A new mouse model of radiation-induced liver disease reveals mitochondrial dysfunction as an underlying fibrotic stimulus.

Details

Serval ID
serval:BIB_0CD190CF6BA1
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
A new mouse model of radiation-induced liver disease reveals mitochondrial dysfunction as an underlying fibrotic stimulus.
Journal
JHEP reports
Author(s)
Melin N., Yarahmadov T., Sanchez-Taltavull D., Birrer F.E., Brodie T.M., Petit B., Felser A., Nuoffer J.M., Montani M., Vozenin M.C., Herrmann E., Candinas D., Aebersold D.M., Stroka D.
ISSN
2589-5559 (Electronic)
ISSN-L
2589-5559
Publication state
Published
Issued date
07/2022
Peer-reviewed
Oui
Volume
4
Number
7
Pages
100508
Language
english
Notes
Publication types: Journal Article
Publication Status: epublish
Abstract
High-dose irradiation is an essential tool to help control the growth of hepatic tumors, but it can cause radiation-induced liver disease (RILD). This life-threatening complication manifests itself months following radiation therapy and is characterized by fibrosis of the pericentral sinusoids. In this study, we aimed to establish a mouse model of RILD to investigate the underlying mechanism of radiation-induced liver fibrosis.
Using a small animal image-guided radiation therapy platform, an irradiation scheme delivering 50 Gy as a single dose to a focal point in mouse livers was designed. Tissues were analyzed 1 and 6 days, and 6 and 20 weeks post-irradiation. Irradiated livers were assessed by histology, immunohistochemistry, imaging mass cytometry and RNA sequencing. Mitochondrial function was assessed using high-resolution respirometry.
At 6 and 20 weeks post-irradiation, pericentral fibrosis was visible in highly irradiated areas together with immune cell infiltration and extravasation of red blood cells. RNA sequencing analysis showed gene signatures associated with acute DNA damage, p53 activation, senescence and its associated secretory phenotype and fibrosis. Moreover, gene profiles of mitochondrial damage and an increase in mitochondrial DNA heteroplasmy were detected. Respirometry measurements of hepatocytes in vitro confirmed irradiation-induced mitochondrial dysfunction. Finally, the highly irradiated fibrotic areas showed markers of reactive oxygen species such as decreased glutathione and increased lipid peroxides and a senescence-like phenotype.
Based on our mouse model of RILD, we propose that irradiation-induced mitochondrial DNA instability contributes to the development of fibrosis via the generation of excessive reactive oxygen species, p53 pathway activation and a senescence-like phenotype.
Irradiation is an efficient cancer therapy, however, its applicability to the liver is limited by life-threatening radiation-induced hepatic fibrosis. We have developed a new mouse model of radiation-induced liver fibrosis, that recapitulates the human disease. Our model highlights the role of mitochondrial DNA instability in the development of irradiation-induced liver fibrosis. This new model and subsequent findings will help increase our understanding of the hepatic reaction to irradiation and to find strategies that protect the liver, enabling the expanded use of radiotherapy to treat hepatic tumors.
Keywords
4HNE, 4-hydroxynonenal, CV, central vein, ECM, extracellular matrix, ETC, electron transfer chain, GSH, reduced glutathione (glutathione), GSSG, oxidized glutathione (glutathione disulfide), HSCs, hepatic stellate cells, IGRT, image-guided radiation therapy, IHC, immunohistochemistry, IMC, imaging mass cytometry, MDA, malondialdehyde, RILD, radiation-induced liver disease, RNAseq, RNA sequencing, ROS, ROS, reactive oxygen species, RT, radiation therapy, SASP, senescence-associated secretory phenotype, SNP, single nucleotide polymorphism, SOS, sinusoidal obstruction syndrome, fibrosis, image guided radiation therapy (IGRT), mitochondrial dysfunction, mitochondrial-DNA, mouse model, mtDNA, mitochondrial DNA, mtROS, mitochondrial reactive oxygen species, p53, radiation-induced liver disease (RILD), rcf, relative centrifuge force, senescence, sinusoidal obstruction syndrome
Pubmed
Open Access
Yes
Create date
05/07/2022 11:27
Last modification date
15/07/2022 6:36
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