Candidate Biomarkers for Systematic Inflammatory Response Syndrome and Inflammation: A Pathway for Novel Translational Therapeutics

Abstract

Objective: Systemic inflammatory response syndrome (SIRS) causes 200,000 deaths/year in the USA and has central nervous system (CNS) and peripheral components. Our aim was to identify candidate biomakers for SIRS and inflammation by studying the molecular pathways implicated in the CNS and the periphery, in order to facilitate translation into conceptually novel treatments. Methods: We used systemic administration of lipopolysaccharide (LPS) of Gram-negative bacteria to cause SIRS in rodents. We compared the transcriptional pattern of gene expression observed in the brain and heart of rodents after intraperitoneal LPS. Results: Only 10 out of 30 transcripts were commonly activated in the brain and the heart, which could be explained by variability of response, dilution effect in the CNS and lack of representation in both microarray platforms. Distinct temporal patterns of transcriptional expression suggest the presence of a tissue-specific inflammatory cascade during SIRS. We found that in the heart there were 240 upregulated transcripts, the majority of which was upregulated at 24 h (n = 154). There were also differences between the total number of transcripts that were upregulated in each ventricle: 209 in the right ventricle (RV) and 114 in the left ventricle; the RV was a site of delayed exacerbated inflammatory response. Conclusions: Given the striking cellular and tissue differences between the mouse brain and the rat heart, the 10 transcripts with shared regulation may be potential candidate biomarkers for SIRS, as they withstand intertissue and interspecies expression variability. We identified two types of temporal transcriptional patterns: (1) transitory activation with a peak around 6 or 24 h and (2) sustained activation. Detailed understanding of specific spatial-temporal patterns in various sites will lead to the identification of candidate biomarkers that can guide future translational efforts towards novel therapeutic strategies for SIRS and related conditions.