Abstract
Over the past decade several investigators have applied microarray technology and related bioinformatic approaches to clinical sepsis and septic shock, thus allowing for an assessment of how, or if, this branch of genomic medicine has meaningfully impacted the field of sepsis research. The ability to simultaneously and efficiently measure the steady-state mRNA abundance of thousands of transcripts from a given tissue source (that is, 'transcriptomics') has provided an unprecedented opportunity to gain a broader, genome-level 'picture' of complex and heterogeneous clinical syndromes such as sepsis. A trancriptomic approach to sepsis and septic shock is technically challenging on multiple levels, but nonetheless modest, tangible advances are being realized. These include a genome-level understanding of the complexity of sepsis and septic shock, identification of novel candidate pathways and targets for potential intervention, discovery of novel, candidate diagnostic and stratification biomarkers, and the ability to stratify patients into clinically relevant, expression-based subclasses. The challenges moving forward include robust validation studies, standardization of technical approaches, standardization and further development of analytical algorithms, and large-scale collaborations.
Highlights
Over the past decade several investigators have applied microarray technology and related bioinformatic approaches to clinical sepsis and septic shock, allowing for an assessment of how, or if, this branch of genomic medicine has meaningfully impacted the sepsis field
There is an emerging technology, RNA sequencing (RNA-Seq) [6], that has potentially intriguing applications for the field, but will not be further discussed as there are no RNA-Seq data related to sepsis
The degree of mRNA abundance is influenced by multiple factors, and does not provide any direct information about gene end products, nor post-translational modifiers of protein function, such as phosphorylation or glycation
Summary
Over the past decade several investigators have applied microarray technology and related bioinformatic approaches to clinical sepsis and septic shock, allowing for an assessment of how, or if, this branch of genomic medicine has meaningfully impacted the sepsis field. A common theme across many of these studies is the massive up-regulation of inflammation- and innate immunity-related genes in patients with sepsis and septic shock These observations are not intrinsically novel, but they are consistent with the long-standing sepsis paradigms centered on a hyperactive inflammatory response, and provide an important layer of biological plausibility with regard to overall microarray data output in the context of clinical sepsis. The ability to identify a subclass of children with a higher illness severity was further corroborated when the gene-expression-based subclassification strategy was applied to a separate validation cohort of children with septic shock [14] These studies demonstrate the feasibility of subclassifying patients with septic shock, in a clinically relevant manner, based on the expression patterns of a discrete set of genes having relevance to sepsis biology. While these studies require further development and validation, the findings are intriguing given that there exist a number of drugs to effectively inhibit MMP-8 activity in the clinical setting [71]
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