[en] BACKGROUND: The pathogenesis of idiopathic pulmonary fibrosis (IPF) in dogs is poorly understood. In human, transforming growth factor beta1 (TGF-beta1) is considered central in the pathogenesis. OBJECTIVES: To investigate TGF-beta1 pathway in IPF. ANIMALS: 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-beta1 protein and proteins involved in TGF-beta1 signaling (TGF-beta receptor type I and phospho-Smad2/3). Pulmonary expression of TGF-beta1 and molecules involved in its storage (latent TGF-beta binding proteins [LTBP] 1, 2, and 4), activation (alphanubeta6 and alphanubeta8 integrins, thrombospondin-1) and signal inhibition (Smad 7) was analyzed by quantitative reverse transcriptase PCR. Circulating TGF-beta1 concentration was measured by ELISA. RESULTS: In IPF, high level of TGF-beta1 protein was found in areas of fibrosis, epithelial cells had strong expression of TGF-beta receptor type 1 and phospho-Smad2/3, gene expression was decreased for LTBP 4 (P = .009) and beta8 integrin (P < .001) and increased for thrombospondin-1 (P = .016); no difference was seen for Smad7, LTBP1 and 2. Serum TGF-beta1 concentration was higher in predisposed compared with nonpredisposed breeds (P < .0001). CONCLUSIONS AND CLINICAL IMPORTANCE: This study identified an enhanced TGF-beta1 signaling activity in IPF. TGF-beta1 storage and activation proteins with altered expression represent potential therapeutic targets. Higher circulating TGF-beta1 concentration in predisposed breeds might partly explain their susceptibility for IPF
Heikkila HP, Lappalainen AK, Day MJ, et al. Clinical, bronchoscopic, histopathologic, diagnostic imaging, and arterial oxygenation findings in West Highland White Terriers with idiopathic pulmonary fibrosis. J Vet Intern Med 2011;25:433-439.
Corcoran BM, King LG, Schwarz T, et al. Further characterisation of the clinical features of chronic pulmonary disease in West Highland white terriers. Vet Rec 2011;168:355.
Heikkila-Laurila HP, Rajamaki MM. Idiopathic pulmonary fibrosis in West Highland white terriers. Vet Clin North Am Small Anim Pract 2014;44:129-142.
Syrja P, Heikkila HP, Lilja-Maula L, et al. The histopathology of idiopathic pulmonary fibrosis in West Highland white terriers shares features of both non-specific interstitial pneumonia and usual interstitial pneumonia in man. J Comp Pathol 2013;149:303-313.
Lobetti RG, Milner R, Lane E. Chronic idiopathic pulmonary fibrosis in five dogs. J Am Anim Hosp Assoc 2001;37:119-127.
Krafft E, Heikkila HP, Jespers P, et al. Serum and bronchoalveolar lavage fluid endothelin-1 concentrations as diagnostic biomarkers of canine idiopathic pulmonary fibrosis. J Vet Intern Med 2011;25:990-996.
Heikkila HP, Krafft E, Jespers P, et al. Procollagen type III amino terminal propeptide concentrations in dogs with idiopathic pulmonary fibrosis compared with chronic bronchitis and eosinophilic bronchopneumopathy. Vet J 2013;196:52-56.
Krafft E, Laurila HP, Peters IR, et al. Analysis of gene expression in canine idiopathic pulmonary fibrosis. Vet J 2013;198:479-486.
Sheppard D. Transforming growth factor beta: A central modulator of pulmonary and airway inflammation and fibrosis. Proc Am Thorac Soc 2006;3:413-417.
Hiwatari N, Shimura S, Yamauchi K, et al. Significance of elevated procollagen-III-peptide and transforming growth factor-beta levels of bronchoalveolar lavage fluids from idiopathic pulmonary fibrosis patients. Tohoku J Exp Med 1997;181:285-295.
Yong SJ, Adlakha A, Limper AH. Circulating transforming growth factor-beta(1): A potential marker of disease activity during idiopathic pulmonary fibrosis. Chest 2001;120:68S-70S.
