Abstract
Background. Sepsis is a leading cause of mortality in intensive care units worldwide. A better understanding of the blood systems response to sepsis should expedite the identification of biomarkers for early diagnosis and therapeutic interventions. Methods. We analyzed microarray studies whose data is available from the GEO repository and which were performed on the whole blood of septic patients and normal controls. Results. We identified 6 cohorts consisting of 450 individuals (sepsis = 323, control = 127) providing genome-wide messenger RNA (mRNA) expression data. Through meta-analysis we found the “Lysosome” and “Cytoskeleton” pathways were upregulated in human sepsis patients relative to controls, in addition to previously known signaling pathways (including MAPK, TLR). The key regulatory genes in the “Lysosome” pathway include lysosomal acid hydrolases (e.g., protease cathepsin A, D) as well as the major (LAMP1, 2) and minor (SORT1, LAPTM4B) membrane proteins. In contrast, pathways related to “Ribosome”, “Spliceosome” and “Cell adhesion molecules” were found to be downregulated, along with known pathways for immune dysfunction. Overall, our study revealed distinct mRNA activation profiles and protein-protein interaction networks in blood of human sepsis. Conclusions. Our findings suggest that aberrant mRNA expression in the lysosome and cytoskeleton pathways may play a pivotal role in the molecular pathobiology of human sepsis.
Highlights
Sepsis, a maladaptive response to infection, is a common and lethal syndrome
We first summarize the results found in the studies we examined and describe the results of our meta-analysis in relation to these findings
Other studies aimed at detecting genes for early diagnosis of sepsis demonstrated that genes directly involved in innate and early adaptive immune function (56%), cell cycling and white blood cell differentiation (32%), and extracellular matrix remodeling (7%), as well as immune modulation (5%), may serve as molecular biomarkers [25]
Summary
A maladaptive response to infection, is a common and lethal syndrome. The hospital incidence of sepsis has been reported as high as 153/100,000 to 353/100,000 in both industrialized [1, 2] and developing countries [3], with an increasing trend year by year [1,2,3]. Adjusted in-hospital mortality has decreased gradually (2-3% per year) according to a recent report [1, 5], sepsis associated mortality remained high, from 50/100,000 to 75/100,000 [1, 6]. It was even higher when sepsis was accompanied by organ dysfunction, ranging from 23% to 58% with dysfunction of one organ [2, 3, 7] and increasing to 77.4% when three or more organs had failure [3]. Our findings suggest that aberrant mRNA expression in the lysosome and cytoskeleton pathways may play a pivotal role in the molecular pathobiology of human sepsis
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