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

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

来源：PLos One, 2013, 8(12): e79804.

DOI：10.1371/journal.pone.0079804

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% O-2) for 1-72 h, and both the cell supernatants and protein lysates were assayed for 18 inflammatory mediators by Luminex (TM) 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 alpha 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.

• 出版日期2013-12-3
• 单位同济大学