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Immunity. 2013 Nov 14;39(5):874-84. doi: 10.1016/j.immuni.2013.08.039. Epub 2013 Oct 31.

Anthracyclines induce DNA damage response-mediated protection against severe sepsis.

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1
Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisboa, Portugal; Clínica Universitária de Cirurgia I, Centro Hospitalar Lisboa Norte, EPE, 1649-028 Lisboa, Portugal; Gulbenkian Programme for Advanced Medical Education, 2780-156 Oeiras, Portugal; Champalimaud Foundation, 1400-038 Lisboa, Portugal.

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.

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PMID:
24184056
PMCID:
PMC3968948
DOI:
10.1016/j.immuni.2013.08.039
[Indexed for MEDLINE]

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