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The Role of Sirtuin 3 in Radiation-Induced Long-Term Persistent Liver Injury.

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-1?, TGF-?) and fibrotic factors (Procollagen 1, ?-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.

SUBMITTER: LoBianco FV

PROVIDER: S-EPMC7278565 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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The Role of Sirtuin 3 in Radiation-Induced Long-Term Persistent Liver Injury.

LoBianco Francesca V FV Krager Kimberly J KJ Carter Gwendolyn S GS Alam Sinthia S Yuan Youzhong Y Lavoie Elise G EG Dranoff Jonathan A JA Aykin-Burns Nukhet N

Antioxidants (Basel, Switzerland) 20200511 5

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<sup>-/-</sup> and Sirt3< ...[more]

PMID: 32403251

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Project description:BackgroundA higher-than-usual resistance to standard sedation regimens in COVID-19 patients suffering from acute respiratory distress syndrome (ARDS) has led to the frequent use of the second-line anaesthetic agent ketamine. Simultaneously, an increased incidence of cholangiopathies in mechanically ventilated patients receiving prolonged infusion of high-dose ketamine has been noted. Therefore, the objective of this study was to investigate a potential dose-response relationship between ketamine and bilirubin levels.MethodsPost hoc analysis of a prospective observational cohort of patients suffering from COVID-19-associated ARDS between March 2020 and August 2021. A time-varying, multivariable adjusted, cumulative weighted exposure mixed-effects model was employed to analyse the exposure-effect relationship between ketamine infusion and total bilirubin levels.ResultsTwo-hundred forty-three critically ill patients were included into the analysis. Ketamine was infused to 170 (70%) patients at a rate of 1.4 [0.9-2.0] mg/kg/h for 9 [4-18] days. The mixed-effects model revealed a positively correlated infusion duration-effect as well as dose-effect relationship between ketamine infusion and rising bilirubin levels (p < 0.0001). In comparison, long-term infusion of propofol and sufentanil, even at high doses, was not associated with increasing bilirubin levels (p = 0.421, p = 0.258). Patients having received ketamine infusion had a multivariable adjusted competing risk hazard of developing a cholestatic liver injury during their ICU stay of 3.2 [95% confidence interval, 1.3-7.8] (p = 0.01).ConclusionsA causally plausible, dose-effect relationship between long-term infusion of ketamine and rising total bilirubin levels, as well as an augmented, ketamine-associated, hazard of cholestatic liver injury in critically ill COVID-19 patients could be shown. High-dose ketamine should be refrained from whenever possible for the long-term analgosedation of mechanically ventilated COVID-19 patients.

Dataset Information

The Role of Sirtuin 3 in Radiation-Induced Long-Term Persistent Liver Injury.

Publications

The Role of Sirtuin 3 in Radiation-Induced Long-Term Persistent Liver Injury.

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