Radiation-induced liver disease: beyond DNA damage

Abstract

Radiation-induced liver disease (RILD), also known as radiation hepatitis, is a serious side effect of radiotherapy (RT) for hepatocellular carcinoma. The therapeutic dose of RT can damage normal liver tissue, and the toxicity that accumulates around the irradiated liver tissue is related to numerous physiological and pathological processes. RILD may restrict treatment use or eventually deteriorate into liver fibrosis. However, the research on the mechanism of radiation-induced liver injury has seen little progress compared with that on radiation injury in other tissues, and no targeted clinical pharmacological treatment for RILD exists. The DNA damage response caused by ionizing radiation plays an important role in the pathogenesis and development of RILD. Therefore, in this review, we systematically summarize the molecular and cellular mechanisms involved in RILD. Such an analysis is essential for preventing the occurrence and development of RILD and further exploring the potential treatment of this disease.

Keywords: DNA damage; Radiation-induced liver injury; ionizing radiation; molecular and cellular mechanism.

Figure 1.

After IR exposure, DNA damage induces the formation of DNA strands, including ssDNA, dsDNA, and CDD (multiple damage sites) in the nucleus and direct damage to DNA. Water molecule ionizing inflicts induces the production of ROS.ATM: ataxia telangiectasia mutation; ATR: ataxia telangiectasia is related to rad3; DNA-PKcs: DNA-dependent protein kinase catalytic subunit; ATRIP: ATR interacting protein; ETAA1: Ewing tumor-associated antigen; TopBP1: topoisomerase II binding protein; 53bp1: p53 binding protein 1; γH2AX: phosphorylated histone H2AX; JNK: c-Jun amino terminal kinase; Rad51ap1:rad51 associated protein-1; HDAC4: histone deacetylase 4; Ubc9: ubiquitin-binding enzyme 9; TGF-α: transforming growth factor α; TNF-α: tumor necrosis factor α.

Figure 2.

Mitochondria are the main targets of radiation-mediated cytotoxic effects. IR inhibits the transmission of the etc during OXPHOS by changing membrane permeability, resulting in the production of excess superoxides. The long-term production of excess superoxides promotes the generation of a large number of endogenous ROS by other pro-oxidases. In living organisms, radiation induces hydrolysis to generate •OH, resulting in a significant increase in the level of exogenous ROS and thereby prompting mitochondrial dysfunction, stimulating MtROS production, and inducing cellular senescence and apoptosis. OXPHOS: oxidative phosphorylation; ETC: electronic transient chain; • OH: hydroxyl radicals; ROS: reactive oxygen species; MtROS: mitochondrial ROS; RONS: reactive oxygen species and nitrogen species; SIRT3: sirtuin 3; SIRT1: sirtuin 1; SOD2: manganese superoxide dismutase; SHP-1: SH2-containing protein tyrosine phosphatase; BCL-2: B-cell lymphoma-2; ATR: recombinant ataxia telangiectasia and Rad3-related protein; ATM: ataxia–telangiectasia mutated proteins; TDG: thymine DNA glycosylase; NBS1: Nijmegen breakage syndrome protein 1; XPA: Xeroderma pigmentosum gene A; c-MYC: cell-MYC.

Figure 3.

Morphological changes in postradiation LSECs. Hepatocytes and hepatic sinus-like endothelial cells are spatially separated by the Disse space, a narrow gap between hepatocytes and blood sinus endothelial cells that also contains ECM. LSECs disappear in the window of the Disse gap and capillaries are formed, while secreting fibronectin EIIIA promotes the activation of HSC and forms a basement membrane. KCs are activated and release inflammatory factors.

Figure 4.

After radiation, hepatocytes interact with NPCs, activate the inflammatory response, and participate in the development of RILD. Radiation directly induces various damages in hepatocytes through oxidative stress and inflammatory response and activates LSECs, KCs, and HSCs by secreting inflammatory factors and growth factors, prompting these cells to secrete TNF-α and TGF-β, which play an important role in RILF. TNF α: tumor necrosis factor α; TGF-α: transformational growth factor α; RIBE: radiation-induced bystander effects; ROS: reactive oxygen species; NOS: reactive nitrogen species; DDR: DNA damage response; IL-1β:interleukin 1β; IL-18: Interleukin 18; IL-6: Interleukin 6; EIIA: fibronectin secretion; TLR4: Toll-like receptor 4; HGF: hepatocyte growth factor; TNFR1: tumor necrosis factor receptor 1; RAC1: Ras-associated C3 Botulinum toxin substrate 1; LPO: lipid peroxidation; Hh: Hedgehog.