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Central role for MCP-1/CCL2 in injury-induced inflammation revealed by in vitro, in silico, and clinical studies

Ziraldo, C and Vodovotz, Y and Namas, RA and Almahmoud, K and Tapias, V and Mi, Q and Barclay, D and Jefferson, BS and Chen, G and Billiar, TR and Zamora, R (2013) Central role for MCP-1/CCL2 in injury-induced inflammation revealed by in vitro, in silico, and clinical studies. PLoS ONE, 8 (12).

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Abstract

The translation of in vitro findings to clinical outcomes is often elusive. Trauma/hemorrhagic shock (T/HS) results in hepatic hypoxia that drives inflammation. We hypothesize that in silico methods would help bridge in vitro hepatocyte data and clinical T/HS, in which the liver is a primary site of inflammation. Primary mouse hepatocytes were cultured under hypoxia (1% O 2) or normoxia (21% O2) for 1-72 h, and both the cell supernatants and protein lysates were assayed for 18 inflammatory mediators by Luminex™ technology. Statistical analysis and data-driven modeling were employed to characterize the main components of the cellular response. Statistical analyses, hierarchical and k-means clustering, Principal Component Analysis, and Dynamic Network Analysis suggested MCP-1/CCL2 and IL-1α as central coordinators of hepatocyte-mediated inflammation in C57BL/6 mouse hepatocytes. Hepatocytes from MCP-1-null mice had altered dynamic inflammatory networks. Circulating MCP-1 levels segregated human T/HS survivors from non-survivors. Furthermore, T/HS survivors with elevated early levels of plasma MCP-1 post-injury had longer total lengths of stay, longer intensive care unit lengths of stay, and prolonged requirement for mechanical ventilation vs. those with low plasma MCP-1. This study identifies MCP-1 as a main driver of the response of hepatocytes in vitro and as a biomarker for clinical outcomes in T/HS, and suggests an experimental and computational framework for discovery of novel clinical biomarkers in inflammatory diseases. © 2013 Ziraldo et al.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Ziraldo, C
Vodovotz, Yvodovotz@pitt.eduVODOVOTZ
Namas, RAran39@pitt.eduRAN390000-0002-8582-5321
Almahmoud, K
Tapias, V
Mi, QQi.Mi@pitt.eduQIM3
Barclay, Ddeb7@pitt.eduDEB7
Jefferson, BSbahiyyah@pitt.eduBAHIYYAH
Chen, G
Billiar, TRbilliar@pitt.eduBILLIAR
Zamora, Rzamorar@pitt.eduZAMORAR
Contributors:
ContributionContributors NameEmailPitt UsernameORCID
EditorAndroulakis, Ioannis PUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Centers: Other Centers, Institutes, or Units > Center for Neuroscience
Other Centers, Institutes, or Units > McGowan Institute for Regenerative Medicine
Date: 3 December 2013
Date Type: Publication
Journal or Publication Title: PLoS ONE
Volume: 8
Number: 12
DOI or Unique Handle: 10.1371/journal.pone.0079804
Schools and Programs: School of Medicine > Anesthesiology
School of Medicine > Computational Biology
School of Medicine > Computational and Systems Biology
School of Medicine > Neurology
School of Medicine > Surgery
Refereed: Yes
Date Deposited: 30 Jan 2014 18:10
Last Modified: 04 Feb 2019 15:57
URI: http://d-scholarship.pitt.edu/id/eprint/20418

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