{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T11:17:35Z","timestamp":1791199055789,"version":"4.1.0"},"reference-count":48,"publisher":"Public Library of Science (PLoS)","issue":"12","license":[{"start":{"date-parts":[[2020,12,11]],"date-time":"2020-12-11T00:00:00Z","timestamp":1607644800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["R01GM111400"],"award-info":[{"award-number":["R01GM111400"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["R35GM13631201"],"award-info":[{"award-number":["R35GM13631201"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["K08AI128006"],"award-info":[{"award-number":["K08AI128006"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["R01GM112799"],"award-info":[{"award-number":["R01GM112799"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Background<\/jats:title>\n<jats:p>The systemic responses to infection and its progression to sepsis remains poorly understood. Progress in the field has been stifled by the shortcomings of experimental models which include poor replication of the human condition. To address these challenges, we developed and piloted a novel large animal model of severe infection that is capable of generating multi-system clinically relevant data.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Methods<\/jats:title>\n<jats:p>Male swine (n = 5) were anesthetized, mechanically ventilated, and surgically instrumented for continuous hemodynamic monitoring and serial blood sampling. Animals were inoculated with uropathogenic <jats:italic>E<\/jats:italic>. <jats:italic>coli<\/jats:italic> by direct injection into the renal parenchyma and were maintained until <jats:italic>a priori<\/jats:italic> endpoints were met. The natural history of the infection was studied. Animals were not resuscitated. Multi-system data were collected hourly to 6 hours; all animals were euthanized at predetermined physiologic endpoints.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Results<\/jats:title>\n<jats:p>Core body temperature progressively increased from mean (SD) 37.9(0.8)\u00b0C at baseline to 43.0(1.2)\u00b0C at experiment termination (p = 0.006). Mean arterial pressure did not begin to decline until 6h post inoculation, dropping from 86(9) mmHg at baseline to 28(5) mmHg (p = 0.005) at termination. Blood glucose progressively declined but lactate levels did not elevate until the last hours of the experiment. There were also temporal changes in whole blood concentrations of a number of metabolites including increases in the catecholamine precursors, tyrosine (p = 0.005) and phenylalanine (p = 0.005). Lung, liver, and kidney function parameters worsened as infection progressed and at study termination there was histopathological evidence of injury in these end-organs.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec004\">\n<jats:title>Conclusion<\/jats:title>\n<jats:p>We demonstrate a versatile, multi-system, longitudinal, swine model of infection that could be used to further our understanding of the mechanisms that underlie infection-induced multi-organ dysfunction and failure, optimize resuscitation protocols and test therapeutic interventions. Such a model could improve translation of findings from the bench to the bedside, circumventing a significant obstacle in sepsis research.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0243577","type":"journal-article","created":{"date-parts":[[2020,12,11]],"date-time":"2020-12-11T18:52:23Z","timestamp":1607712743000},"page":"e0243577","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":8,"title":["A comprehensive assessment of multi-system responses to a renal inoculation of uropathogenic E. coli in swine"],"prefix":"10.1371","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6789-7532","authenticated-orcid":true,"given":"Mohamad Hakam","family":"Tiba","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brendan M.","family":"McCracken","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert P.","family":"Dickson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean A.","family":"Nemzek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmen I.","family":"Colmenero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danielle C.","family":"Leander","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3962-6014","authenticated-orcid":true,"given":"Thomas L.","family":"Flott","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rodney C.","family":"Daniels","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4582-0120","authenticated-orcid":true,"given":"Kristine E.","family":"Konopka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. Scott","family":"VanEpps","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathleen A.","family":"Stringer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin R.","family":"Ward","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2020,12,11]]},"reference":[{"key":"pone.0243577.ref001","unstructured":"Sepsis, Data & Reports: CDC; 2016. Sepsis, Data and Reports]. Available from: https:\/\/www.cdc.gov\/sepsis\/datareports\/index.html."