uu.seUppsala University Publications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
A non-linear mixed effect model for innate immune response: In vivo kinetics of endotoxin and its induction of the cytokines tumor necrosis factor alpha and interleukin-6
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine. Uppsala Univ Hosp, Sect Clin Microbiol & Infect Med, Dept Med Sci, Uppsala, Sweden.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases. Karolinska Univ Hosp, Div Perioperat Med & Intens Care, Stockholm, Sweden;Karolinska Inst, Dept Clin Sci Intervent & Technol, Stockholm, Sweden.
Show others and affiliations
2019 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 14, no 2, article id e0211981Article in journal (Refereed) Published
Abstract [en]

Endotoxin, a component of the outer membrane of Gram-negative bacteria, has been extensively studied as a stimulator of the innate immune response. However, the temporal aspects and exposure-response relationship of endotoxin and resulting cytokine induction and tolerance development is less well defined. The aim of this work was to establish an in silico model that simultaneously captures and connects the in vivo time-courses of endotoxin, tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6), and associated tolerance development. Data from six studies of porcine endotoxemia in anesthetized piglets (n = 116) were combined and used in the analysis, with purified endotoxin (Escherichia coli O111: B4) being infused intravenously for 1-30 h in rates of 0.063-16.0 mu g/kg/h across studies. All data were modelled simultaneously by means of importance sampling in the non-linear mixed effects modelling software NONMEM. The infused endotoxin followed one-compartment disposition and non-linear elimination, and stimulated the production of TNF-alpha to describe the rapid increase in plasma concentration. Tolerance development, observed as declining TNF-alpha concentration with continued infusion of endotoxin, was also driven by endotoxin as a concentration-dependent increase in the potency parameter related to TNF-alpha production (EC50). Production of IL-6 was stimulated by both endotoxin and TNF-a, and four consecutive transit compartments described delayed increase in plasma IL-6. A model which simultaneously account for the time-courses of endotoxin and two immune response markers, the cytokines TNF-alpha and IL-6, as well as the development of endotoxin tolerance, was successfully established. This model-based approach is unique in its description of the time-courses and their interrelation and may be applied within research on immune response to bacterial endotoxin, or in pre-clinical pharmaceutical research when dealing with study design or translational aspects.

Place, publisher, year, edition, pages
2019. Vol. 14, no 2, article id e0211981
National Category
Physiology
Identifiers
URN: urn:nbn:se:uu:diva-379038DOI: 10.1371/journal.pone.0211981ISI: 000459330800014PubMedID: 30789941OAI: oai:DiVA.org:uu-379038DiVA, id: diva2:1295338
Funder
Swedish Foundation for Strategic Research Available from: 2019-03-11 Created: 2019-03-11 Last updated: 2019-03-11Bibliographically approved

Open Access in DiVA

No full text in DiVA

Other links

Publisher's full textPubMed

Authority records BETA

Thorsted, AndersBouchene, SalimTano, EvaCastegren, MarkusLipcsey, MiklósSjölin, JanKarlsson, Mats OFriberg, Lena E.Nielsen, Elisabet I.

Search in DiVA

By author/editor
Thorsted, AndersBouchene, SalimTano, EvaCastegren, MarkusLipcsey, MiklósSjölin, JanKarlsson, Mats OFriberg, Lena E.Nielsen, Elisabet I.
By organisation
Department of Pharmaceutical BiosciencesInfection medicineInfectious DiseasesAnaesthesiology and Intensive CareHedenstierna laboratory
In the same journal
PLoS ONE
Physiology

Search outside of DiVA

GoogleGoogle Scholar

doi
pubmed
urn-nbn

Altmetric score

doi
pubmed
urn-nbn
Total: 192 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf