{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T22:28:36Z","timestamp":1791412116481,"version":"4.3.3"},"reference-count":63,"publisher":"Public Library of Science (PLoS)","issue":"10","license":[{"start":{"date-parts":[[2014,10,20]],"date-time":"2014-10-20T00:00:00Z","timestamp":1413763200000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"DOI":"10.1371\/journal.pone.0110183","type":"journal-article","created":{"date-parts":[[2014,10,20]],"date-time":"2014-10-20T22:05:58Z","timestamp":1413842758000},"page":"e110183","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":22,"title":["The \u201cGenomic Storm\u201d Induced by Bacterial Endotoxin Is Calmed by a Nuclear Transport Modifier That Attenuates Localized and Systemic Inflammation"],"prefix":"10.1371","volume":"9","author":[{"given":"Antonio","family":"DiGiandomenico","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruth Ann","family":"Veach","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jozef","family":"Zienkiewicz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel J.","family":"Moore","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lukasz S.","family":"Wylezinski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martha A.","family":"Hutchens","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacek","family":"Hawiger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2014,10,20]]},"reference":[{"key":"ref1","unstructured":"Rosenberg HF, Gallin JI (2003) Inflammation. In: Paul WE, editor. Fundamental Immunology. 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins. pp. p. 1151\u20131169."},{"key":"ref2","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1016\/j.molimm.2003.10.005","article-title":"Innate immunity: an overview","volume":"40","author":"B Beutler","year":"2004","journal-title":"Mol Immunol"},{"key":"ref3","doi-asserted-by":"crossref","first-page":"S70","DOI":"10.1016\/j.ijantimicag.2010.11.008","article-title":"New perspectives on immunomodulatory therapy for bacteraemia and sepsis","volume":"36","author":"SM Opal","year":"2010","journal-title":"Int J Antimicrob Agents"},{"key":"ref4","doi-asserted-by":"crossref","first-page":"1399","DOI":"10.1182\/blood-2008-07-019307","article-title":"TLRs and innate immunity","volume":"113","author":"BA Beutler","year":"2009","journal-title":"Blood"},{"key":"ref5","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1385\/IR:23:2-3:099","article-title":"Innate immunity and inflammation: a transcriptional paradigm","volume":"23","author":"J Hawiger","year":"2001","journal-title":"Immunol Res"},{"key":"ref6","doi-asserted-by":"crossref","first-page":"e000093","DOI":"10.1161\/JAHA.113.000093","article-title":"Nuclear transport modulation reduces hypercholesterolemia, atherosclerosis, and fatty liver","volume":"2","author":"Y Liu","year":"2013","journal-title":"J Am Heart Assoc"},{"key":"ref7","doi-asserted-by":"crossref","first-page":"6084","DOI":"10.4049\/jimmunol.161.11.6084","article-title":"Regulation of NF-kappa B, AP-1, NFAT, and STAT1 nuclear import in T lymphocytes by noninvasive delivery of peptide carrying the nuclear localization sequence of NF-kappa B p50","volume":"161","author":"TR Torgerson","year":"1998","journal-title":"J Immunol"},{"key":"ref8","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1016\/S0092-8674(03)00082-5","article-title":"Regulating access to the genome: nucleocytoplasmic transport throughout the cell cycle","volume":"112","author":"K Weis","year":"2003","journal-title":"Cell"},{"key":"ref9","doi-asserted-by":"crossref","first-page":"e000386","DOI":"10.1161\/JAHA.113.000386","article-title":"Targeting nuclear import shuttles, importins\/karyopherins alpha by a peptide mimicking the NFkappaB1\/p50 nuclear localization sequence","volume":"2","author":"J Zienkiewicz","year":"2013","journal-title":"J Am Heart Assoc"},{"key":"ref10","doi-asserted-by":"crossref","first-page":"2581","DOI":"10.1084\/jem.20111354","article-title":"A