Coker RK, Laurent GJ, Jeffery PK, et al. Localisation of transforming growth factor beta1 and beta3 mRNA transcripts in normal and fibrotic human lung. Thorax 2001;56:549-556.
Broekelmann TJ, Limper AH, Colby TV, et al. Transforming growth factor beta 1 is present at sites of extracellular matrix gene expression in human pulmonary fibrosis. Proc Natl Acad Sci U S A 1991;88:6642-6646.
Bergeron A, Soler P, Kambouchner M, et al. Cytokine profiles in idiopathic pulmonary fibrosis suggest an important role for TGF-beta and IL-10. Eur Respir J 2003;22:69-76.
Sime PJ, O'Reilly KM. Fibrosis of the lung and other tissues: New concepts in pathogenesis and treatment. Clin Immunol 2001;99:308-319.
Todorovic V, Rifkin DB. LTBPs, more than just an escort service. J Cell Biochem 2012;113:410-418.
Nishimura SL. Integrin-mediated transforming growth factor-beta activation, a potential therapeutic target in fibrogenic disorders. Am J Pathol 2009;175:1362-1370.
Munger JS, Huang X, Kawakatsu H, et al. The integrin alpha v beta 6 binds and activates latent TGF beta 1: A mechanism for regulating pulmonary inflammation and fibrosis. Cell 1999;96:319-328.
Mu D, Cambier S, Fjellbirkeland L, et al. The integrin alpha(v)beta8 mediates epithelial homeostasis through MT1-MMP-dependent activation of TGF-beta1. J Cell Biol 2002;157:493-507.
Murphy-Ullrich JE, Poczatek M. Activation of latent TGF-beta by thrombospondin-1: Mechanisms and physiology. Cytokine Growth Factor Rev 2000;11:59-69.
Ribeiro SM, Poczatek M, Schultz-Cherry S, et al. The activation sequence of thrombospondin-1 interacts with the latency-associated peptide to regulate activation of latent transforming growth factor-beta. J Biol Chem 1999;274:13586-13593.
Crawford SE, Stellmach V, Murphy-Ullrich JE, et al. Thrombospondin-1 is a major activator of TGF-beta1 in vivo. Cell 1998;93:1159-1170.
Massague J, Wotton D. Transcriptional control by the TGF-beta/Smad signaling system. EMBO J 2000;19:1745-1754.
Vercelli A, Bellone G, Abate O, et al. Expression of transforming growth factor-beta isoforms in the skin, kidney, pancreas and bladder in a German shepherd dog affected by renal cystadenocarcinoma and nodular dermatofibrosis. J Vet Med A Physiol Pathol Clin Med 2003;50:506-510.
Jugdutt BI, Palaniyappan A, Uwiera RR, et al. Role of healing-specific-matricellular proteins and matrix metalloproteinases in age-related enhanced early remodeling after reperfused STEMI in dogs. Mol Cell Biochem 2009;322:25-36.
Obayashi K, Miyagawa-Tomita S, Matsumoto H, et al. Effects of transforming growth factor-beta3 and matrix metalloproteinase-3 on the pathogenesis of chronic mitral valvular disease in dogs. Am J Vet Res 2011;72:194-202.
Yu CH, Yhee JY, Kim JH, et al. Pro- and anti-inflammatory cytokine expression and histopathological characteristics in canine brain with traumatic brain injury. J Vet Sci 2011;12:299-301.
Moyano JV, Greciano PG, Buschmann MM, et al. Autocrine transforming growth factor-{beta}1 activation mediated by integrin {alpha}V{beta}3 regulates transcriptional expression of laminin-332 in Madin-Darby canine kidney epithelial cells. Mol Biol Cell 2010;21:3654-3668.
Peters IR, Peeters D, Helps CR, et al. Development and application of multiple internal reference (housekeeper) gene assays for accurate normalisation of canine gene expression studies. Vet Immunol Immunopathol 2007;117:55-66.
Peeters D, Peters IR, Farnir F, et al. Real-time RT-PCR quantification of mRNA encoding cytokines and chemokines in histologically normal canine nasal, bronchial and pulmonary tissue. Vet Immunol Immunopathol 2005;104:195-204.
