Expression of fibrosis-related genes in liver allografts: Association with histology and long-term outcome after pediatric liver transplantation.
fibrosis
gene expression
inflammation
liver transplantation
pediatrics
Journal
Clinical transplantation
ISSN: 1399-0012
Titre abrégé: Clin Transplant
Pays: Denmark
ID NLM: 8710240
Informations de publication
Date de publication:
08 2021
08 2021
Historique:
revised:
11
05
2021
received:
21
11
2020
accepted:
16
05
2021
pubmed:
28
5
2021
medline:
25
2
2023
entrez:
27
5
2021
Statut:
ppublish
Résumé
Unexplained graft fibrosis and inflammation are common after pediatric liver transplantation (LT). We investigated the graft expression of fibrogenic genes and correlated the findings with transplant histopathology and outcome. Liver biopsies from 29 recipients were obtained at a median of 13.1 (IQR: 5.0-18.4) years after pediatric LT. Control samples were from six liver-healthy subjects. Hepatic expression of 40 fibrosis-related genes was correlated to histological findings: normal histology, fibrosis with no inflammation, and fibrosis with inflammation. Liver function was evaluated after a subsequent follow-up of 9.0 years (IQR: 8.0-9.4). Patients with fibrosis and no inflammation had significantly increased gene expression of profibrotic TGF-β3 (1.17 vs. 1.02 p = .005), CTGF (1.64 vs. 0.66 p = .014), PDGF-α (1.79 vs. 0.98 p = .049), PDGF -β (0.99 vs. 0.76 p = .006), integrin-subunit-β1 (1.19 vs. 1.02 p = .045), α-SMA (1.12 vs. 0.58 p = .013), type I collagen (0.82 vs. 0.53 p = .005) and antifibrotic decorin (1.15 vs. 0.99 p = .045) compared to patients with normal histology. mRNA expression of VEGF A (0.84 vs. 1.06 p = .049) was lower. Only a few of the studied genes were upregulated in patients with both fibrosis and inflammation. The gene expression levels showed no association with later graft outcome. Altered hepatic expression of fibrosis-related genes is associated with graft fibrosis without concurrent inflammation.
Sections du résumé
BACKGROUND
Unexplained graft fibrosis and inflammation are common after pediatric liver transplantation (LT).
OBJECTIVE
We investigated the graft expression of fibrogenic genes and correlated the findings with transplant histopathology and outcome.
METHODS
Liver biopsies from 29 recipients were obtained at a median of 13.1 (IQR: 5.0-18.4) years after pediatric LT. Control samples were from six liver-healthy subjects. Hepatic expression of 40 fibrosis-related genes was correlated to histological findings: normal histology, fibrosis with no inflammation, and fibrosis with inflammation. Liver function was evaluated after a subsequent follow-up of 9.0 years (IQR: 8.0-9.4).
RESULTS
Patients with fibrosis and no inflammation had significantly increased gene expression of profibrotic TGF-β3 (1.17 vs. 1.02 p = .005), CTGF (1.64 vs. 0.66 p = .014), PDGF-α (1.79 vs. 0.98 p = .049), PDGF -β (0.99 vs. 0.76 p = .006), integrin-subunit-β1 (1.19 vs. 1.02 p = .045), α-SMA (1.12 vs. 0.58 p = .013), type I collagen (0.82 vs. 0.53 p = .005) and antifibrotic decorin (1.15 vs. 0.99 p = .045) compared to patients with normal histology. mRNA expression of VEGF A (0.84 vs. 1.06 p = .049) was lower. Only a few of the studied genes were upregulated in patients with both fibrosis and inflammation. The gene expression levels showed no association with later graft outcome.
CONCLUSIONS
Altered hepatic expression of fibrosis-related genes is associated with graft fibrosis without concurrent inflammation.
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e14373Subventions
Organisme : Helsingin ja Uudenmaan Sairaanhoitopiiri
Organisme : Lastentautien Tutkimussäätiö
Organisme : Sigrid Juselius foundation
Informations de copyright
© 2021 The Authors. Clinical Transplantation published by John Wiley & Sons Ltd.
Références
Duffy JP, Kao K, Ko CY, et al. Long-term patient outcome and quality of life after liver transplantation: analysis of 20-year survivors. Ann Surg. 2010;252(4):652-661.
Kelly D, Verkade HJ, Rajanayagam J, McKiernan P, Mazariegos G, Hübscher S. Late graft hepatitis and fibrosis in pediatric liver allograft recipients: current concepts and future developments. Liver Transpl. 2016;22(11):1593-1602.
Neil DA, Hubscher SG. Current views on rejection pathology in liver transplantation. Transpl Int. 2010;23(10):971-983.
O'Leary JG, Cai J, Freeman R, et al. Proposed diagnostic criteria for chronic antibody-mediated rejection in liver allografts. Am J Transplant. 2016;16(2):603-614.
