Global transcriptional regulation of STAT3- and MYC-mediated sepsis-induced ARDS

BACKGROUND: In recent years, sepsis-induced acute respiratory distress syndrome (ARDS) has remained a major clinical challenge for patients in intensive care units. While some progress has been reported over the years, the pathogenesis of ARDS still needs to be further expounded. METHODS: In the present study, gene set enrichment analysis, differentially expressed genes analysis, short time-series expression miner, protein–protein interaction (PPI) networks, module analysis, hypergeometric test, and functional enrichment analysis were performed in whole blood gene expression profiles of sepsis and induced-sepsis ARDS to explore the molecular mechanism of sepsis-induced ARDS. RESULTS: Further dysregulated genes in the process evolving from healthy control through sepsis to sepsis-induced ARDS were identified and organized into 10 functional modules based on their PPI networks. These functional modules were significantly involved in cell cycle, ubiquitin mediated proteolysis, spliceosome, and other pathways. MYC, STAT3, LEF1, and BRCA1 were potential transcription factors (TFs) regulating these modules. A TF-module-pathway global regulation network was constructed. In particular, our findings suggest that MYC and STAT3 may be the key regulatory genes in the underlying dysfunction of sepsis-induced ARDS. Receiver operating characteristic curve analysis showed the core genes in the global regulation network may be biomarkers for sepsis or sepsis-induced ARDS. CONCLUSIONS: We found that MYC and STAT3 may be the key regulatory genes in the underlying dysfunction of sepsis-induced ARDS. The reviews of this paper are available via the supplementary material section.