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c-Abl kinase regulates neutrophil extracellular trap formation and lung injury in abdominal sepsis

Hawez, Avin LU orcid ; Ding, Zhiyi LU ; Taha, Dler LU ; Madhi, Raed LU ; Rahman, Milladur LU orcid and Thorlacius, Henrik LU (2022) In Laboratory Investigation 102(3). p.263-271
Abstract

Sepsis is associated with exaggerated neutrophil responses although mechanisms remain elusive. The aim of this study was to investigate the role of c-Abelson (c-Abl) kinase in neutrophil extracellular trap (NET) formation and inflammation in septic lung injury. Abdominal sepsis was induced by cecal ligation and puncture (CLP). NETs were detected by electron microscopy in the lung and by confocal microscopy in vitro. Plasma levels of DNA-histone complexes, interleukin-6 (IL-6) and CXC chemokines were quantified. CLP-induced enhanced phosphorylation of c-Abl kinase in circulating neutrophils. Administration of the c-Abl kinase inhibitor GZD824 not only abolished activation of c-Abl kinase in neutrophils but also reduced NET formation in... (More)

Sepsis is associated with exaggerated neutrophil responses although mechanisms remain elusive. The aim of this study was to investigate the role of c-Abelson (c-Abl) kinase in neutrophil extracellular trap (NET) formation and inflammation in septic lung injury. Abdominal sepsis was induced by cecal ligation and puncture (CLP). NETs were detected by electron microscopy in the lung and by confocal microscopy in vitro. Plasma levels of DNA-histone complexes, interleukin-6 (IL-6) and CXC chemokines were quantified. CLP-induced enhanced phosphorylation of c-Abl kinase in circulating neutrophils. Administration of the c-Abl kinase inhibitor GZD824 not only abolished activation of c-Abl kinase in neutrophils but also reduced NET formation in the lung and plasma levels of DNA-histone complexes in CLP mice. Moreover, inhibition of c-Abl kinase decreased CLP-induced lung edema and injury. Administration of GDZ824 reduced CLP-induced increases in the number of alveolar neutrophils. Inhibition of c-Abl kinase also markedly attenuated levels of CXC chemokines in the lung and plasma as well as IL-6 levels in the plasma of septic animals. Taken together, this study demonstrates that c-Abl kinase is a potent regulator of NET formation and we conclude that c-Abl kinase might be a useful target to ameliorate lung damage in abdominal sepsis.

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author
; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Laboratory Investigation
volume
102
issue
3
pages
263 - 271
publisher
Nature Publishing Group
external identifiers
  • scopus:85118682802
  • pmid:34732849
ISSN
0023-6837
DOI
10.1038/s41374-021-00683-6
language
English
LU publication?
yes
additional info
Publisher Copyright: © 2021, The Author(s), under exclusive licence to United States and Canadian Academy of Pathology.
id
ac869b59-4063-49b2-b310-beff690c6de9
date added to LUP
2021-11-29 11:25:33
date last changed
2024-06-15 21:44:18
@article{ac869b59-4063-49b2-b310-beff690c6de9,
  abstract     = {{<p>Sepsis is associated with exaggerated neutrophil responses although mechanisms remain elusive. The aim of this study was to investigate the role of c-Abelson (c-Abl) kinase in neutrophil extracellular trap (NET) formation and inflammation in septic lung injury. Abdominal sepsis was induced by cecal ligation and puncture (CLP). NETs were detected by electron microscopy in the lung and by confocal microscopy in vitro. Plasma levels of DNA-histone complexes, interleukin-6 (IL-6) and CXC chemokines were quantified. CLP-induced enhanced phosphorylation of c-Abl kinase in circulating neutrophils. Administration of the c-Abl kinase inhibitor GZD824 not only abolished activation of c-Abl kinase in neutrophils but also reduced NET formation in the lung and plasma levels of DNA-histone complexes in CLP mice. Moreover, inhibition of c-Abl kinase decreased CLP-induced lung edema and injury. Administration of GDZ824 reduced CLP-induced increases in the number of alveolar neutrophils. Inhibition of c-Abl kinase also markedly attenuated levels of CXC chemokines in the lung and plasma as well as IL-6 levels in the plasma of septic animals. Taken together, this study demonstrates that c-Abl kinase is a potent regulator of NET formation and we conclude that c-Abl kinase might be a useful target to ameliorate lung damage in abdominal sepsis.</p>}},
  author       = {{Hawez, Avin and Ding, Zhiyi and Taha, Dler and Madhi, Raed and Rahman, Milladur and Thorlacius, Henrik}},
  issn         = {{0023-6837}},
  language     = {{eng}},
  number       = {{3}},
  pages        = {{263--271}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Laboratory Investigation}},
  title        = {{c-Abl kinase regulates neutrophil extracellular trap formation and lung injury in abdominal sepsis}},
  url          = {{http://dx.doi.org/10.1038/s41374-021-00683-6}},
  doi          = {{10.1038/s41374-021-00683-6}},
  volume       = {{102}},
  year         = {{2022}},
}