Boxhammer, Elke and Lehle, Karla and Schmid, Christof and von Suesskind-Schwendi, Marietta (2020) Anti-oxidative effect of the tyrosine kinase inhibitor nintedanib: a potential therapy for chronic lung allograft dysfunction? EXPERIMENTAL LUNG RESEARCH, 46 (5). pp. 128-145. ISSN 0190-2148, 1521-0499
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Background: The long-term survival after lung transplantation (LTx) is often limited by the development of chronic lung allograft dysfunction (CLAD). Increased oxidative stress has been found to occur in chronic lung allograft dysfunction because of several risk factors, e.g. immunological factors or drug related factors. The aim of this study was to investigate the anti-oxidative effect of the receptor tyrosine kinase (RTK) inhibitor nintedanib on immunologically induced oxidative stress and on drug induced oxidative stress. Methods: In-vivo studies were used for investigation of immunologically induced oxidative stress: Immunohistochemistry of transglutaminase-2 (TGM-2) was used to figure out a potential anti-oxidative effect of receptor tyrosine kinase inhibitor nintedanib in a rat model of allogeneic left LTx. In-vitro studies were used for investigation of drug induced oxidative stress: Cell viability assay, 2'7'-dichlorodihydrofluorescein diacetate (DCFDA) and immunofluorescence of transglutaminase-2 were disposed to examine the potential impact of nintedanib on cyclosporin A (CsA) treated lung fibroblasts of the rat. Results: In-vivo studies: Allogeneic transplanted animals without drug interaction showed severe chronic rejection and an excessive expression of TGM-2, whereas the application of nintedanib significantly decreased the number of TGM-2 positive cells. In-vitro studies: Concentrations of CsA ranging from 250 ng/ml to 500 ng/ml demonstrated oxidative stress caused by an increased production of reactive oxygen species (ROS) and an overexpression of TGM-2 without inducing apoptosis in cells. Concentrations of more than 1000 ng/ml led to a considerable decrease of cellularity. 30 min-pre-incubation with nintedanib at a concentration between 25 and 100 nM reduced generation of intracellular ROS and expression of TGM-2. Conclusion: These results demonstrate a downregulation of ROS and TGM-2 by pretreatment with the receptor tyrosine kinase inhibitor nintedanib and present its potential anti-oxidative and immunomodulatory effect in the treatment of chronic lung allograft dysfunction.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | BRONCHIOLITIS OBLITERANS SYNDROME; OXIDATIVE STRESS; CYCLOSPORINE-A; TISSUE TRANSGLUTAMINASE; COLORIMETRIC ASSAY; GROWTH-FACTOR; INFLAMMATION; FIBROBLASTS; PROTECTS; FIBROSIS; Cyclosporin A; chronic lung allograft dysfunction; nintedanib; oxidative stress; transglutaminase-2 |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Herz-, Thorax- und herznahe Gefäßchirurgie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 29 Mar 2021 11:58 |
| Last Modified: | 29 Mar 2021 11:58 |
| URI: | https://pred.uni-regensburg.de/id/eprint/44939 |
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