genomic storm in critically injured humans","volume":"208","author":"W Xiao","year":"2011","journal-title":"J Exp Med"},{"key":"ref11","doi-asserted-by":"crossref","first-page":"840","DOI":"10.1056\/NEJMra1208623","article-title":"Severe sepsis and septic shock","volume":"369","author":"DC Angus","year":"2013","journal-title":"N Engl J Med"},{"key":"ref12","doi-asserted-by":"crossref","first-page":"1007","DOI":"10.1186\/cc10482","article-title":"How to approach genome wars in sepsis?","volume":"15","author":"J Hawiger","year":"2011","journal-title":"Crit Care"},{"key":"ref13","doi-asserted-by":"crossref","first-page":"1589","DOI":"10.1097\/01.CCM.0000217961.75225.E9","article-title":"Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock","volume":"34","author":"A Kumar","year":"2006","journal-title":"Crit Care Med"},{"key":"ref14","doi-asserted-by":"crossref","first-page":"1","DOI":"10.7326\/0003-4819-76-1-1","article-title":"Gram-negative sepsis: detection of endotoxemia with the limulus test. With studies of associated changes in blood coagulation, serum lipids, and complement","volume":"76","author":"J Levin","year":"1972","journal-title":"Ann Intern Med"},{"key":"ref15","doi-asserted-by":"crossref","first-page":"e97673","DOI":"10.1371\/journal.pone.0097673","article-title":"Cytokine and nitric oxide levels in patients with sepsis - temporal evolvement and relation to platelet mitochondrial respiratory function","volume":"9","author":"F Sjovall","year":"2014","journal-title":"PLoS One"},{"key":"ref16","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1097\/01.shk.0000191343.21228.78","article-title":"Neutralization of tumor necrosis factor in preclinical models of sepsis","volume":"24","author":"JA Lorente","year":"2005","journal-title":"Shock"},{"key":"ref17","doi-asserted-by":"crossref","first-page":"5939","DOI":"10.1073\/pnas.76.11.5939","article-title":"Galactosamine-induced sensitization to the lethal effects of endotoxin","volume":"76","author":"C Galanos","year":"1979","journal-title":"Proc Natl Acad Sci U S A"},{"key":"ref18","doi-asserted-by":"crossref","first-page":"796","DOI":"10.1038\/mt.2009.18","article-title":"Suppression of acute lung inflammation by intracellular peptide delivery of a nuclear import inhibitor","volume":"17","author":"D Liu","year":"2009","journal-title":"Mol Ther"},{"key":"ref19","doi-asserted-by":"crossref","first-page":"14255","DOI":"10.1074\/jbc.270.24.14255","article-title":"Inhibition of nuclear translocation of transcription factor NF-kappa B by a synthetic peptide containing a cell membrane-permeable motif and nuclear localization sequence","volume":"270","author":"YZ Lin","year":"1995","journal-title":"J Biol Chem"},{"key":"ref20","doi-asserted-by":"crossref","first-page":"11425","DOI":"10.1074\/jbc.M311089200","article-title":"Receptor\/transporter-independent targeting of functional peptides across the plasma membrane","volume":"279","author":"RA Veach","year":"2004","journal-title":"J Biol Chem"},{"key":"ref21","doi-asserted-by":"crossref","first-page":"16774","DOI":"10.1074\/jbc.C000083200","article-title":"Peptide-directed suppression of a pro-inflammatory cytokine response","volume":"275","author":"XY Liu","year":"2000","journal-title":"J Biol Chem"},{"key":"ref22","doi-asserted-by":"crossref","first-page":"48434","DOI":"10.1074\/jbc.M407190200","article-title":"Nuclear import of proinflammatory transcription factors is required for massive liver apoptosis induced by bacterial lipopolysaccharide","volume":"279","author":"D Liu","year":"2004","journal-title":"J Biol Chem"},{"key":"ref23","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1097\/CCM.0b013e318194ab65","article-title":"Modulation of nuclear factor-kappaB improves cardiac dysfunction associated with cardiopulmonary bypass and deep hypothermic circulatory arrest","volume":"37","author":"JY Duffy","year":"2009","journal-title":"Crit Care