title: Central role for MCP-1/CCL2 in injury-induced inflammation revealed by in vitro, in silico, and clinical studies.
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.
authors: Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America ; Department of Computational and Systems Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America ; Joint Carnegie Mellon University - University of Pittsburgh Ph.D. Program in Computational Biology, Pittsburgh, Pennsylvania, United States of America.
authors: Cordelia
authors: C
authors: Ziraldo
authors: Yoram
authors: Y
authors: Vodovotz
authors: Rami A
authors: RA
authors: Namas
authors: Khalid
authors: K
authors: Almahmoud
authors: Victor
authors: V
authors: Tapias
authors: Qi
authors: Q
authors: Mi
authors: Derek
authors: D
authors: Barclay
authors: Bahiyyah S
authors: BS
authors: Jefferson
authors: Guoqiang
authors: G
authors: Chen
authors: Timothy R
authors: TR
authors: Billiar
authors: Ruben
authors: R
authors: Zamora
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D015687:Cell Hypoxia; D018932:Chemokine CCL2 / Q000097:blood*; D018572:Disease-Free Survival; D005260:Female; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000097:blood / Q000401:mortality; D053582:Interleukin-1alpha / Q000097:blood; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D012771:Shock, Hemorrhagic / Q000097:blood* / Q000401:mortality*; D015996:Survival Rate; D014947:Wounds and Injuries / Q000097:blood* / Q000401:mortality*
chemical_list: D015415:Biomarkers; C111835:CCL2 protein, human; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; C508584:IL1A protein, human; D053582:Interleukin-1alpha