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Anthracyclines Induce DNA Damage Response-Mediated Protection against Severe Sepsis

Figueiredo, Nuno and Zhao, Jimmy L. and Baltimore, David (2013) Anthracyclines Induce DNA Damage Response-Mediated Protection against Severe Sepsis. Immunity, 39 (5). pp. 874-884. ISSN 1074-7613. PMCID PMC3968948. doi:10.1016/j.immuni.2013.08.039. https://resolver.caltech.edu/CaltechAUTHORS:20140306-114228881

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


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1016/j.immuni.2013.08.039DOIArticle
http://www.sciencedirect.com/science/article/pii/S1074761313004652PublisherArticle
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3968948/PubMed CentralArticle
ORCID:
AuthorORCID
Baltimore, David0000-0001-8723-8190
Additional Information:© 2013 Elsevier Inc. Received: February 22, 2013. Accepted: August 13, 2013. Published: October 31, 2013. We are grateful to Vasco Barreto for Atm-/- and Frederick Alt for Atm^(loxP/loxP) mice. We thank Mario Ramirez for bacterial strains to probe epirubicin protection in different models of sepsis. The authors greatly appreciate the critical contribution of Professor Gerd Döring, who sadly passed away before the publication of this manuscript. L.F.M. receives support from FLAD and FCT (grants PTDC/SAU-IMU/110303/2009, PTDC/SAU-MII/100780/2008, and PTDC/SAU-IMU/110303/2009), A.C. receives support from FCT (PTDC/SAU-IMU/110303/2009), J.A.F. receives support from a Gulbenkian grant (96526/2009), and P.P. is an FCT fellow (SFRH/BD/45502/2008).
Funders:
Funding AgencyGrant Number
FLADUNSPECIFIED
Fundação para a Ciência e a Tecnologia (FCT)PTDC/SAU-IMU/110303/2009
Fundação para a Ciência e a Tecnologia (FCT)PTDC/SAU-MII/100780/2008
Fundação Calouste Gulbenkian96526/2009
Fundação para a Ciência e a Tecnologia (FCT)SFRH/BD/45502/2008
Issue or Number:5
PubMed Central ID:PMC3968948
DOI:10.1016/j.immuni.2013.08.039
Record Number:CaltechAUTHORS:20140306-114228881
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20140306-114228881
Official Citation:Nuno Figueiredo, Angelo Chora, Helena Raquel, Nadja Pejanovic, Pedro Pereira, Björn Hartleben, Ana Neves-Costa, Catarina Moita, Dora Pedroso, Andreia Pinto, Sofia Marques, Hafeez Faridi, Paulo Costa, Raffaella Gozzelino, Jimmy L. Zhao, Miguel P. Soares, Margarida Gama-Carvalho, Jennifer Martinez, Qingshuo Zhang, Gerd Döring, Markus Grompe, J. Pedro Simas, Tobias B. Huber, David Baltimore, Vineet Gupta, Douglas R. Green, João A. Ferreira, Luis F. Moita, Anthracyclines Induce DNA Damage Response-Mediated Protection against Severe Sepsis, Immunity, Volume 39, Issue 5, 14 November 2013, Pages 874-884, ISSN 1074-7613, http://dx.doi.org/10.1016/j.immuni.2013.08.039. (http://www.sciencedirect.com/science/article/pii/S1074761313004652)
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:44182
Collection:CaltechAUTHORS
Deposited By: Ruth Sustaita
Deposited On:06 Mar 2014 21:13
Last Modified:10 Nov 2021 16:48

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