Khalil N, Parekh TV, O'Connor R, et al. Regulation of the effects of TGF-beta 1 by activation of latent TGF-beta 1 and differential expression of TGF-beta receptors (T beta R-I and T beta R-II) in idiopathic pulmonary fibrosis. Thorax 2001;56:907-915.
Khalil N, O'Connor RN, Flanders KC, et al. TGF-beta 1, but not TGF-beta 2 or TGF-beta 3, is differentially present in epithelial cells of advanced pulmonary fibrosis: An immunohistochemical study. Am J Respir Cell Mol Biol 1996;14:131-138.
Khalil N, O'Connor R, Unruh H, et al. Enhanced expression and immunohistochemical distribution of transforming growth factor-beta in idiopathic pulmonary fibrosis. Chest 1991;99:65S-66S.
Flanders KC, Thompson NL, Cissel DS, et al. Transforming growth factor-beta 1: Histochemical localization with antibodies to different epitopes. J Cell Biol 1989;108:653-660.
Chen YG. Endocytic regulation of TGF-beta signaling. Cell Res 2009;19:58-70.
Lepparanta O, Sens C, Salmenkivi K, et al. Regulation of TGF-beta storage and activation in the human idiopathic pulmonary fibrosis lung. Cell Tissue Res 2012;348:491-503.
Saharinen J, Keski-Oja J. Specific sequence motif of 8-Cys repeats of TGF-beta binding proteins, LTBPs, creates a hydrophobic interaction surface for binding of small latent TGF-beta. Mol Biol Cell 2000;11:2691-2704.
Vehvilainen P, Koli K, Myllarniemi M, et al. Latent TGF-beta binding proteins (LTBPs) 1 and 3 differentially regulate transforming growth factor-beta activity in malignant mesothelioma. Hum Pathol 2011;42:269-278.
Klopfleisch R, Schütze M, Gruber AD. Downregulation of transforming growth factor [beta] (TGF[beta]) and latent TGF[beta] binding protein (LTBP)-4 expression in late stage canine mammary tumours. Vet J 2010;186:379-384.
Breuss JM, Gallo J, DeLisser HM, et al. Expression of the beta 6 integrin subunit in development, neoplasia and tissue repair suggests a role in epithelial remodeling. J Cell Sci 1995;108:2241-2251.
Horan GS, Wood S, Ona V, et al. Partial inhibition of integrin alpha(v)beta6 prevents pulmonary fibrosis without exacerbating inflammation. Am J Respir Crit Care Med 2008;177:56-65.
Kuhn C, Mason RJ. Immunolocalization of SPARC, tenascin, and thrombospondin in pulmonary fibrosis. Am J Pathol 1995;147:1759-1769.
Ide M, Ishii H, Mukae H, et al. High serum levels of thrombospondin-1 in patients with idiopathic interstitial pneumonia. Respir Med 2008;102:1625-1630.
Grainger DJ, Heathcote K, Chiano M, et al. Genetic control of the circulating concentration of transforming growth factor type beta1. Hum Mol Genet 1999;8:93-97.
Son JY, Kim SY, Cho SH, et al. TGF-beta1 T869C polymorphism may affect susceptibility to idiopathic pulmonary fibrosis and disease severity. Lung 2013;191:199-205.
Li XX, Li N, Ban CJ, et al. Idiopathic pulmonary fibrosis in relation to gene polymorphisms of transforming growth factor-beta1 and plasminogen activator inhibitor 1. Chin Med J 2011;124:1923-1927.
Xaubet A, Marin-Arguedas A, Lario S, et al. Transforming growth factor-beta1 gene polymorphisms are associated with disease progression in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2003;168:431-435.
Haider Y, Malizia AP, Keating DT, et al. Host predisposition by endogenous transforming growth factor-beta1 overexpression promotes pulmonary fibrosis following bleomycin injury. J Inflamm (Lond) 2007;4:18.
Lilja-Maula L, Syrja P, Laurila HP, et al. Comparative study of transforming growth factor-beta signalling and regulatory molecules in human and canine idiopathic pulmonary fibrosis. J Comp Pathol 2013;150:399-407.
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