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
| Autor: | Urszula Wojcik-Trechcinska, Krzysztof Goryca, Michal Kopczynski, Kazimiera Pysniak, Jerzy Ostrowski, Katarzyna Wojcik-Jaszczynska, Maria Kulecka, Zuzanna Sandowska-Markiewicz, Izabela Rumienczyk, Eliza Majewska, Malgorzata Statkiewicz, Karolina Pyziak, Magdalena Masiejczyk, Karol Bomsztyk, Michal Mikula, Tomasz Rzymski |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Lipopolysaccharides
Male Pyrrolidines Pyridines Anti-Inflammatory Agents Pharmacology Piperazines sepsis Mice Medicine Biology (General) Spectroscopy Chemokine CCL2 Mitogen-Activated Protein Kinase 3 ERK1/2 cecal ligation and puncture General Medicine Computer Science Applications Chemistry Tumor necrosis factor alpha Signal transduction SCH772984 Extracellular matrix organization Indazoles MAP Kinase Signaling System QH301-705.5 Down-Regulation Catalysis Article Cell Line Inorganic Chemistry Sepsis Downregulation and upregulation In vivo Intensive care Extracellular Animals Physical and Theoretical Chemistry Molecular Biology QD1-999 business.industry Tumor Necrosis Factor-alpha Organic Chemistry Drug Repositioning drugs repurposing Triazoles medicine.disease Platelet Activation Endotoxemia Mice Inbred C57BL Disease Models Animal RAW 264.7 Cells Gene Expression Regulation business Transcriptome |
| Zdroj: | International Journal of Molecular Sciences Volume 22 Issue 19 International Journal of Molecular Sciences, Vol 22, Iss 10204, p 10204 (2021) |
| ISSN: | 1422-0067 |
| DOI: | 10.3390/ijms221910204 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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