Abstract
In patients with abdominal region cancers, ionizing radiation (IR)-induced long-term liver injury is a major limiting factor in the use of radiotherapy. Previously, the major mitochondrial deacetylase, sirtuin 3 (SIRT3), has been implicated to play an important role in the development of acute liver injury after total body irradiation but no studies to date have examined the role of SIRT3 in liver’s chronic response to radiation. In the current study, ten-month-old Sirt3−/− and Sirt3+/+ male mice received 24 Gy radiation targeted to liver. Six months after exposure, irradiated Sirt3−/− mice livers demonstrated histopathological elevations in inflammatory infiltration, the loss of mature bile ducts and higher DNA damage (TUNEL) as well as protein oxidation (3-nitrotyrosine). In addition, increased expression of inflammatory chemokines (IL-6, IL-1β, TGF-β) and fibrotic factors (Procollagen 1, α-SMA) were also measured in Sirt3−/− mice following 24 Gy IR. The alterations measured in enzymatic activities of catalase, glutathione peroxidase, and glutathione reductase in the livers of irradiated Sirt3−/− mice also implied that hydrogen peroxide and hydroperoxide sensitive signaling cascades in the absence of SIRT3 might contribute to the IR-induced long-term liver injury.
Highlights
The lifetime probability of males developing an invasive cancer is 42% and for females, 38%.Approximately 50% of all cancer cases benefit from radiation therapy [1]
These increases in inflammatory chemokines and profibrotic factors could contribute to the removal of necrotic tissue after irradiation and stimulate extracellular matrix deposits that assist in regeneration
In our targeted irradiation model, we found that there was a significant increase in TGF-β, IL-1β, and IL-6 mRNA expression, suggesting a persistent inflammatory response and continuous liver injury progression 6 months after treatment in the absence of sirtuin 3 (SIRT3)
Summary
The lifetime probability of males developing an invasive cancer is 42% and for females, 38%.Approximately 50% of all cancer cases benefit from radiation therapy [1]. More than 333,000 new cases of abdominal-region cancers are expected in the U.S alone in 2020 [1], and a serious limitation to radiation therapy for these cancers is the possibility of irradiating the liver [2,3,4]. Clinical studies showed that IR-induced liver pathologies could be observed within 3 months of IR, even with IR doses as low as 30 Gy [10]. Previous clinical studies have shown patients can develop radiation damage within three months post-irradiation, which is caused by a veno-occlusive process. Fibrin accumulation of central veins and sinusoids followed by collagen deposition increases, resulting in increased portal pressure. These clinical manifestations have been termed “radiation-induced liver disease (RILD)”, which could
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