A Computational analysis of dynamic, multi-organ inflammatory crosstalk induced by endotoxin in mice

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• dc.contributor.author Zamora, Ruben
• dc.contributor.author Korff, Sebastian
• dc.contributor.author Mi, Qi
• dc.contributor.author Barclay, Derek A.
• dc.contributor.author Schimunek, Lukas
• dc.contributor.author Zucca, Riccardo
• dc.contributor.author Arsiwalla, Xerxes D.
• dc.contributor.author Simmons, Richard L.
• dc.contributor.author Verschure, Paul F. M. J.
• dc.contributor.author Billiar, Timothy R.
• dc.contributor.author Vodovotz, Yoram
• dc.date.accessioned 2020-02-27T17:33:31Z
• dc.date.available 2020-02-27T17:33:31Z
• dc.date.issued 2018
• dc.description.abstract Bacterial lipopolysaccharide (LPS) induces an acute inflammatory response across multiple organs, primarily via Toll-like receptor 4 (TLR4). We sought to define novel aspects of the complex spatiotemporal dynamics of LPS-induced inflammation using computational modeling, with a special focus on the timing of pathological systemic spillover. An analysis of principal drivers of LPS-induced inflammation in the heart, gut, lung, liver, spleen, and kidney to assess organ-specific dynamics, as well as in the plasma (as an assessment of systemic spillover), was carried out using data on 20 protein-level inflammatory mediators measured over 0-48h in both C57BL/6 and TLR4-null mice. Using a suite of computational techniques, including a time-interval variant of Principal Component Analysis, we confirm key roles for cytokines such as tumor necrosis factor-α and interleukin-17A, define a temporal hierarchy of organ-localized inflammation, and infer the point at which organ-localized inflammation spills over systemically. Thus, by employing a systems biology approach, we obtain a novel perspective on the time- and organ-specific components in the propagation of acute systemic inflammation.
• dc.description.sponsorship This work was supported by NIH grants P50-GM-53789 and RO1-GM-107231, as well as Department of Defense grant W81XWH-14-DMRDP-CRMRP-RTRA.
• dc.format.mimetype application/pdf
• dc.identifier.citation Zamora R, Korff S, Mi Q, Barclay D, Schimunek L, Zucca R, Arsiwalla XD, Simmons RL, Verschure P, Billiar TR, Vodovotz Y. A Computational analysis of dynamic, multi-organ inflammatory crosstalk induced by endotoxin in mice. PLoS Comput Biol. 2018 Nov 6;14(11):e1006582. DOI: 10.1371/journal.pcbi.1006582
• dc.identifier.doi http://dx.doi.org/10.1371/journal.pcbi.1006582
• dc.identifier.issn 1553-734X
• dc.identifier.uri http://hdl.handle.net/10230/43738
• dc.language.iso eng
• dc.publisher Public Library of Science (PLoS)
• dc.relation.ispartof PLoS Computational Biology. 2018 Nov 6;14(11):e1006582
• dc.rights © 2018 Zamora et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri https://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword Inflammation
• dc.subject.keyword Blood plasma
• dc.subject.keyword Mouse models
• dc.subject.keyword Principal component analysis
• dc.subject.keyword Heart
• dc.subject.keyword Kidneys
• dc.subject.keyword Sepsis
• dc.subject.keyword Spleen
• dc.title A Computational analysis of dynamic, multi-organ inflammatory crosstalk induced by endotoxin in mice
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion