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Combined In Silico, In Vivo, and In Vitro Studies Shed Insights into the Acute Inflammatory Response in Middle-Aged Mice

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  • Rami A Namas
  • John Bartels
  • Rosemary Hoffman
  • Derek Barclay
  • Timothy R Billiar
  • Ruben Zamora
  • Yoram Vodovotz

Abstract

We combined in silico, in vivo, and in vitro studies to gain insights into age-dependent changes in acute inflammation in response to bacterial endotoxin (LPS). Time-course cytokine, chemokine, and NO2−/NO3− data from “middle-aged” (6–8 months old) C57BL/6 mice were used to re-parameterize a mechanistic mathematical model of acute inflammation originally calibrated for “young” (2–3 months old) mice. These studies suggested that macrophages from middle-aged mice are more susceptible to cell death, as well as producing higher levels of pro-inflammatory cytokines, vs. macrophages from young mice. In support of the in silico-derived hypotheses, resident peritoneal cells from endotoxemic middle-aged mice exhibited reduced viability and produced elevated levels of TNF-α, IL-6, IL-10, and KC/CXCL1 as compared to cells from young mice. Our studies demonstrate the utility of a combined in silico, in vivo, and in vitro approach to the study of acute inflammation in shock states, and suggest hypotheses with regard to the changes in the cytokine milieu that accompany aging.

Suggested Citation

  • Rami A Namas & John Bartels & Rosemary Hoffman & Derek Barclay & Timothy R Billiar & Ruben Zamora & Yoram Vodovotz, 2013. "Combined In Silico, In Vivo, and In Vitro Studies Shed Insights into the Acute Inflammatory Response in Middle-Aged Mice," PLOS ONE, Public Library of Science, vol. 8(7), pages 1-11, July.
  • Handle: RePEc:plo:pone00:0067419
    DOI: 10.1371/journal.pone.0067419
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    References listed on IDEAS

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    1. Zhou Yang & Edward C. Norton & Sally C. Stearns, 2003. "Longevity and Health Care Expenditures," The Journals of Gerontology: Series B, The Gerontological Society of America, vol. 58(1), pages 2-10.
    2. 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.
    3. Carl Nathan, 2002. "Points of control in inflammation," Nature, Nature, vol. 420(6917), pages 846-852, December.
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