title: Anthracyclines induce DNA damage response-mediated protection against severe sepsis.
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.
authors.affiliation: 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.
authors.forename: Nuno
authors.initials: N
authors.lastname: Figueiredo
authors.forename: Angelo
authors.initials: A
authors.lastname: Chora
authors.forename: Helena
authors.initials: H
authors.lastname: Raquel
authors.forename: Nadja
authors.initials: N
authors.lastname: Pejanovic
authors.forename: Pedro
authors.initials: P
authors.lastname: Pereira
authors.forename: Björn
authors.initials: B
authors.lastname: Hartleben
authors.forename: Ana
authors.initials: A
authors.lastname: Neves-Costa
authors.forename: Catarina
authors.initials: C
authors.lastname: Moita
authors.forename: Dora
authors.initials: D
authors.lastname: Pedroso
authors.forename: Andreia
authors.initials: A
authors.lastname: Pinto
authors.forename: Sofia
authors.initials: S
authors.lastname: Marques
authors.forename: Hafeez
authors.initials: H
authors.lastname: Faridi
authors.forename: Paulo
authors.initials: P
authors.lastname: Costa
authors.forename: Raffaella
authors.initials: R
authors.lastname: Gozzelino
authors.forename: Jimmy L
authors.initials: JL
authors.lastname: Zhao
authors.forename: Miguel P
authors.initials: MP
authors.lastname: Soares
authors.forename: Margarida
authors.initials: M
authors.lastname: Gama-Carvalho
authors.forename: Jennifer
authors.initials: J
authors.lastname: Martinez
authors.forename: Qingshuo
authors.initials: Q
authors.lastname: Zhang
authors.forename: Gerd
authors.initials: G
authors.lastname: Döring
authors.forename: Markus
authors.initials: M
authors.lastname: Grompe
authors.forename: J Pedro
authors.initials: JP
authors.lastname: Simas
authors.forename: Tobias B
authors.initials: TB
authors.lastname: Huber
authors.forename: David
authors.initials: D
authors.lastname: Baltimore
authors.forename: Vineet
authors.initials: V
authors.lastname: Gupta
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Green
authors.forename: João A
authors.initials: JA
authors.lastname: Ferreira
authors.forename: Luis F
authors.initials: LF
authors.lastname: Moita
mesh_terms: D000257:Adenoviridae Infections / Q000276:immunology; D000818:Animals; D018943:Anthracyclines / Q000494:pharmacology* / Q000627:therapeutic use; D000900:Anti-Bacterial Agents / Q000494:pharmacology* / Q000627:therapeutic use; D064007:Ataxia Telangiectasia Mutated Proteins / Q000172:deficiency / Q000502:physiology; D000071193:Autophagy-Related Protein 7; D002432:Cecum / Q000293:injuries; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects*; D015251:Epirubicin / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000502:physiology; D007249:Inflammation; D018836:Inflammation Mediators / Q000032:analysis; D007274:Injections, Intraperitoneal; D008168:Lung / Q000187:drug effects* / Q000378:metabolism; D000077731:Meropenem; D051379:Mice; D008810:Mice, Inbred C57BL; D008869:Microtubule-Associated Proteins / Q000172:deficiency / Q000502:physiology; D009928:Organ Specificity; D010538:Peritonitis / Q000188:drug therapy* / Q000209:etiology / Q000235:genetics / Q000276:immunology / Q000503:physiopathology; D012141:Respiratory Tract Infections / Q000276:immunology; D018805:Sepsis / Q000517:prevention & control*; D012772:Shock, Septic / Q000517:prevention & control; D013845:Thienamycins / Q000627:therapeutic use; D014916:Whole-Body Irradiation
chemical_list: D018943:Anthracyclines; D000900:Anti-Bacterial Agents; C502661:Atg7 protein, mouse; C499904:Fancd2 protein, mouse; D052236:Fanconi Anemia Complementation Group D2 Protein; D018836:Inflammation Mediators; D008869:Microtubule-Associated Proteins; D013845:Thienamycins; D015251:Epirubicin; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D000071193:Autophagy-Related Protein 7; D000077731:Meropenem