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.
引用
收藏
页数:17
相关论文
共 50 条
  • [31] Selective Inhibition of Extracellular Signal-regulated Kinases 1 and 2: When Less Is More
    Hao, Yuan
    Garcia-de-Alba-Rivas, Carolina
    AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY, 2023, 68 (01) : 1 - 2
  • [32] Pharmacologic Resuscitation Promotes Survival and Attenuates Hemorrhage-Induced Activation of Extracellular Signal-Regulated Kinase 1/2
    Fukudome, Eugene Y.
    Kochanek, Ashley R.
    Li, Yongqing
    Smith, Eleanor J.
    Liu, Baoling
    Kheirbek, Tareq
    Lu, Jennifer
    Kim, Kyuseok
    Hamwi, Kristopher
    Velmahos, George C.
    Alam, Hasan B.
    JOURNAL OF SURGICAL RESEARCH, 2010, 163 (01) : 118 - 126
  • [33] CXCR7 CONTRIBUTES TO BRAIN TUMOR ANGIOGENESIS THROUGH THE EXTRACELLULAR SIGNAL-REGULATED KINASE (ERK1/2) PATHWAY
    Liu, Yang
    Carson-Walter, Eleanor
    Walter, Kevin
    NEURO-ONCOLOGY, 2012, 14 : 4 - 4
  • [34] Substrate-Selective Targeting of Extracellular Signal-Regulated Kinase (ERK1/2) Mitigates Multiple Pathophysiological Features of Allergen-Induced Asthma
    Shah, S. D.
    Nayak, A. P.
    Sharma, P.
    Addya, S.
    Huang, W.
    Kane, M.
    Shaprio, P.
    Deshpande, D. A.
    AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 2022, 205
  • [35] Ligand-directed activation of extracellular signal-regulated kinases (ERK1/2) in enteric neurons
    Duraffourd, Celine
    Kumala, Erica
    Anselmi, Laura
    Brecha, Nick
    Sternini, Catia
    FASEB JOURNAL, 2014, 28 (01):
  • [36] Remote preconditioning by bilateral carotid artery occlusion limits myocardial infarct size in in vivo rabbit hearts: involvement of extracellular signal-regulated kinase 1/2 (ERK1/2)
    Arishiro, K.
    Momota, Y.
    Miyamae, M.
    Okusa, C.
    Kaneda, K.
    Kotani, J.
    Domae, N.
    Figueredo, V. M.
    EUROPEAN HEART JOURNAL, 2010, 31 : 46 - 47
  • [37] EXTRACELLULAR SIGNAL-REGULATED KINASES IN T-CELLS - CHARACTERIZATION OF HUMAN ERK1 AND ERK2 CDNAS
    OWAKI, H
    MAKAR, R
    BOULTON, TG
    COBB, MH
    GEPPERT, TD
    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1992, 182 (03) : 1416 - 1422
  • [38] Protective effects of intestinal trefoil factor (ITF) on gastric mucosal epithelium through activation of extracellular signal-regulated kinase 1/2 (ERK1/2)
    Lin, Jinfeng
    Sun, Zhaorui
    Zhang, Wei
    Liu, Hongmei
    Shao, Danbing
    Ren, Yi
    Wen, Yanfang
    Cao, Liping
    Wolfram, Joy
    Yang, Zhizhou
    Nie, Shinan
    MOLECULAR AND CELLULAR BIOCHEMISTRY, 2015, 404 (1-2) : 263 - 270
  • [39] Protective effects of intestinal trefoil factor (ITF) on gastric mucosal epithelium through activation of extracellular signal-regulated kinase 1/2 (ERK1/2)
    Jinfeng Lin
    Zhaorui Sun
    Wei Zhang
    Hongmei Liu
    Danbing Shao
    Yi Ren
    Yanfang Wen
    Liping Cao
    Joy Wolfram
    Zhizhou Yang
    Shinan Nie
    Molecular and Cellular Biochemistry, 2015, 404 : 263 - 270