Herzog D, Soglio DB, Fournet JC, Martin S, Marleau D, Alvarez F. Interface hepatitis is associated with a high incidence of late graft fibrosis in a group of tightly monitored pediatric orthotopic liver transplantation patients. Liver Transpl. 2008;14(7):945-955.
Varma S, Ambroise M, Komuta D, et al. Progressive fibrosis is driven by genetic predisposition, allo-immunity, and inflammation in pediatric liver transplant recipients. EBioMedicine. 2016;9:346-555.
Hirata Y, Yoshizawa A, Egawa H, et al. Impact of antibodies that react with liver tissue and donor-specific anti-HLA antibodies in pediatric idiopathic posttransplantation hepatitis. Transplantation. 2017;101(5):1074-1083.
Kivela JM, Kosola S, Perasaari J, et al. Donor-specific antibodies after pediatric liver transplantation: a cross-sectional study of 50 patients. Transpl Int. 2016;29(4):494-505.
Mack M. Inflammation and fibrosis. Matrix Biol. 2018;68-69:106-121.
Parola M, Pinzani M. Liver fibrosis: pathophysiology, pathogenetic targets and clinical issues. Mol Aspects Med. 2019;65:37-55.
Zhang CY, Yuan WG, He P, Lei JH, Wang CX. Liver fibrosis and hepatic stellate cells: etiology, pathological hallmarks and therapeutic targets. World J Gastroenterol. 2016;22(48):10512-10522.
Dewidar B, Meyer C, Dooley S, Meindl-Beinker AN. TGF-β in hepatic stellate cell activation and liver fibrogenesis-updated 2019. Cells. 2019;8(11):1419.
Fabregat I, Moreno-Càceres J, Sánchez A, et al. TGF-β signalling and liver disease. FEBS J. 2016;283(12):2219-2232.
Rifkin DB, Rifkin WJ, Zilberberg L. LTBPs in biology and medicine: LTBP diseases. Matrix Biol. 2018;71-72:90-99.
Annes JP, Munger JS, Rifkin DB. Making sense of latent TGFbeta activation. J Cell. 2003;116(Pt 2):217-224.
Ramazani Y, Knops N, Elmonem MA, et al. Connective tissue growth factor (CTGF) from basics to clinics. Matrix Biol. 2018;68-69:44-66.
Ying HZ, Chen WY, Zhang HH, et al. PDGF signaling pathway in hepatic fibrosis pathogenesis and therapeutics (Review). Mol Med Rep. 2017;16(6):7879-7889.
Halloran PF, Venner JM, Madill-Thomsen KS, et al. Review: the transcripts associated with organ allograft rejection. Am J Transplant. 2018;18(4):785-795.
Spivey TL, Uccellini L, Ascierto ML, et al. Gene expression profiling in acute allograft rejection: challenging the immunologic constant of rejection hypothesis. J Trnas Med. 2011;12(9):174.
Feng S, Bucuvalas JC, Demetris AJ, et al. Evidence of chronic allograft injury in liver biopsies from long-term pediatric recipients of liver transplants. Gastroenterology. 2018;155(6):1837-1851.
Banff working group. Banff schema for grading allograft rejection: an international consensus document. Hepatology. 1997;25(3):658-663.
Goodman ZD. Grading and staging systems for inflammation and fibrosis in chronic liver diseases. J Hepatol. 2007;47(4):598-607.
Fabregat I, Caballero-Diaz D. Transforming growth factor-beeta-induced cell plasticity in liver fibrosis and hepatocarcinogenesis. Front Oncol. 2018;8:357.
Tsuchida D, Friedmann SL. Mechanisms of hepatic stellate cell activation. Nat Rev Gastroenterol Hepatol. 2017;14:397-411.
Schrum L, Bird MA, Salcher O, et al. Autocrine expression of activated transforming growth factor-beta1 induces apoptosis in normal rat liver. Am J Physiol Gastrointest Liver Physiol. 2001;280:G139-G148.
Gressner AM, Weiskirchen R, Breitkopft K, Dooley S. Roles of TFG-beta in hepatic fibrosis. Front Biosci. 2002;7:d793-d807.
Derynck R, Zhang YE. Smad-dependent ans Smad-independent pathways in TGF-beta signaling. Nature. 2003;425:577-584.
Letamendia A, Lastres P, Botella LM, et al. Role of endoglin in cellular responses to transforming growth factor-beta. A comparative study with betaglycan. J Biol Chem. 1998;273:33011-33019.
Baghy K, Iozzo V, Kovalszky I. Decorin-TGF-beta axis in hepatic fibrosis and cirrhosis. J Histochem Cytochem. 2012;60(4):262-268.
Zhong L, Wang X, Wang S, Yang L, Gao H, Yang C. The antifibrotic effect of boen morphogenic protein-7 (BMP7) on liver fibrosis. Int J Med Sci. 2013;10:442-450.
Herrera B, Addante A, Sánchez A. BMP signalling at the crossroad of liver fibrosis and regeneration. Int J Mol Sci. 2017;19(1):39.
