title: Combined in silico, in vivo, and in vitro studies shed insights into the acute inflammatory response in middle-aged mice.
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.
authors.affiliation: Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Rami A
authors.initials: RA
authors.lastname: Namas
authors.forename: John
authors.initials: J
authors.lastname: Bartels
authors.forename: Rosemary
authors.initials: R
authors.lastname: Hoffman
authors.forename: Derek
authors.initials: D
authors.lastname: Barclay
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Billiar
authors.forename: Ruben
authors.initials: R
authors.lastname: Zamora
authors.forename: Yoram
authors.initials: Y
authors.lastname: Vodovotz
mesh_terms: D000367:Age Factors; D000818:Animals; D016923:Cell Death / Q000276:immunology; D002470:Cell Survival / Q000276:immunology; D054360:Chemokine CXCL1 / Q000096:biosynthesis / Q000276:immunology; D003198:Computer Simulation; D007249:Inflammation / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology; D016753:Interleukin-10 / Q000096:biosynthesis / Q000276:immunology; D015850:Interleukin-6 / Q000096:biosynthesis / Q000276:immunology; D008070:Lipopolysaccharides / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018448:Models, Immunological; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000276:immunology
chemical_list: D054360:Chemokine CXCL1; C475895:Cxcl1 protein, mouse; D015850:Interleukin-6; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10