Med"},{"key":"ref24","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/j.jss.2008.04.030","article-title":"NF-kappaB and p38 MAPK inhibition improve survival in endotoxin shock and in a cecal ligation and puncture model of sepsis in combination with antibiotic therapy","volume":"152","author":"AW O'Sullivan","year":"2009","journal-title":"J Surg Res"},{"key":"ref25","doi-asserted-by":"crossref","first-page":"e13235","DOI":"10.1371\/journal.pone.0013235","article-title":"In vivo islet protection by a nuclear import inhibitor in a mouse model of type 1 diabetes","volume":"5","author":"DJ Moore","year":"2010","journal-title":"PLoS One"},{"key":"ref26","doi-asserted-by":"crossref","first-page":"e30527","DOI":"10.1371\/journal.pone.0030527","article-title":"Lethality in a Murine Model of Pulmonary Anthrax is Reduced by Combining Nuclear Transport Modifier with Antimicrobial Therapy","volume":"7","author":"RA Veach","year":"2012","journal-title":"PLoS ONE"},{"key":"ref27","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1038\/nrmicro1068","article-title":"LPS, TLR4 and infectious disease diversity","volume":"3","author":"SI Miller","year":"2005","journal-title":"Nat Rev Microbiol"},{"key":"ref28","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1161\/01.RES.0000255691.76142.4a","article-title":"Phenotypic heterogeneity of the endothelium: I. Structure, function, and mechanisms","volume":"100","author":"WC Aird","year":"2007","journal-title":"Circ Res"},{"key":"ref29","doi-asserted-by":"crossref","first-page":"2731","DOI":"10.1172\/JCI60331","article-title":"The acute respiratory distress syndrome","volume":"122","author":"MA Matthay","year":"2012","journal-title":"J Clin Invest"},{"key":"ref30","doi-asserted-by":"crossref","unstructured":"Takao K, Miyakawa T (2014) Genomic responses in mouse models greatly mimic human inflammatory diseases. Proc Natl Acad Sci U S A; published ahead of print August 4, 2014, doi:10.1073\/pnas.1401965111.","DOI":"10.1073\/pnas.1401965111"},{"key":"ref31","doi-asserted-by":"crossref","first-page":"3507","DOI":"10.1073\/pnas.1222878110","article-title":"Genomic responses in mouse models poorly mimic human inflammatory diseases","volume":"110","author":"J Seok","year":"2013","journal-title":"Proc Natl Acad Sci U S A"},{"key":"ref32","doi-asserted-by":"crossref","first-page":"862","DOI":"10.1001\/jama.288.7.862","article-title":"Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock","volume":"288","author":"D Annane","year":"2002","journal-title":"JAMA"},{"key":"ref33","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1056\/NEJMoa071366","article-title":"Hydrocortisone therapy for patients with septic shock","volume":"358","author":"CL Sprung","year":"2008","journal-title":"N Engl J Med"},{"key":"ref34","doi-asserted-by":"crossref","first-page":"704","DOI":"10.1136\/bjo.82.6.704","article-title":"Systemic corticosteroid therapy\u2013side effects and their management","volume":"82","author":"RM Stanbury","year":"1998","journal-title":"Br J Ophthalmol"},{"key":"ref35","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1016\/j.cmet.2008.08.001","article-title":"The glucocorticoid receptor controls hepatic dyslipidemia through Hes1","volume":"8","author":"U Lemke","year":"2008","journal-title":"Cell Metab"},{"key":"ref36","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1186\/2045-3701-2-19","article-title":"Regulation of triglyceride metabolism by glucocorticoid receptor","volume":"2","author":"JC Wang","year":"2012","journal-title":"Cell Biosci"},{"key":"ref37","doi-asserted-by":"crossref","first-page":"S498","DOI":"10.1086\/432005","article-title":"Triglyceride-rich lipoproteins as agents of innate immunity","volume":"41","author":"AM Barcia","year":"2005","journal-title":"Clin Infect Dis"},{"key":"ref38","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1016\/j.metabol.2009.12.022","article-title":"Metabolic response to endotoxin in vivo in the conscious mouse: role of interleukin-6","volume":"60","author":"A