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A dynamic view of trauma/hemorrhage-induced inflammation in mice: Principal drivers and networks

Mi, Q and Constantine, G and Ziraldo, C and Solovyev, A and Torres, A and Namas, R and Bentley, T and Billiar, TR and Zamora, R and Puyana, JC and Vodovotz, Y (2011) A dynamic view of trauma/hemorrhage-induced inflammation in mice: Principal drivers and networks. PLoS ONE, 6 (5).

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Background: Complex biological processes such as acute inflammation induced by trauma/hemorrhagic shock/ (T/HS) are dynamic and multi-dimensional. We utilized multiplexing cytokine analysis coupled with data-driven modeling to gain a systems perspective into T/HS. Methodology/Principal Findings: Mice were subjected to surgical cannulation trauma (ST) ± hemorrhagic shock (HS; 25 mmHg), and followed for 1, 2, 3, or 4 h in each case. Serum was assayed for 20 cytokines and NO2-/NO3-. These data were analyzed using four data-driven methods (Hierarchical Clustering Analysis [HCA], multivariate analysis [MA], Principal Component Analysis [PCA], and Dynamic Network Analysis [DyNA]). Using HCA, animals subjected to ST vs. ST + HS could be partially segregated based on inflammatory mediator profiles, despite a large overlap. Based on MA, interleukin [IL]-12p40/p70 (, monokine induced by interferon-γ (CXCL-9) [MIG], and IP-10 were the best discriminators between ST and ST/HS. PCA suggested that the inflammatory mediators found in the three main principal components in animals subjected to ST were IL-6, IL-10, and IL-13, while the three principal components in ST + HS included a large number of cytokines including IL-6, IL-10, keratinocyte-derived cytokine (CXCL-1) [KC], and tumor necrosis factor-α [TNF-α]. DyNA suggested that the circulating mediators produced in response to ST were characterized by a high degree of interconnection/complexity at all time points; the response to ST + HS consisted of different central nodes, and exhibited zero network density over the first 2 h with lesser connectivity vs. ST at all time points. DyNA also helped link the conclusions from MA and PCA, in that central nodes consisting of IP-10 and IL-12 were seen in ST, while MIG and IL-6 were central nodes in ST + HS. Conclusions/Significance: These studies help elucidate the dynamics of T/HS-induced inflammation, complementing other forms of dynamic mechanistic modeling. These methods should be applicable to the analysis of other complex biological processes.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Mi, Qqim3@pitt.eduQIM3
Constantine, Ggmc@pitt.eduGMC
Ziraldo, C
Solovyev, A
Torres, A
Namas, R
Bentley, T
Billiar, TR
Zamora, Rzamorar@pitt.eduZAMORAR
Puyana, JCjcp51@pitt.eduJCP51
Vodovotz, Yvodovotz@pitt.eduVODOVOTZ
ContributionContributors NameEmailPitt UsernameORCID
Centers: Other Centers, Institutes, Offices, or Units > McGowan Institute for Regenerative Medicine
Date: 17 May 2011
Date Type: Publication
Journal or Publication Title: PLoS ONE
Volume: 6
Number: 5
DOI or Unique Handle: 10.1371/journal.pone.0019424
Schools and Programs: Dietrich School of Arts and Sciences > Mathematics
School of Medicine > Surgery
Refereed: Yes
MeSH Headings: Animals; Cluster Analysis; Inflammation--blood; Inflammation--etiology; Interleukin-10--blood; Interleukin-6--blood; Male; Mice; Mice, Inbred C57BL; Multivariate Analysis; Nitrates--blood; Nitrogen Dioxide--blood; Principal Component Analysis; Shock, Hemorrhagic--blood; Shock, Hemorrhagic--complications; Tumor Necrosis Factor-alpha--blood; Wounds and Injuries--blood; Wounds and Injuries--complications
Other ID: NLM PMC3091861
PubMed Central ID: PMC3091861
PubMed ID: 21573002
Date Deposited: 29 Aug 2012 21:11
Last Modified: 29 Apr 2022 11:55


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