TY  - JOUR
ID  - pittir20418
UR  - http://d-scholarship-dev.library.pitt.edu/20418/
IS  - 12
A1  - Ziraldo, C
A1  - Vodovotz, Y
A1  - Namas, RA
A1  - Almahmoud, K
A1  - Tapias, V
A1  - Mi, Q
A1  - Barclay, D
A1  - Jefferson, BS
A1  - Chen, G
A1  - Billiar, TR
A1  - Zamora, R
Y1  - 2013/12/03/
N2  - 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-1? 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.
JF  - PLoS ONE
VL  - 8
TI  - Central role for MCP-1/CCL2 in injury-induced inflammation revealed by in vitro, in silico, and clinical studies
AV  - public
ER  -