Selective Extracellular Signal-Regulated Kinase 1/2 (ERK1/2) Inhibition by the SCH772984 Compound Attenuates In Vitro and In Vivo Inflammatory Responses and Prolongs Survival in Murine Sepsis Models

被引:15
|
作者
Kopczynski, Michal [1 ]
Rumienczyk, Izabela [1 ]
Kulecka, Maria [1 ,2 ]
Statkiewicz, Malgorzata [1 ]
Pysniak, Kazimiera [1 ]
Sandowska-Markiewicz, Zuzanna [1 ]
Wojcik-Trechcinska, Urszula [1 ]
Goryca, Krzysztof [3 ]
Pyziak, Karolina [4 ]
Majewska, Eliza [4 ]
Masiejczyk, Magdalena [4 ]
Wojcik-Jaszczynska, Katarzyna [4 ]
Rzymski, Tomasz [4 ]
Bomsztyk, Karol [5 ]
Ostrowski, Jerzy [1 ,2 ]
Mikula, Michal [1 ]
机构
[1] Maria Sklodowska Curie Natl Res Inst Oncol, Dept Genet, PL-02781 Warsaw, Poland
[2] Ctr Postgrad Med Educ, Dept Gastroenterol Hepatol & Clin Oncol, PL-01813 Warsaw, Poland
[3] Univ Warsaw, Ctr New Technol, Genom Core Facil, PL-02097 Warsaw, Poland
[4] Ryvu Therapeut SA, Biol R&D, PL-30394 Krakow, Poland
[5] Univ Washington, UW Med South Lake Union, Seattle, WA 98109 USA
基金
美国国家卫生研究院;
关键词
sepsis; drugs repurposing; ERK1/2; SCH772984; cecal ligation and puncture; READ ALIGNMENT; CECAL LIGATION; PATHWAY; TRANSCRIPTION; DEFINITIONS; DYSFUNCTION; DISRUPTION; DISCOVERY; ROLES; EGFR;
D O I
10.3390/ijms221910204
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Sepsis is the leading cause of death in intensive care units worldwide. Current treatments of sepsis are largely supportive and clinical trials using specific pharmacotherapy for sepsis have failed to improve outcomes. Here, we used the lipopolysaccharide (LPS)-stimulated mouse RAW264.7 cell line and AlphaLisa assay for TNFa as a readout to perform a supervised drug repurposing screen for sepsis treatment with compounds targeting epigenetic enzymes, including kinases. We identified the SCH772984 compound, an extracellular signal-regulated kinase (ERK) 1/2 inhibitor, as an effective blocker of TNFa production in vitro. RNA-Seq of the SCH772984-treated RAW264.7 cells at 1, 4, and 24 h time points of LPS challenge followed by functional annotation of differentially expressed genes highlighted the suppression of cellular pathways related to the immune system. SCH772984 treatment improved survival in the LPS-induced lethal endotoxemia and cecal ligation and puncture (CLP) mouse models of sepsis, and reduced plasma levels of Ccl2/Mcp1. Functional analyses of RNA-seq datasets for kidney, lung, liver, and heart tissues from SCH772984-treated animals collected at 6 h and 12 h post-CLP revealed a significant downregulation of pathways related to the immune response and platelets activation but upregulation of the extracellular matrix organization and retinoic acid signaling pathways. Thus, this study defined transcriptome signatures of SCH772984 action in vitro and in vivo, an agent that has the potential to improve sepsis outcome.
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页数:17
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