Tweedell","year":"2011","journal-title":"Metabolism"},{"key":"ref39","doi-asserted-by":"crossref","first-page":"914","DOI":"10.1161\/hc3401.093153","article-title":"Immunopathogenesis of atherosclerosis: endotoxin accelerates atherosclerosis in rabbits on hypercholesterolemic diet","volume":"104","author":"HA Lehr","year":"2001","journal-title":"Circulation"},{"key":"ref40","doi-asserted-by":"crossref","first-page":"1571","DOI":"10.1126\/science.1088372","article-title":"The structure of importin-beta bound to SREBP-2: nuclear import of a transcription factor","volume":"302","author":"SJ Lee","year":"2003","journal-title":"Science"},{"key":"ref41","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1038\/labinvest.3700366","article-title":"Lipopolysaccharide signaling in endothelial cells","volume":"86","author":"SM Dauphinee","year":"2006","journal-title":"Lab Invest"},{"key":"ref42","doi-asserted-by":"crossref","first-page":"L899","DOI":"10.1152\/ajplung.00338.2002","article-title":"Mechanisms of bacterial lipopolysaccharide-induced endothelial apoptosis","volume":"284","author":"DD Bannerman","year":"2003","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"key":"ref43","doi-asserted-by":"crossref","first-page":"1604","DOI":"10.1093\/infdis\/jis552","article-title":"Elevated serum interleukin-10 at time of hospital admission is predictive of mortality in patients with Staphylococcus aureus bacteremia","volume":"206","author":"WE Rose","year":"2012","journal-title":"J Infect Dis"},{"key":"ref44","doi-asserted-by":"crossref","first-page":"R49","DOI":"10.1186\/cc5783","article-title":"Cytokine profiles as markers of disease severity in sepsis: a multiplex analysis","volume":"11","author":"FA Bozza","year":"2007","journal-title":"Crit Care"},{"key":"ref45","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1016\/j.cyto.2011.12.002","article-title":"A combined score of pro- and anti-inflammatory interleukins improves mortality prediction in severe sepsis","volume":"57","author":"D Andaluz-Ojeda","year":"2012","journal-title":"Cytokine"},{"key":"ref46","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1152\/physrev.1996.76.3.651","article-title":"Regulation of protein transport to the nucleus: central role of phosphorylation","volume":"76","author":"DA Jans","year":"1996","journal-title":"Physiol Rev"},{"key":"ref47","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/S1473-3099(08)70018-5","article-title":"Treatment of health-care-associated infections caused by Gram-negative bacteria: a consensus statement","volume":"8","author":"I Chopra","year":"2008","journal-title":"Lancet Infect Dis"},{"key":"ref48","doi-asserted-by":"crossref","first-page":"1804","DOI":"10.1056\/NEJMra0904124","article-title":"Hospital-acquired infections due to gram-negative bacteria","volume":"362","author":"AY Peleg","year":"2010","journal-title":"N Engl J Med"},{"key":"ref49","doi-asserted-by":"crossref","first-page":"2323","DOI":"10.1001\/jama.2009.1754","article-title":"International study of the prevalence and outcomes of infection in intensive care units","volume":"302","author":"JL Vincent","year":"2009","journal-title":"JAMA"},{"key":"ref50","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/0002-9343(93)90060-3","article-title":"Nosocomial pneumonia in ventilated patients: a cohort study evaluating attributable mortality and hospital stay","volume":"94","author":"JY Fagon","year":"1993","journal-title":"Am J Med"},{"key":"ref51","doi-asserted-by":"crossref","first-page":"2183","DOI":"10.1378\/chest.122.6.2183","article-title":"Nosocomial pneumonia: the importance of a de-escalating strategy for antibiotic treatment of pneumonia in the ICU","volume":"122","author":"G Hoffken","year":"2002","journal-title":"Chest"},{"key":"ref52","doi-asserted-by":"crossref","first-page":"R55","DOI":"10.1186\/cc10026","article-title":"Pseudomonas aeruginosa acquisition on an intensive care unit: relationship between antibiotic selective pressure and patients' environment","volume":"15","author":"A Boyer","year":"2011","journal-title":"Crit Care"},{"key":"ref53","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/S0195-6701(07)60005-X","article-title":"The Lowbury Lecture. The United States approach to strategies in the battle against healthcare-associated infections, 2006: transitioning from benchmarking to zero tolerance and clinician accountability","volume":"65","author":"WR Jarvis","year":"2007","journal-title":"J Hosp Infect"},{"key":"ref54","doi-asserted-by":"crossref","first-page":"3161","DOI":"10.1128\/IAI.00191-12","article-title":"Host response signature to Staphylococcus aureus alpha-hemolysin implicates pulmonary Th17 response","volume":"80","author":"KM Frank","year":"2012","journal-title":"Infect Immun"},{"key":"ref55","doi-asserted-by":"crossref","first-page":"371","DOI":"10.2165\/00002018-199513060-00006","article-title":"Clinical toxicity of cytokines used as haemopoietic growth factors","volume":"13","author":"T Vial","year":"1995","journal-title":"Drug Saf"},{"key":"ref56","doi-asserted-by":"crossref","first-page":"L134","DOI":"10.1152\/ajplung.00390.2004","article-title":"Acid and particulate-induced aspiration lung injury in mice: importance of MCP-1","volume":"289","author":"K Raghavendran","year":"2005","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"key":"ref57","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1172\/JCI27009","article-title":"Critical role of endothelial CXCR2 in LPS-induced neutrophil migration into the lung","volume":"116","author":"J Reutershan","year":"2006","journal-title":"J Clin Invest"},{"key":"ref58","doi-asserted-by":"crossref","first-page":"1521","DOI":"10.1002\/art.11143","article-title":"Anti-interleukin-6 receptor antibody therapy reduces vascular endothelial growth factor production in rheumatoid arthritis","volume":"48","author":"H Nakahara","year":"2003","journal-title":"Arthritis Rheum"},{"key":"ref59","doi-asserted-by":"crossref","first-page":"1646","DOI":"10.4049\/jimmunol.156.4.1646","article-title":"In vivo blockade of TNF-alpha by intravenous infusion of a chimeric monoclonal TNF-alpha antibody in patients with rheumatoid arthritis. Short term cellular and molecular effects","volume":"156","author":"HM Lorenz","year":"1996","journal-title":"J Immunol"},{"key":"ref60","first-page":"259","article-title":"Treatment of severe rheumatoid arthritis by anti-interleukin 6 monoclonal antibody","volume":"20","author":"D Wendling","year":"1993","journal-title":"J Rheumatol"},{"key":"ref61","doi-asserted-by":"crossref","first-page":"972","DOI":"10.1172\/JCI119648","article-title":"Role of NFkappaB in the mortality of sepsis","volume":"100","author":"H Bohrer","year":"1997","journal-title":"J Clin Invest"},{"key":"ref62","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1096\/fj.07-9574LSF","article-title":"Dose translation from animal to human studies revisited","volume":"22","author":"S Reagan-Shaw","year":"2008","journal-title":"Faseb Journal"},{"key":"ref63","doi-asserted-by":"crossref","first-page":"912","DOI":"10.1056\/NEJM199703273361303","article-title":"The effects of ibuprofen on the physiology and survival of patients with sepsis. The Ibuprofen in Sepsis Study Group","volume":"336","author":"GR Bernard","year":"1997","journal-title":"N Engl J Med"}],"container-title":["PLoS ONE"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/dx.plos.org\/10.1371\/journal.pone.0110183","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,7,17]],"date-time":"2023-07-17T11:35:20Z","timestamp":1689593720000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0110183"}},"subtitle":[],"editor":[{"given":"Liwu","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2014,10,20]]},"references-count":63,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2014,10,20]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0110183","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,10,20]]}}}