Melin 2022 JHEP Rep

Melin N, Yarahmadov T, Sanchez-Taltavull D, Birrer FE, Brodie TM, Petit B, Felser A, Nuoffer JM, Montani M, Vozenin MC, Herrmann E, Candinas D, Aebersold DM, Stroka D (2022) A new mouse model of radiation-induced liver disease reveals mitochondrial dysfunction as an underlying fibrotic stimulus. https://doi.org/10.1016/j.jhepr.2022.100508

» JHEP Rep 4:100508. PMID: 35712694 Open Access

Melin Nicolas,  Yarahmadov Tural,  Sanchez-Taltavull Daniel,  Birrer Fabienne E,  Brodie Tess M,  Petit Benoit,  Felser Andrea,  Nuoffer Jean-Marc,  Montani Matteo,  Vozenin Marie-Catherine,  Herrmann Evelyn,  Candinas Daniel,  Aebersold Daniel M,  Stroka Deborah (2022) JHEP Rep

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. • 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 • Bioblast editor: Plangger M

Labels: MiParea: Respiration  Pathology: Other 

Organism: Mouse  Tissue;cell: Liver  Preparation: Permeabilized cells 

HRR: Oxygraph-2k 

2022-11