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.
Highlights
Among many other functions, the liver plays a critical role in inflammation and innate immunity, processes that are controlled by multiple cell types including hepatocytes, Kupffer cells, and other non-parenchymal cells
This study identifies the chemokine Monocyte Chemoattractant Protein-1 (MCP-1/CCL2) as a main driver of the response of hepatocytes in vitro and as a biomarker for organ damage in clinical settings of trauma hemorrhagic shock (T/HS), and, more generally, suggests a pathway for combined experimental and computational studies to facilitate the discovery of novel clinical biomarkers of inflammation
MCP-1 is a central component of the dynamic, multidimensional response of hepatocytes to cell stress
Summary
The liver plays a critical role in inflammation and innate immunity, processes that are controlled by multiple cell types including hepatocytes, Kupffer cells, and other non-parenchymal cells. At least 15 different cell types can be found in normal liver [1], hepatocytes constitute the largest pool of parenchymal cells, comprising approximately 60– 80% of the total liver cells [1,2]. Inflammatory conditions such as ischemia/reperfusion (I/R) and post-trauma hemorrhagic shock (T/HS) are associated with liver hypoxia [3,4]. The goal of the present study was to determine if combined in vitro/in silico studies could help elucidate key hepatic inflammatory mediators relevant to human T/HS. This study identifies the chemokine Monocyte Chemoattractant Protein-1 (MCP-1/CCL2) as a main driver of the response of hepatocytes in vitro and as a biomarker for organ damage in clinical settings of T/HS, and, more generally, suggests a pathway for combined experimental and computational studies to facilitate the discovery of novel clinical biomarkers of inflammation
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