Open AccessTransforming Growth Factor Beta 1 Activation, Storage, and Signaling Pathways in Idiopathic Pulmonary Fibrosis in Dogs
Author(s) -
Krafft E.,
Lybaert P.,
Roels E.,
Laurila H.P.,
Rajamäki M.M.,
Farnir F.,
Myllärniemi M.,
Day M.J.,
Mc Entee K.,
Clercx C.
Publication year - 2014
Publication title -
journal of veterinary internal medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.356
H-Index - 103
eISSN - 1939-1676
pISSN - 0891-6640
DOI - 10.1111/jvim.12432
Subject(s) - transforming growth factor , pulmonary fibrosis , medicine , pathogenesis , thrombospondin , idiopathic pulmonary fibrosis , signal transduction , smad , receptor , transforming growth factor beta , fibrosis , lung , thrombospondin 1 , pathology , endocrinology , immunology , biology , microbiology and biotechnology , metalloproteinase , matrix metalloproteinase , angiogenesis
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. Objectives To investigate TGF ‐β1 pathway in IPF . Animals Lung tissues from 12 affected and 11 control dogs. Serum from 16 affected West Highland white Terriers ( WHWT s) and healthy dogs from predisposed (13 WHWT s, 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, LTBP 1 and 2. Serum TGF ‐β1 concentration was higher in predisposed compared with nonpredisposed breeds ( P < .0001). Conclusions and Clinical Importance 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 .