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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

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 an...

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Autores principales: Kopczynski, Michal, Rumienczyk, Izabela, Kulecka, Maria, Statkiewicz, Małgorzata, Pysniak, Kazimiera, Sandowska-Markiewicz, Zuzanna, Wojcik-Trechcinska, Urszula, Goryca, Krzysztof, Pyziak, Karolina, Majewska, Eliza, Masiejczyk, Magdalena, Wojcik-Jaszczynska, Katarzyna, Rzymski, Tomasz, Bomsztyk, Karol, Ostrowski, Jerzy, Mikula, Michal
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8508766/
https://www.ncbi.nlm.nih.gov/pubmed/34638546
http://dx.doi.org/10.3390/ijms221910204
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author Kopczynski, Michal
Rumienczyk, Izabela
Kulecka, Maria
Statkiewicz, Małgorzata
Pysniak, Kazimiera
Sandowska-Markiewicz, Zuzanna
Wojcik-Trechcinska, Urszula
Goryca, Krzysztof
Pyziak, Karolina
Majewska, Eliza
Masiejczyk, Magdalena
Wojcik-Jaszczynska, Katarzyna
Rzymski, Tomasz
Bomsztyk, Karol
Ostrowski, Jerzy
Mikula, Michal
author_facet Kopczynski, Michal
Rumienczyk, Izabela
Kulecka, Maria
Statkiewicz, Małgorzata
Pysniak, Kazimiera
Sandowska-Markiewicz, Zuzanna
Wojcik-Trechcinska, Urszula
Goryca, Krzysztof
Pyziak, Karolina
Majewska, Eliza
Masiejczyk, Magdalena
Wojcik-Jaszczynska, Katarzyna
Rzymski, Tomasz
Bomsztyk, Karol
Ostrowski, Jerzy
Mikula, Michal
author_sort Kopczynski, Michal
collection PubMed
description 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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spelling pubmed-85087662021-10-13 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 Kopczynski, Michal Rumienczyk, Izabela Kulecka, Maria Statkiewicz, Małgorzata Pysniak, Kazimiera Sandowska-Markiewicz, Zuzanna Wojcik-Trechcinska, Urszula Goryca, Krzysztof Pyziak, Karolina Majewska, Eliza Masiejczyk, Magdalena Wojcik-Jaszczynska, Katarzyna Rzymski, Tomasz Bomsztyk, Karol Ostrowski, Jerzy Mikula, Michal Int J Mol Sci Article 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. MDPI 2021-09-22 /pmc/articles/PMC8508766/ /pubmed/34638546 http://dx.doi.org/10.3390/ijms221910204 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Kopczynski, Michal
Rumienczyk, Izabela
Kulecka, Maria
Statkiewicz, Małgorzata
Pysniak, Kazimiera
Sandowska-Markiewicz, Zuzanna
Wojcik-Trechcinska, Urszula
Goryca, Krzysztof
Pyziak, Karolina
Majewska, Eliza
Masiejczyk, Magdalena
Wojcik-Jaszczynska, Katarzyna
Rzymski, Tomasz
Bomsztyk, Karol
Ostrowski, Jerzy
Mikula, Michal
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
title 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
title_full 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
title_fullStr 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
title_full_unstemmed 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
title_short 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
title_sort 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
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8508766/
https://www.ncbi.nlm.nih.gov/pubmed/34638546
http://dx.doi.org/10.3390/ijms221910204
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