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Central Role for MCP-1/CCL2 in Injury-Induced Inflammation Revealed by In Vitro, In Silico, and Clinical Studies

Author

Listed:
  • Cordelia Ziraldo
  • Yoram Vodovotz
  • Rami A Namas
  • Khalid Almahmoud
  • Victor Tapias
  • Qi Mi
  • Derek Barclay
  • Bahiyyah S Jefferson
  • Guoqiang Chen
  • Timothy R Billiar
  • Ruben Zamora

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% O2) 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.

Suggested Citation

  • Cordelia Ziraldo & Yoram Vodovotz & Rami A Namas & Khalid Almahmoud & Victor Tapias & Qi Mi & Derek Barclay & Bahiyyah S Jefferson & Guoqiang Chen & Timothy R Billiar & Ruben Zamora, 2013. "Central Role for MCP-1/CCL2 in Injury-Induced Inflammation Revealed by In Vitro, In Silico, and Clinical Studies," PLOS ONE, Public Library of Science, vol. 8(12), pages 1-18, December.
    • Handle: RePEc:plo:pone00:0079804
    DOI: 10.1371/journal.pone.0079804
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    References listed on IDEAS

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    1. Qi Mi & Gregory Constantine & Cordelia Ziraldo & Alexey Solovyev & Andres Torres & Rajaie Namas & Timothy Bentley & Timothy R Billiar & Ruben Zamora & Juan Carlos Puyana & Yoram Vodovotz, 2011. "A Dynamic View of Trauma/Hemorrhage-Induced Inflammation in Mice: Principal Drivers and Networks," PLOS ONE, Public Library of Science, vol. 6(5), pages 1-12, May.
    2. Hui-Min Wang & Ching-Lin Hsiao & Ai-Ru Hsieh & Ying-Chao Lin & Cathy S J Fann, 2012. "Constructing Endophenotypes of Complex Diseases Using Non-Negative Matrix Factorization and Adjusted Rand Index," PLOS ONE, Public Library of Science, vol. 7(7), pages 1-12, July.
    3. Yoram Vodovotz & Marie Csete & John Bartels & Steven Chang & Gary An, 2008. "Translational Systems Biology of Inflammation," PLOS Computational Biology, Public Library of Science, vol. 4(4), pages 1-6, April.
    4. Lawrence Hubert & Phipps Arabie, 1985. "Comparing partitions," Journal of Classification, Springer;The Classification Society, vol. 2(1), pages 193-218, December.
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    Cited by:

    1. Khalid Almahmoud & Andrew Abboud & Rami A Namas & Ruben Zamora & Jason Sperry & Andrew B Peitzman & Michael S Truitt & Greg E Gaski & Todd O McKinley & Timothy R Billiar & Yoram Vodovotz, 2019. "Computational evidence for an early, amplified systemic inflammation program in polytrauma patients with severe extremity injuries," PLOS ONE, Public Library of Science, vol. 14(6), pages 1-20, June.
    2. Ruben Zamora & Sebastian Korff & Qi Mi & Derek Barclay & Lukas Schimunek & Riccardo Zucca & Xerxes D Arsiwalla & Richard L Simmons & Paul Verschure & Timothy R Billiar & Yoram Vodovotz, 2018. "A computational analysis of dynamic, multi-organ inflammatory crosstalk induced by endotoxin in mice," PLOS Computational Biology, Public Library of Science, vol. 14(11), pages 1-16, November.

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