Connective Tissue Growth Factor Is Overexpressed in Explant Lung Tissue and Broncho-Alveolar Lavage in Transplant-Related Pulmonary Fibrosis
Vanstapel, Arno; Goldschmeding, Roel; Broekhuizen, Roel; Nguyen, Tri; Sacreas, Annelore; Kaes, Janne; Heigl, Tobias; Verleden, Stijn E.; De Zutter, Alexandra; Verleden, Geert; Weynand, Birgit; Verbeken, Erik; Ceulemans, Laurens J.; Van Raemdonck, Dirk E.; Neyrinck, Arne P.; Schoemans, Helene M.; Vanaudenaerde, Bart M.; Vos, Robin
(2021) Frontiers in Immunology, volume 12, pp. 1 - 14
(Article)
Abstract
Background: Connective tissue growth factor (CTGF) is an important mediator in several fibrotic diseases, including lung fibrosis. We investigated CTGF-expression in chronic lung allograft dysfunction (CLAD) and pulmonary graft-versus-host disease (GVHD). Materials and Methods: CTGF expression was assessed by quantitative real-time polymerase chain reaction (qPCR) and immunohistochemistry in end-stage CLAD
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explant lung tissue (bronchiolitis obliterans syndrome (BOS), n=20; restrictive allograft syndrome (RAS), n=20), pulmonary GHVD (n=9). Unused donor lungs served as control group (n=20). Next, 60 matched lung transplant recipients (BOS, n=20; RAS, n=20; stable lung transplant recipients, n=20) were included for analysis of CTGF protein levels in plasma and broncho-alveolar lavage (BAL) fluid at 3 months post-transplant, 1 year post-transplant, at CLAD diagnosis or 2 years post-transplant in stable patients. Results: qPCR revealed an overall significant difference in the relative content of CTGF mRNA in BOS, RAS and pulmonary GVHD vs. controls (p=0.014). Immunohistochemistry showed a significant higher percentage and intensity of CTGF-positive respiratory epithelial cells in BOS, RAS and pulmonary GVHD patients vs. controls (p<0.0001). BAL CTGF protein levels were significantly higher at 3 months post-transplant in future RAS vs. stable or BOS (p=0.028). At CLAD diagnosis, BAL protein content was significantly increased in RAS patients vs. stable (p=0.0007) and BOS patients (p=0.042). CTGF plasma values were similar in BOS, RAS, and stable patients (p=0.74). Conclusions: Lung CTGF-expression is increased in end-stage CLAD and pulmonary GVHD; and higher CTGF-levels are present in BAL of RAS patients at CLAD diagnosis. Our results suggest a potential role for CTGF in CLAD, especially RAS, and pulmonary GVHD.
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Keywords: BOS, CLAD, CTGF, fibrosis, GVHD, lung transplantation, RAS, Gene Expression, Lung/chemistry, Humans, Middle Aged, Pulmonary Fibrosis/etiology, Bronchoalveolar Lavage Fluid/chemistry, Connective Tissue Growth Factor/genetics, Male, Transplantation, Homologous, Graft vs Host Disease/physiopathology, Lung Transplantation/adverse effects, Adult, Female, Immunology and Allergy, Immunology, Research Support, Non-U.S. Gov't, Journal Article
ISSN: 1664-3224
Publisher: Frontiers Media S. A.
Note: Funding Information: AV is sponsored by a fundamental research grant from the FWO (1102020N). JK is sponsored by a fundamental research grant from the FWO (1198920N). SV is sponsored by a grant from the FWO (FWO12G8715N) and the KU Leuven (C24/18/073). BV is funded by the KU Leuven (C24/050). RV is supported by the FWO (senior clinical researcher) and by a Roche Research Grant from the Belgian Transplant Society. LC is supported by a KU Leuven University chair sponsored by the company Medtronic. DR and GV are supported by the Broere Charitable foundation. Publisher Copyright: © Copyright © 2021 Vanstapel, Goldschmeding, Broekhuizen, Nguyen, Sacreas, Kaes, Heigl, Verleden, De Zutter, Verleden, Weynand, Verbeken, Ceulemans, Van Raemdonck, Neyrinck, Schoemans, Vanaudenaerde and Vos. Copyright © 2021 Vanstapel, Goldschmeding, Broekhuizen, Nguyen, Sacreas, Kaes, Heigl, Verleden, De Zutter, Verleden, Weynand, Verbeken, Ceulemans, Van Raemdonck, Neyrinck, Schoemans, Vanaudenaerde and Vos.
(Peer reviewed)