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

ABSTRACT: 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.

SUBMITTER: Zhang J

PROVIDER: S-EPMC6769203 | biostudies-literature | 2019 Jan-Dec

REPOSITORIES: biostudies-literature

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

Zhang Jianfeng J Luo Yifeng Y Wang Xiaoling X Zhu Jieyun J Li Qian Q Feng Jihua J He Dan D Zhong Zhimei Z Zheng Xiaowen X Lu Junyu J Zou Donghua D Luo Jiefeng J

Therapeutic advances in respiratory disease 20190101

<h4>Background</h4>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.<h4>Methods</h4>In the present study, gene set enrichment analysis, differentially expressed genes analysis, short time-series expression miner, protein-protein interaction (PPI) networks, module analysis, hyperge ...[more]

PMID: 31566109

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Project description:BackgroundAcute respiratory distress syndrome (ARDS), a life-threatening condition characterized by hypoxemia and poor lung compliance, is associated with high mortality. ARDS induced by COVID-19 has similar clinical presentations and pathological manifestations as non-COVID-19 ARDS. However, COVID-19 ARDS is associated with a more protracted inflammatory respiratory failure compared to traditional ARDS. Therefore, a comprehensive molecular comparison of ARDS of different etiologies groups may pave the way for more specific clinical interventions.Methods and findingsIn this study, we compared COVID-19 ARDS (n = 43) and bacterial sepsis-induced (non-COVID-19) ARDS (n = 24) using multi-omic plasma profiles covering 663 metabolites, 1,051 lipids, and 266 proteins. To address both between- and within- ARDS group variabilities we followed two approaches. First, we identified 706 molecules differently abundant between the two ARDS etiologies, revealing more than 40 biological processes differently regulated between the two groups. From these processes, we assembled a cascade of therapeutically relevant pathways downstream of sphingosine metabolism. The analysis suggests a possible overactivation of arginine metabolism involved in long-term sequelae of ARDS and highlights the potential of JAK inhibitors to improve outcomes in bacterial sepsis-induced ARDS. The second part of our study involved the comparison of the two ARDS groups with respect to clinical manifestations. Using a data-driven multi-omic network, we identified signatures of acute kidney injury (AKI) and thrombocytosis within each ARDS group. The AKI-associated network implicated mitochondrial dysregulation which might lead to post-ARDS renal-sequalae. The thrombocytosis-associated network hinted at a synergy between prothrombotic processes, namely IL-17, MAPK, TNF signaling pathways, and cell adhesion molecules. Thus, we speculate that combination therapy targeting two or more of these processes may ameliorate thrombocytosis-mediated hypercoagulation.ConclusionWe present a first comprehensive molecular characterization of differences between two ARDS etiologies-COVID-19 and bacterial sepsis. Further investigation into the identified pathways will lead to a better understanding of the pathophysiological processes, potentially enabling novel therapeutic interventions.

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

Publications

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

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