c-Abl kinase regulates neutrophil extracellular trap formation and lung injury in abdominal sepsis
(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.
(Less)
- author
- Hawez, Avin LU ; Ding, Zhiyi LU ; Taha, Dler LU ; Madhi, Raed LU ; Rahman, Milladur LU and Thorlacius, Henrik LU
- organization
- publishing date
- 2022
- 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}}, }