Zamora, RubenKorff, SebastianMi, QiBarclay, Derek A.Schimunek, LukasZucca, RiccardoArsiwalla, Xerxes D.Simmons, Richard L.Verschure, Paul F. M. J.Billiar, Timothy R.Vodovotz, Yoram2020-02-272020-02-272018Zamora 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.10065821553-734Xhttp://hdl.handle.net/10230/43738Bacterial 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.application/pdfeng© 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.info:eu-repo/semantics/articlehttp://dx.doi.org/10.1371/journal.pcbi.1006582InflammationBlood plasmaMouse modelsPrincipal component analysisHeartKidneysSepsisSpleeninfo:eu-repo/semantics/openAccess