},{"issue":"3","key":"pone.0243577.ref002","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1097\/CCM.0000000000002899","article-title":"Sepsis: A Threat That Needs a Global Solution","volume":"46","author":"FR Machado","year":"2018","journal-title":"Crit Care Med"},{"issue":"10219","key":"pone.0243577.ref003","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1016\/S0140-6736(19)32989-7","article-title":"Global, regional, and national sepsis incidence and mortality, 1990\u20132017: analysis for the Global Burden of Disease Study","volume":"395","author":"KE Rudd","year":"2020","journal-title":"Lancet"},{"issue":"3","key":"pone.0243577.ref004","doi-asserted-by":"crossref","first-page":"754","DOI":"10.1097\/CCM.0b013e318232db65","article-title":"Hospitalizations, costs, and outcomes of severe sepsis in the United States 2003 to 2007","volume":"40","author":"T Lagu","year":"2012","journal-title":"Crit Care Med"},{"issue":"2","key":"pone.0243577.ref005","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1513\/AnnalsATS.201411-498BC","article-title":"Trends in sepsis and infection sources in the United States. A population-based study","volume":"12","author":"AJ Walkey","year":"2015","journal-title":"Ann Am Thorac Soc"},{"issue":"1","key":"pone.0243577.ref006","doi-asserted-by":"crossref","first-page":"143","DOI":"10.4161\/viru.26083","article-title":"Animal models of sepsis","volume":"5","author":"MP Fink","year":"2014","journal-title":"Virulence"},{"issue":"2","key":"pone.0243577.ref007","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1001\/jama.2011.909","article-title":"Novel therapies for septic shock over the past 4 decades","volume":"306","author":"AF Suffredini","year":"2011","journal-title":"JAMA"},{"issue":"14","key":"pone.0243577.ref008","doi-asserted-by":"crossref","first-page":"1731","DOI":"10.1001\/jama.296.14.1731","article-title":"Translation of research evidence from animals to humans","volume":"296","author":"DG Hackam","year":"2006","journal-title":"Jama"},{"issue":"4","key":"pone.0243577.ref009","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1038\/ni777","article-title":"Human Toll-like receptor 4 recognizes host-specific LPS modifications","volume":"3","author":"AM Hajjar","year":"2002","journal-title":"Nat Immunol"},{"issue":"7586","key":"pone.0243577.ref010","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1136\/bmj.39048.407928.BE","article-title":"Comparison of treatment effects between animal experiments and clinical trials: systematic review","volume":"334","author":"P Perel","year":"2007","journal-title":"Bmj"},{"issue":"7438","key":"pone.0243577.ref011","doi-asserted-by":"crossref","first-page":"514","DOI":"10.1136\/bmj.328.7438.514","article-title":"Where is the evidence that animal research benefits humans?","volume":"328","author":"P Pound","year":"2004","journal-title":"Bmj"},{"issue":"2","key":"pone.0243577.ref012","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1038\/ni0202-102a","article-title":"Species differences in macrophage NO production are important","volume":"3","author":"M Schneemann","year":"2002","journal-title":"Nat Immunol"},{"issue":"9","key":"pone.0243577.ref013","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"},{"issue":"4","key":"pone.0243577.ref014","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1097\/SHK.0000000000001212","article-title":"Minimum Quality Threshold in Pre-Clinical Sepsis Studies (Mqtipss): An International Expert Consensus Initiative for Improvement of Animal Modeling in Sepsis","volume":"50","author":"MF Osuchowski","year":"2018","journal-title":"Shock"},{"issue":"1","key":"pone.0243577.ref015","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1097\/SHK.0000000000000904","article-title":"An Ovine Model of Hyperdynamic Endotoxemia and Vital Organ Metabolism","volume":"49","author":"L Byrne","year":"2018","journal-title":"Shock"},{"key":"pone.0243577.ref016","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.thromres.2019.02.015","article-title":"Fluid resuscitation with 0.9% saline alters haemostasis in an ovine model of endotoxemic shock","volume":"176","author":"MR Passmore","year":"2019","journal-title":"Thromb Res"},{"issue":"5","key":"pone.0243577.ref017","doi-asserted-by":"crossref","first-page":"808","DOI":"10.1002\/mus.26013","article-title":"Muscle membrane properties in A pig sepsis model: Effect of norepinephrine","volume":"57","author":"D Boerio","year":"2018","journal-title":"Muscle Nerve"},{"key":"pone.0243577.ref018","doi-asserted-by":"crossref","first-page":"11","DOI":"10.3389\/fphys.2019.00011","article-title":"The Systemic Alterations of Lipids, Alanine-Glucose Cycle and Inter-Organ Amino Acid Metabolism in Swine Model Confirms the Role of Liver in Early Phase of Septic Shock","volume":"10","author":"M Ferrario","year":"2019","journal-title":"Front Physiol"},{"key":"pone.0243577.ref019","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.thromres.2017.07.030","article-title":"Characteristics of thrombin generation in a fulminant porcine sepsis model","volume":"158","author":"J Toth","year":"2017","journal-title":"Thromb Res"},{"key":"pone.0243577.ref020","unstructured":"National Research Council (U.S.). Committee for the Update of the Guide for the Care and Use of Laboratory Animals. IfLARUS. Guide for the care and use of laboratory animals. (U.S.) NAP, editor. Washington, D.C.2011."},{"issue":"2","key":"pone.0243577.ref021","doi-asserted-by":"crossref","first-page":"e1003175","DOI":"10.1371\/journal.ppat.1003175","article-title":"A phyletically rare gene promotes the niche-specific fitness of an E. coli pathogen during bacteremia","volume":"9","author":"TJ Wiles","year":"2013","journal-title":"PLoS Pathog"},{"issue":"9","key":"pone.0243577.ref022","doi-asserted-by":"crossref","first-page":"4411","DOI":"10.1128\/IAI.66.9.4411-4417.1998","article-title":"Genomic analysis of a pathogenicity island in uropathogenic Escherichia coli CFT073: distribution of homologous sequences among isolates from patients with pyelonephritis, cystitis, and Catheter-associated bacteriuria and from fecal samples","volume":"66","author":"DM Guyer","year":"1998","journal-title":"Infect Immun"},{"issue":"7","key":"pone.0243577.ref023","doi-asserted-by":"crossref","first-page":"2812","DOI":"10.1128\/IAI.65.7.2812-2820.1997","article-title":"Pathogenicity island sequences of pyelonephritogenic Escherichia coli CFT073 are associated with virulent uropathogenic strains","volume":"65","author":"JS Kao","year":"1997","journal-title":"Infect Immun"},{"issue":"9","key":"pone.0243577.ref024","doi-asserted-by":"crossref","DOI":"10.1128\/IAI.00942-19","article-title":"Can the Cecal Ligation and Puncture Model Be Repurposed To Better Inform Therapy in Human Sepsis?","volume":"88","author":"JC Alverdy","year":"2020","journal-title":"Infect Immun"},{"issue":"4","key":"pone.0243577.ref025","doi-asserted-by":"crossref","first-page":"e10128","DOI":"10.15252\/emmm.201810128","article-title":"Sepsis therapies: learning from 30 years of failure of translational research to propose new leads","volume":"12","author":"JM Cavaillon","year":"2020","journal-title":"EMBO Mol Med"},{"issue":"11","key":"pone.0243577.ref026","doi-asserted-by":"crossref","first-page":"1793","DOI":"10.1097\/00003246-199811000-00016","article-title":"Use of the SOFA score to assess the incidence of organ dysfunction\/failure in intensive care units: results of a multicenter, prospective study. Working group on \"sepsis-related problems\" of the European Society of Intensive Care Medicine","volume":"26","author":"JL Vincent","year":"1998","journal-title":"Crit Care Med"},{"issue":"6","key":"pone.0243577.ref027","doi-asserted-by":"crossref","first-page":"1169","DOI":"10.1001\/archinte.1986.00360180179026","article-title":"Fever and cardiac rhythm","volume":"146","author":"J Karjalainen","year":"1986","journal-title":"Arch Intern Med"},{"issue":"1","key":"pone.0243577.ref028","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1186\/s13054-016-1375-5","article-title":"The pathophysiological basis and consequences of fever","volume":"20","author":"EJ Walter","year":"2016","journal-title":"Crit Care"},{"issue":"3","key":"pone.0243577.ref029","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1007\/s00134-017-4683-6","article-title":"Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016","volume":"43","author":"A Rhodes","year":"2017","journal-title":"Intensive Care Med"},{"issue":"10","key":"pone.0243577.ref030","doi-asserted-by":"crossref","first-page":"2367","DOI":"10.1097\/CCM.0b013e31822a5be5","article-title":"Hypoglycemia in sepsis: Biomarker, mediator, or both?*","volume":"39","author":"R Bellomo","year":"2011","journal-title":"Critical Care Medicine"},{"issue":"1","key":"pone.0243577.ref031","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1186\/2052-0492-1-9","article-title":"Thrombocytopenia in adult patients with sepsis: incidence, risk factors, and its association with clinical outcome","volume":"1","author":"C Venkata","year":"2013","journal-title":"J Intensive Care"},{"issue":"1","key":"pone.0243577.ref032","doi-asserted-by":"crossref","first-page":"R70","DOI":"10.1186\/cc10059","article-title":"Upregulation of programmed death-1 on T cells and programmed death ligand-1 on monocytes in septic shock patients","volume":"15","author":"Y Zhang","year":"2011","journal-title":"Crit Care"},{"issue":"7","key":"pone.0243577.ref033","doi-asserted-by":"crossref","first-page":"e0181704","DOI":"10.1371\/journal.pone.0181704","article-title":"Diagnostic accuracy of procalcitonin, neutrophil-lymphocyte count ratio, C-reactive protein, and lactate in patients with suspected bacterial sepsis","volume":"12","author":"L Ljungstrom","year":"2017","journal-title":"PLoS One"},{"issue":"2","key":"pone.0243577.ref034","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1006\/brbi.1996.0009","article-title":"Catecholamine-induced