학술논문
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.
Document Type
Academic Journal
Author
Kopczynski M; Department of Genetics, Maria Sklodowska-Curie National Research Institute of Oncology, 02-781 Warsaw, Poland.; Rumienczyk I; Department of Genetics, Maria Sklodowska-Curie National Research Institute of Oncology, 02-781 Warsaw, Poland.; Kulecka M; Department of Genetics, Maria Sklodowska-Curie National Research Institute of Oncology, 02-781 Warsaw, Poland.; Department of Gastroenterology, Hepatology and Clinical Oncology, Centre for Postgraduate Medical Education, 01-813 Warsaw, Poland.; Statkiewicz M; Department of Genetics, Maria Sklodowska-Curie National Research Institute of Oncology, 02-781 Warsaw, Poland.; Pysniak K; Department of Genetics, Maria Sklodowska-Curie National Research Institute of Oncology, 02-781 Warsaw, Poland.; Sandowska-Markiewicz Z; Department of Genetics, Maria Sklodowska-Curie National Research Institute of Oncology, 02-781 Warsaw, Poland.; Wojcik-Trechcinska U; Department of Genetics, Maria Sklodowska-Curie National Research Institute of Oncology, 02-781 Warsaw, Poland.; Goryca K; Genomics Core Facility, Centre of New Technologies, University of Warsaw, 02-097 Warsaw, Poland.; Pyziak K; Biology R&D, Ryvu Therapeutics S.A., 30-394 Krakow, Poland.; Majewska E; Biology R&D, Ryvu Therapeutics S.A., 30-394 Krakow, Poland.; Masiejczyk M; Biology R&D, Ryvu Therapeutics S.A., 30-394 Krakow, Poland.; Wojcik-Jaszczynska K; Biology R&D, Ryvu Therapeutics S.A., 30-394 Krakow, Poland.; Rzymski T; Biology R&D, Ryvu Therapeutics S.A., 30-394 Krakow, Poland.; Bomsztyk K; UW Medicine South Lake Union, University of Washington, Seattle, WA 98109, USA.; Ostrowski J; Department of Genetics, Maria Sklodowska-Curie National Research Institute of Oncology, 02-781 Warsaw, Poland.; Department of Gastroenterology, Hepatology and Clinical Oncology, Centre for Postgraduate Medical Education, 01-813 Warsaw, Poland.; Mikula M; Department of Genetics, Maria Sklodowska-Curie National Research Institute of Oncology, 02-781 Warsaw, Poland.
Source
Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE
Subject
Language
English
Abstract
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.