12 affected and 11 control dogs. Serum from 16 affected West Highland white Terriers (WHWTs) and healthy dogs from predisposed (13 WHWTs, 12 Scottish Terriers and 13 Bichons Frise) and nonpredisposed breeds (10 Whippets, 10 Belgian shepherds, 8 Labradors).
  
  
  METHODS
  In this prospective study, immunohistochemistry was used to evaluate expression and localization of TGF-β1 protein and proteins involved in TGF-β1 signaling (TGF-β receptor type I and phospho-Smad2/3). Pulmonary expression of TGF-β1 and molecules involved in its storage (latent TGF-β binding proteins [LTBP] 1, 2, and 4), activation (ανβ6 and ανβ8 integrins, thrombospondin-1) and signal inhibition (Smad 7) was analyzed by quantitative reverse transcriptase PCR. Circulating TGF-β1 concentration was measured by ELISA.
  
  
  RESULTS
  In IPF, high level of TGF-β1 protein was found in areas of fibrosis, epithelial cells had strong expression of TGF-β receptor type 1 and phospho-Smad2/3, gene expression was decreased for LTBP 4 (P = .009) and β8 integrin (P < .001) and increased for thrombospondin-1 (P = .016); no difference was seen for Smad7, LTBP1 and 2. Serum TGF-β1 concentration was higher in predisposed compared with nonpredisposed breeds (P < .0001).
  
  
  CONCLUSIONS
  This study identified an enhanced TGF-β1 signaling activity in IPF. TGF-β1 storage and activation proteins with altered expression represent potential therapeutic targets. Higher circulating TGF-β1 concentration in predisposed breeds might partly explain their susceptibility for IPF.
authors.affiliation: Division of Companion Animal Internal Medicine, Department of Veterinary Clinical Sciences, Faculty of Veterinary Medicine, University of Liège, Liège, Belgium.
authors.forename: E
authors.initials: E
authors.lastname: Krafft
authors.forename: P
authors.initials: P
authors.lastname: Lybaert
authors.forename: E
authors.initials: E
authors.lastname: Roels
authors.forename: H P
authors.initials: HP
authors.lastname: Laurila
authors.forename: M M
authors.initials: MM
authors.lastname: Rajamäki
authors.forename: F
authors.initials: F
authors.lastname: Farnir
authors.forename: M
authors.initials: M
authors.lastname: Myllärniemi
authors.forename: M J
authors.initials: MJ
authors.lastname: Day
authors.forename: K
authors.initials: K
authors.lastname: Mc Entee
authors.forename: C
authors.initials: C
authors.lastname: Clercx
mesh_terms: D000818:Animals; D016022:Case-Control Studies; D004283:Dog Diseases / Q000209:etiology* / Q000503:physiopathology; D004285:Dogs; D054990:Idiopathic Pulmonary Fibrosis / Q000209:etiology / Q000503:physiopathology / Q000662:veterinary*; D008168:Lung / Q000737:chemistry / Q000378:metabolism / Q000503:physiopathology; D018125:Receptors, Transforming Growth Factor beta / Q000032:analysis / Q000378:metabolism / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000662:veterinary; D015398:Signal Transduction / Q000502:physiology*; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000032:analysis / Q000097:blood / Q000378:metabolism / Q000502:physiology*
chemical_list: D018125:Receptors, Transforming Growth Factor beta; D051899:Smad2 Protein; D051900:Smad3 Protein; D053773:Transforming Growth Factor beta1
keywords: Integrin; Latent binding protein; Smads; Thrombospondin-1