leukocytosis: early observations, current research, and future directions","volume":"10","author":"RJ Benschop","year":"1996","journal-title":"Brain Behav Immun"},{"issue":"5","key":"pone.0243577.ref035","doi-asserted-by":"crossref","first-page":"582","DOI":"10.1164\/rccm.201812-2342OC","article-title":"Understanding Lactatemia in Human Sepsis. Potential Impact for Early Management","volume":"200","author":"L Gattinoni","year":"2019","journal-title":"Am J Respir Crit Care Med"},{"issue":"1","key":"pone.0243577.ref036","doi-asserted-by":"crossref","first-page":"1539S","DOI":"10.1093\/jn\/137.6.1539S","article-title":"Tyrosine, phenylalanine, and catecholamine synthesis and function in the brain","volume":"137","author":"JD Fernstrom","year":"2007","journal-title":"J Nutr"},{"key":"pone.0243577.ref037","doi-asserted-by":"crossref","first-page":"165974","DOI":"10.1155\/2013\/165974","article-title":"Cytokines in sepsis: potent immunoregulators and potential therapeutic targets\u2014an updated view","volume":"2013","author":"W Schulte","year":"2013","journal-title":"Mediators Inflamm"},{"key":"pone.0243577.ref038","doi-asserted-by":"crossref","unstructured":"Srisangthong P, Wongsa A, Kittiworawitkul P, Wattanathum A. Early IL-6 response in sepsis is correlated with mortality and severity score. The 33rd International Symposium on Intensive Care and Emergency Medicine; March 19\u201322; Brussels, Belgium2013. p. S13.","DOI":"10.1186\/cc11972"},{"issue":"1","key":"pone.0243577.ref039","doi-asserted-by":"crossref","first-page":"65","DOI":"10.3109\/08941938809141077","article-title":"Swine as models in experimental surgery","volume":"1","author":"MM Swindle","year":"1988","journal-title":"J Invest Surg"},{"issue":"1","key":"pone.0243577.ref040","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1097\/01.shk.0000191337.01036.b7","article-title":"Porcine models of severe sepsis: emphasis on porcine peritonitis","volume":"24","author":"RD Goldfarb","year":"2005","journal-title":"Shock"},{"issue":"5","key":"pone.0243577.ref041","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1097\/SHK.0b013e318249bb0d","article-title":"Differences in organ dysfunction in endotoxin-tolerant pigs under intensive care exposed to a second hit of endotoxin","volume":"37","author":"M Castegren","year":"2012","journal-title":"Shock"},{"issue":"6","key":"pone.0243577.ref042","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1097\/00024382-199612000-00009","article-title":"A porcine model of peritonitis and bacteremia simulates human septic shock","volume":"6","author":"RD Goldfarb","year":"1996","journal-title":"Shock"},{"issue":"3","key":"pone.0243577.ref043","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1097\/00024382-199403000-00008","article-title":"Porcine peritoneal sepsis: modeling for clinical relevance","volume":"1","author":"KK Kazarian","year":"1994","journal-title":"Shock"},{"issue":"3","key":"pone.0243577.ref044","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1016\/j.jinf.2005.10.023","article-title":"Validation of a Pseudomonas aeruginosa porcine model of septic shock","volume":"53","author":"T Rimmele","year":"2006","journal-title":"J Infect"},{"issue":"3","key":"pone.0243577.ref045","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1086\/519268","article-title":"Population-based epidemiologic analysis of acute pyelonephritis","volume":"45","author":"CA Czaja","year":"2007","journal-title":"Clin Infect Dis"},{"key":"pone.0243577.ref046","unstructured":"Torio CM, Andrews RM. National Inpatient Hospital Costs: The Most Expensive Conditions by Payer, 2011: Statistical Brief #160. Healthcare Cost and Utilization Project (HCUP) Statistical Briefs. Rockville (MD)2006."},{"issue":"1","key":"pone.0243577.ref047","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1097\/SHK.0000000000001242","article-title":"Part II: Minimum Quality Threshold in Preclinical Sepsis Studies (MQTiPSS) for Types of Infections and Organ Dysfunction Endpoints","volume":"51","author":"C Libert","year":"2019","journal-title":"Shock"},{"issue":"8","key":"pone.0243577.ref048","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1001\/jama.2016.0287","article-title":"The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3)","volume":"315","author":"M Singer","year":"2016","journal-title":"JAMA"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0243577","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,12,11]],"date-time":"2020-12-11T18:53:16Z","timestamp":1607712796000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0243577"}},"subtitle":[],"editor":[{"given":"Anasuya","family":"Sarkar","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2020,12,11]]},"references-count":48,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2020,12,11]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0243577","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,12,11]]}}}