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Anthracyclines induce DNA damage response-mediated protection against severe sepsis.
- Source :
-
Immunity [Immunity] 2013 Nov 14; Vol. 39 (5), pp. 874-84. Date of Electronic Publication: 2013 Oct 31. - Publication Year :
- 2013
-
Abstract
- Severe sepsis remains a poorly understood systemic inflammatory condition with high mortality rates and limited therapeutic options in addition to organ support measures. Here we show that the clinically approved group of anthracyclines acts therapeutically at a low dose regimen to confer robust protection against severe sepsis in mice. This salutary effect is strictly dependent on the activation of DNA damage response and autophagy pathways in the lung, as demonstrated by deletion of the ataxia telangiectasia mutated (Atm) or the autophagy-related protein 7 (Atg7) specifically in this organ. The protective effect of anthracyclines occurs irrespectively of pathogen burden, conferring disease tolerance to severe sepsis. These findings demonstrate that DNA damage responses, including the ATM and Fanconi Anemia pathways, are important modulators of immune responses and might be exploited to confer protection to inflammation-driven conditions, including severe sepsis.<br /> (Copyright © 2013 Elsevier Inc. All rights reserved.)
- Subjects :
- Adenoviridae Infections immunology
Animals
Anthracyclines therapeutic use
Anti-Bacterial Agents therapeutic use
Ataxia Telangiectasia Mutated Proteins deficiency
Ataxia Telangiectasia Mutated Proteins physiology
Autophagy-Related Protein 7
Cecum injuries
DNA Damage
Epirubicin administration & dosage
Epirubicin pharmacology
Epirubicin therapeutic use
Fanconi Anemia Complementation Group D2 Protein physiology
Inflammation
Inflammation Mediators analysis
Injections, Intraperitoneal
Lung metabolism
Meropenem
Mice
Mice, Inbred C57BL
Microtubule-Associated Proteins deficiency
Microtubule-Associated Proteins physiology
Organ Specificity
Peritonitis etiology
Peritonitis genetics
Peritonitis immunology
Peritonitis physiopathology
Respiratory Tract Infections immunology
Shock, Septic prevention & control
Thienamycins therapeutic use
Whole-Body Irradiation
Anthracyclines pharmacology
Anti-Bacterial Agents pharmacology
DNA Repair drug effects
Lung drug effects
Peritonitis drug therapy
Sepsis prevention & control
Subjects
Details
- Language :
- English
- ISSN :
- 1097-4180
- Volume :
- 39
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Immunity
- Publication Type :
- Academic Journal
- Accession number :
- 24184056
- Full Text :
- https://doi.org/10.1016/j.immuni.2013.08.039