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Targeting s100a9 reduces neutrophil recruitment, inflammation and lung damage in abdominal sepsis

Ding, Zhiyi LU ; Du, Feifei LU ; Averitt V, Richard Garland LU ; Jakobsson, Gabriel LU ; Rönnow, Carl Fredrik LU ; Rahman, Milladur LU orcid ; Schiopu, Alexandru LU and Thorlacius, Henrik LU (2021) In International Journal of Molecular Sciences 22(23).
Abstract

S100A9, a pro-inflammatory alarmin, is up-regulated in inflamed tissues. However, the role of S100A9 in regulating neutrophil activation, inflammation and lung damage in sepsis is not known. Herein, we hypothesized that blocking S100A9 function may attenuate neutrophil recruitment in septic lung injury. Male C57BL/6 mice were pretreated with the S100A9 inhibitor ABR-238901 (10 mg/kg), prior to cercal ligation and puncture (CLP). Bronchoalveolar lavage fluid (BALF) and lung tissue were harvested for analysis of neutrophil infiltration as well as edema and CXC chemokine production. Blood was collected for analysis of membrane-activated complex-1 (Mac-1) expression on neutrophils as well as CXC chemokines and IL-6 in plasma. Induction of... (More)

S100A9, a pro-inflammatory alarmin, is up-regulated in inflamed tissues. However, the role of S100A9 in regulating neutrophil activation, inflammation and lung damage in sepsis is not known. Herein, we hypothesized that blocking S100A9 function may attenuate neutrophil recruitment in septic lung injury. Male C57BL/6 mice were pretreated with the S100A9 inhibitor ABR-238901 (10 mg/kg), prior to cercal ligation and puncture (CLP). Bronchoalveolar lavage fluid (BALF) and lung tissue were harvested for analysis of neutrophil infiltration as well as edema and CXC chemokine production. Blood was collected for analysis of membrane-activated complex-1 (Mac-1) expression on neutrophils as well as CXC chemokines and IL-6 in plasma. Induction of CLP mark-edly increased plasma levels of S100A9. ABR-238901 decreased CLP-induced neutrophil infiltration and edema formation in the lung. In addition, inhibition of S100A9 decreased the CLP-induced up-regulation of Mac-1 on neutrophils. Administration of ABR-238901 also inhibited the CLP-induced increase of CXCL-1, CXCL-2 and IL-6 in plasma and lungs. Our results suggest that S100A9 promotes neutrophil activation and pulmonary accumulation in sepsis. Targeting S100A9 function decreased formation of CXC chemokines in circulation and lungs and attenuated sepsis-induced lung damage. These novel findings suggest that S1000A9 plays an important pro-inflammatory role in sepsis and could be a useful target to protect against the excessive inflammation and lung damage associated with the disease.

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author
; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Infection, Inflammation, Leukocyte, Lung, Sepsis
in
International Journal of Molecular Sciences
volume
22
issue
23
article number
12923
publisher
MDPI AG
external identifiers
  • scopus:85119998927
  • pmid:34884728
ISSN
1661-6596
DOI
10.3390/ijms222312923
language
English
LU publication?
yes
id
7ca6e4a3-46ce-42d2-b4ce-ba0f8ee38ce1
date added to LUP
2021-12-15 11:24:48
date last changed
2024-06-15 22:44:59
@article{7ca6e4a3-46ce-42d2-b4ce-ba0f8ee38ce1,
  abstract     = {{<p>S100A9, a pro-inflammatory alarmin, is up-regulated in inflamed tissues. However, the role of S100A9 in regulating neutrophil activation, inflammation and lung damage in sepsis is not known. Herein, we hypothesized that blocking S100A9 function may attenuate neutrophil recruitment in septic lung injury. Male C57BL/6 mice were pretreated with the S100A9 inhibitor ABR-238901 (10 mg/kg), prior to cercal ligation and puncture (CLP). Bronchoalveolar lavage fluid (BALF) and lung tissue were harvested for analysis of neutrophil infiltration as well as edema and CXC chemokine production. Blood was collected for analysis of membrane-activated complex-1 (Mac-1) expression on neutrophils as well as CXC chemokines and IL-6 in plasma. Induction of CLP mark-edly increased plasma levels of S100A9. ABR-238901 decreased CLP-induced neutrophil infiltration and edema formation in the lung. In addition, inhibition of S100A9 decreased the CLP-induced up-regulation of Mac-1 on neutrophils. Administration of ABR-238901 also inhibited the CLP-induced increase of CXCL-1, CXCL-2 and IL-6 in plasma and lungs. Our results suggest that S100A9 promotes neutrophil activation and pulmonary accumulation in sepsis. Targeting S100A9 function decreased formation of CXC chemokines in circulation and lungs and attenuated sepsis-induced lung damage. These novel findings suggest that S1000A9 plays an important pro-inflammatory role in sepsis and could be a useful target to protect against the excessive inflammation and lung damage associated with the disease.</p>}},
  author       = {{Ding, Zhiyi and Du, Feifei and Averitt V, Richard Garland and Jakobsson, Gabriel and Rönnow, Carl Fredrik and Rahman, Milladur and Schiopu, Alexandru and Thorlacius, Henrik}},
  issn         = {{1661-6596}},
  keywords     = {{Infection; Inflammation; Leukocyte; Lung; Sepsis}},
  language     = {{eng}},
  number       = {{23}},
  publisher    = {{MDPI AG}},
  series       = {{International Journal of Molecular Sciences}},
  title        = {{Targeting s100a9 reduces neutrophil recruitment, inflammation and lung damage in abdominal sepsis}},
  url          = {{http://dx.doi.org/10.3390/ijms222312923}},
  doi          = {{10.3390/ijms222312923}},
  volume       = {{22}},
  year         = {{2021}},
}