Anthracyclines Induce DNA Damage Response-Mediated Protection against Severe Sepsis

作者：Figueiredo Nuno; Chora Angelo; Raquel Helena; Pejanovic Nadja; Pereira Pedro; Hartleben Bjoern; Neves Costa Ana; Moita Catarina; Pedroso Dora; Pinto Andreia; Marques Sofia; Faridi Hafeez; Costa Paulo; Gozzelino Raffaella; Zhao Jimmy L; Soares Miguel P; Gama Carvalho Margarida; Martinez Jennifer; Zhang Qingshuo; Doering Gerd; Grompe Markus; Pedro Simas J; Huber Tobias B; Baltimore David; Gupta Vineet; Green Douglas R; Ferreira Joao A; Moita Luis F^*

来源：Immunity, 2013, 39(5): 874-884.

DOI：10.1016/j.immuni.2013.08.039

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 Fancony Anemia pathways, are important modulators of immune responses and might be exploited to confer protection to inflammation-driven conditions, including severe sepsis.

• 出版日期2013-11-14
• 单位河北医科大学