Robertson IB, Horiguchi M, Zillberberg L, Dabovic B, Hadjiolova K, Rifkin DB. Latent TGF-beta-binding proteins. Matrix Biol. 2015;47:44-53.
Gressner OA, Gressner AM. Connective tissue growth factor: a fibrogenic master switch in fibrotic liver diseases. Liver Int. 2008;28:1065-1079.
Funchs BC, Hoshida Y, Fujii T, et al. Epidermal growth factor receptor inhibition attenuates liver fibrosis and development of hepatocellular carcinoma. Hepatology. 2014;59:1577-1590.
Nakamura T, Sakai K, Nakamura T, Matsumoto K. Hepatocyte growth factor twenty years on: much more than a growth factor. J Gastroenterol Hepatol. 2011;26:188-202.
Hoeben A, Landuyt B, Higley MS, Wildiers H, van Oosterom AT, de Bruijn EA. Vascular endothelial growth factor and angiogenesis. Pharmacol Rev. 2004;56:549-580.
Deleve LD, Wang X, Guo Y. Sinusoidal endothelial cells prevent rat stellate cell activation and promote reversion to quiescence. Hepatology. 2008;48:920-930.
Zhang Y, Ikegami T, Honda A, et al. Involvement of integrin-linked kinase in carbon tetrachloride-induced hepatic fibrosis in rats. Hepatology. 2006;44(3):612-622.
van der Flier A, Sonnenberg A. Function and interactions of integrins. Cell Tissue Res. 2001;305(3):285-298.
Conroy KP, Kitto LJ, Henderson NC. Alphav integrins: key regulators of tissue fibrosis. Cell Tissue Res. 2016;365(3):511-519.
Li Y, Turpin CP, Wang S. Role of thrombospondin 1 in liver disease. Hepatol Res. 2016;47(2):186-193.
Lou Y, Tian GY, Song Y, et al. Characterization of transcriptional modules related to fibrosing-NAFLD progression. Sci Rep. 2017;7(1):4748.
Zorio E, Gilabert-Estelles J, Espana F, Ramon RA, Cosin R, Estelles A. Fibrinolysis: the key to new pathogenic mechanism. Curr Med Chem. 2008;15:923.929.
Schuliga M, Grainge C, Westall G, Knight D. The fibrogenic actions of the coagulant and plasminogen activation systems in pulmonary fibrosis. Int J Biochem Cell Biol. 2018;97:108-117.
Eyden B. The myofibroblast: phenotypic characterization as a prerequisite to understanding its functions in translational medicine. J Cell Mol Med. 2008;12:22-37.
Basturk O, Farris AB, Adsay NV. Chapter 15 immunohistology of pancreas and hepatobiliary system. In: Dabbs DJ, ed. Diagnostic immunohistochemistry, 5th edn. Amsterdam, The Netherlands: Elsevier; 2019.
Thompson KJ, McKillop IH, Schrum LW. Targeting collagen expression in alcoholic liver disease. World J Gastroenterol. 2011;17:2473-2481.
Napoli J, Prentice D, Niinami C, Bishop GA, Desmond P, McCaughan GW. Sequential increases in the intrahepatic expression of epidermal growth factor, basic fibroblast growth factor, and transforming growth factor beta in a bile duct ligated rat model of cirrhosis. Hepatology. 1997;26(3):624-633.
Al N, Dalpiaz T, Pedroso JA, et al. Expression of fibrosis-related genes in human renal allografts with interstitial fibrosis and tubular atrophy. J Nephrol. 2013;26(6):1179-1187.
Fullár A, Firneisz G, Regős E, et al. Response of hepatic stellate cells to TGFB1 differs from the response of myofibroblasts. Decorin protects against the action of growth factor. Pathol Oncol Res. 2017;23(2):287-294.
Dosanjh A, Robison E, Mondala T. Genomic meta-analysis of growth factor and integring pathways in chronic kidney transplant injury. BMC Genom. 2013;14:275.
Smith MW, Walters MJ, Korht M, et al. Gene expression patterns that correlate with hepatitis C and early progression to fibrosis in liver transplant recipients. Gastroenterology. 2016;130(1):179-187.
Jalanko H, Mattila I, Holmberg C. Renal transplantation in infants. Pediatr Nephrol. 2016;31(5):725-735.
Yu Q, Xiong X, Zhao L, Xu T, Wang Q. Antifibrotic effects of specific siRNA targeting connective tissue growth factor delivered by polyethyleneimine-functionalized magnetic iron oxide nanoparticles on LX-2 cells. Mol Med Rep. 2020;21(1):181-190.
Guo YC, Lu LG. Antihepatic fibrosis drugs in clinical trials. J Clin Transl Hepatol. 2020;8(3):304-312.
Roehlen N, Crouchet E, Baumert TF. Liver fibrosis: mechanistic concepts and therapeutic perspectives. Cells. 2020;9(4):875.