Abstract
AbstractSepsis 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.This study investigates the role of c-Abelson (c-Abl) kinase in neutrophil extracellular trap (NET) formation and inflammation during sepsis. The authors demonstrate that c-Abl kinase plays a pivotal role in NET formation, pulmonary formation of CXC chemokines and lung injury in sepsis. Authors conclude that targeting c-Abl kinase might be a useful strategy to ameliorate local and systemic inflammation in sepsis.
Highlights
Abdominal sepsis is a life-threatening condition caused by an exaggerated and misdirected host responses characterized by wide-spread activation of innate immune cells[1]
C-Abl-kinase regulates neutrophil extracellular trap (NET) formation in sepsis By use of scanning electron microscopy, we observed that cecal ligation and puncture (CLP) induced formation of extracellular fibrillar and web-like structures in the lung compatible with NETs (Fig. 2A)
Knowing that reactive oxygen species (ROS) plays a key role in NET formation[29], it was of interest to study the role of c-Abl kinase in TNF-α-induced formation of ROS
Summary
Abdominal sepsis is a life-threatening condition caused by an exaggerated and misdirected host responses characterized by wide-spread activation of innate immune cells[1]. Neutrophils are critical for eliminating invading microorganisms but on the other hand, excessive neutrophil responses cause organ damage and failure[4]. Convincing data have shown that neutrophil recruitment constitute a rate-limiting step in septic lung injury[2,5]. Beside secretion of antimicrobial compounds and phagocytic killing[6], neutrophils can eliminate pathogens through expulsion of neutrophil extracellular traps (NETs) composed of neutrophilderived DNA forming extracellular web-like structures decorated with nuclear histones as well as granular and cytoplasmic proteins[7,8]. NETs and their associated histones have been demonstrated to cause epithelial and endothelial cell damage[9]. Defective clearance of NETs increases organ damage in sepsis[13]. NETs seem to be important in the pathophysiology, the signaling mechanisms controlling NET generation in sepsis are not known
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