Anthracyclines Induce DNA Damage Response-Mediated Protection against Severe Sepsis

被引：140

作者：

Figueiredo, Nuno ^{[1
,2
,3
,4
]}

Chora, Angelo ^{[1
]}

Raquel, Helena ^{[1
]}

Pejanovic, Nadja ^{[1
]}

Pereira, Pedro ^{[1
]}

Hartleben, Bjoern ^{[5
]}

Neves-Costa, Ana ^{[1
]}

Moita, Catarina ^{[1
]}

Pedroso, Dora ^{[1
]}

Pinto, Andreia ^{[1
]}

Marques, Sofia ^{[1
]}

Faridi, Hafeez ^{[6
]}

Costa, Paulo ^{[2
]}

Gozzelino, Raffaella ^{[7
]}

Zhao, Jimmy L. ^{[8
]}

Soares, Miguel P. ^{[7
]}

Gama-Carvalho, Margarida ^{[9
]}

Martinez, Jennifer ^{[10
]}

Zhang, Qingshuo ^{[11
]}

Doering, Gerd ^{[12
]}

Grompe, Markus ^{[11
]}

Pedro Simas, J. ^{[1
]}

Huber, Tobias B. ^{[5
]}

Baltimore, David ^{[8
]}

Gupta, Vineet ^{[6
]}

Green, Douglas R. ^{[10
]}

Ferreira, Joao A. ^{[1
]}

Moita, Luis F. ^{[1
,13
]}

机构：

[1] Univ Lisbon, Fac Med, Inst Mol Med, P-1649028 Lisbon, Portugal

[2] Ctr Hosp Lisboa Norte, EPE, Clin Univ Cirurgia 1, P-1649028 Lisbon, Portugal

[3] Gulbenkian Programme Adv Med Educ, P-2780156 Oeiras, Portugal

[4] Champalimaud Fdn, P-1400038 Lisbon, Portugal

[5] Univ Hosp Freiburg, Div Renal, D-79106 Freiburg, Germany

[6] Rush Univ, Dept Internal Med, Med Ctr, Chicago, IL 60612 USA

[7] Inst Gulbenkian Ciencias, P-2780156 Oeiras, Portugal

[8] CALTECH, Div Biol, Pasadena, CA 91125 USA

[9] Univ Lisbon, Fac Ciencias, Ctr Biodiversidade Genom Func & Integrat BioFIG, P-1749016 Lisbon, Portugal

[10] St Jude Childrens Res Hosp, Dept Immunol, Memphis, TN 38105 USA

[11] Oregon Hlth & Sci Univ, Dept Pediat, Oregon Stem Cell Ctr, Portland, OR 97239 USA

[12] Univ Tubingen, Inst Med Mikrobiol & Hyg, D-72076 Tubingen, Germany

[13] Lisbon Acad Med Ctr, Clin Res Ctr, P-1649028 Lisbon, Portugal

来源：

IMMUNITY | 2013年 / 39卷 / 05期

关键词：

SEPTIC SHOCK; AUTOPHAGY; RESISTANCE; TOLERANCE; EPIDEMIOLOGY; NECROSIS; DOXORUBICIN; ACTIVATION; INFECTION; SURVIVAL;

D O I：

10.1016/j.immuni.2013.08.039

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

071005 [微生物学]; 100108 [医学免疫学];

摘要：

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.

引用

页码：874 / 884

页数：11

共 53 条

[1]

ATM engages the TSC2/mTORC1 signaling node to regulate autophagy [J].

Alexander, Angela ;

Kim, Jinhee ;

Walker, Cheryl L. .

AUTOPHAGY, 2010, 6 (05) :672-673

[2]

ATM signals to TSC2 in the cytoplasm to regulate mTORC1 in response to ROS [J].

Alexander, Angela ;

Cai, Sheng-Li ;

Kim, Jinhee ;

Nanez, Adrian ;

Sahin, Mustafa ;

MacLean, Kirsteen H. ;

Inoki, Ken ;

Guan, Kun-Liang ;

Shen, Jianjun ;

Person, Maria D. ;

Kusewitt, Donna ;

Mills, Gordon B. ;

Kastan, Michael B. ;

Walker, Cheryl Lyn .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2010, 107 (09) :4153-4158

[3]

Epidemiology of severe sepsis in the United States: Analysis of incidence, outcome, and associated costs of care [J].

Angus, DC ;

Linde-Zwirble, WT ;

Lidicker, J ;

Clermont, G ;

Carcillo, J ;

Pinsky, MR .

CRITICAL CARE MEDICINE, 2001, 29 (07) :1303-1310

[4]

Current epidemiology of septic shock - The CUB-Rea network [J].

Annane, D ;

Aegerter, P ;

Jars-Guincestre, MC ;

Guidet, B .

AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 2003, 168 (02) :165-172

[5]

miR-146a is a significant brake on autoimmunity, myeloproliferation, and cancer in mice [J].

Boldin, Mark P. ;

Taganov, Konstantin D. ;

Rao, Dinesh S. ;

Yang, Lili ;

Zhao, Jimmy L. ;

Kalwani, Manorama ;

Garcia-Flores, Yvette ;

Luong, Mui ;

Devrekanli, Asli ;

Xu, Jessica ;

Sun, Guizhen ;

Tay, Jia ;

Linsley, Peter S. ;

Baltimore, David .

JOURNAL OF EXPERIMENTAL MEDICINE, 2011, 208 (06) :1189-1201

[6]

THE ACCP-SCCM CONSENSUS CONFERENCE ON SEPSIS AND ORGAN FAILURE [J].

BONE, RC ;

SIBBALD, WJ ;

SPRUNG, CL .

CHEST, 1992, 101 (06) :1481-1482

[7]

Autophagy Suppresses RIP Kinase-Dependent Necrosis Enabling Survival to mTOR Inhibition [J].

Bray, Kevin ;

Mathew, Robin ;

Lau, Alexandria ;

Kamphorst, Jurre J. ;

Fan, Jing ;

Chen, Jim ;

Chen, Hsin-Yi ;

Ghavami, Anahita ;

Stein, Mark ;

DiPaola, Robert S. ;

Zhang, Donna ;

Rabinowitz, Joshua D. ;

White, Eileen .

PLOS ONE, 2012, 7 (07)

[8]

Aberrant activation of stress-response pathways leads to TNF-α oversecretion in Fanconi anemia [J].

Briot, Delphine ;

Mace-Aime, Gaetane ;

Subra, Frederic ;

Rosselli, Filippo .

BLOOD, 2008, 111 (04) :1913-1923

[9]

SUPPRESSION OF AUTOPHAGY IN RAT LIVER AT LATE STAGE OF POLYMICROBIAL SEPSIS [J].

Chien, Wei-Shan ;

Chen, Yen-Hsu ;

Chiang, Pei-Chi ;

Hsiao, Hsiu-Wen ;

Chuang, Shu-Mien ;

Lue, Sheng-I ;

Hsu, Chin .

SHOCK, 2011, 35 (05) :506-511

[10]

The DNA Damage Response: Making It Safe to Play with Knives [J].

Ciccia, Alberto ;

Elledge, Stephen J. .

MOLECULAR CELL, 2010, 40 (02) :179-204

← 1 2 3 4 5 6 →