Cargando…
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...
Autores principales: | , , , , , , , , , , , , , , , |
---|---|
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 |
_version_ | 1784582174903631872 |
---|---|
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. |
format | Online Article Text |
id | pubmed-8508766 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT kopczynskimichal selectiveextracellularsignalregulatedkinase12erk12inhibitionbythesch772984compoundattenuatesinvitroandinvivoinflammatoryresponsesandprolongssurvivalinmurinesepsismodels AT rumienczykizabela selectiveextracellularsignalregulatedkinase12erk12inhibitionbythesch772984compoundattenuatesinvitroandinvivoinflammatoryresponsesandprolongssurvivalinmurinesepsismodels AT kuleckamaria selectiveextracellularsignalregulatedkinase12erk12inhibitionbythesch772984compoundattenuatesinvitroandinvivoinflammatoryresponsesandprolongssurvivalinmurinesepsismodels AT statkiewiczmałgorzata selectiveextracellularsignalregulatedkinase12erk12inhibitionbythesch772984compoundattenuatesinvitroandinvivoinflammatoryresponsesandprolongssurvivalinmurinesepsismodels AT pysniakkazimiera selectiveextracellularsignalregulatedkinase12erk12inhibitionbythesch772984compoundattenuatesinvitroandinvivoinflammatoryresponsesandprolongssurvivalinmurinesepsismodels AT sandowskamarkiewiczzuzanna selectiveextracellularsignalregulatedkinase12erk12inhibitionbythesch772984compoundattenuatesinvitroandinvivoinflammatoryresponsesandprolongssurvivalinmurinesepsismodels AT wojciktrechcinskaurszula selectiveextracellularsignalregulatedkinase12erk12inhibitionbythesch772984compoundattenuatesinvitroandinvivoinflammatoryresponsesandprolongssurvivalinmurinesepsismodels AT gorycakrzysztof selectiveextracellularsignalregulatedkinase12erk12inhibitionbythesch772984compoundattenuatesinvitroandinvivoinflammatoryresponsesandprolongssurvivalinmurinesepsismodels AT pyziakkarolina selectiveextracellularsignalregulatedkinase12erk12inhibitionbythesch772984compoundattenuatesinvitroandinvivoinflammatoryresponsesandprolongssurvivalinmurinesepsismodels AT majewskaeliza selectiveextracellularsignalregulatedkinase12erk12inhibitionbythesch772984compoundattenuatesinvitroandinvivoinflammatoryresponsesandprolongssurvivalinmurinesepsismodels AT masiejczykmagdalena selectiveextracellularsignalregulatedkinase12erk12inhibitionbythesch772984compoundattenuatesinvitroandinvivoinflammatoryresponsesandprolongssurvivalinmurinesepsismodels AT wojcikjaszczynskakatarzyna selectiveextracellularsignalregulatedkinase12erk12inhibitionbythesch772984compoundattenuatesinvitroandinvivoinflammatoryresponsesandprolongssurvivalinmurinesepsismodels AT rzymskitomasz selectiveextracellularsignalregulatedkinase12erk12inhibitionbythesch772984compoundattenuatesinvitroandinvivoinflammatoryresponsesandprolongssurvivalinmurinesepsismodels AT bomsztykkarol selectiveextracellularsignalregulatedkinase12erk12inhibitionbythesch772984compoundattenuatesinvitroandinvivoinflammatoryresponsesandprolongssurvivalinmurinesepsismodels AT ostrowskijerzy selectiveextracellularsignalregulatedkinase12erk12inhibitionbythesch772984compoundattenuatesinvitroandinvivoinflammatoryresponsesandprolongssurvivalinmurinesepsismodels AT mikulamichal selectiveextracellularsignalregulatedkinase12erk12inhibitionbythesch772984compoundattenuatesinvitroandinvivoinflammatoryresponsesandprolongssurvivalinmurinesepsismodels |