Rac1 signaling regulates sepsis-induced pathologic inflammation in the lung via attenuation of Mac-1 expression and CXC chemokine formation.
Hwaiz, Rundk LU ; Hasan, Zirak LU ; Rahman, Milladur LU
; Zhang, Su
LU
; Palani, Karzan
LU
; Syk, Ingvar
LU
; Jeppsson, Bengt
LU
and Thorlacius, Henrik
LU
(2013)
In Journal of Surgical Research
183(2).
p.798-807
- Abstract
- Excessive neutrophil recruitment is a major feature in septic lung damage although the signaling mechanisms behind pulmonary infiltration of neutrophils in sepsis remain elusive. In the present study, we hypothesized that Rac1 might play an important role in pulmonary neutrophil accumulation and tissue injury in abdominal sepsis. Male C57BL/6 mice were treated with Rac1 inhibitor NSC23766 (5 mg/kg) before cecal ligation and puncture (CLP). Bronchoalveolar lavage fluid and lung tissue were collected for the quantification of neutrophil recruitment and edema and CXC chemokine formation. Blood was collected for the determination of Mac-1 on neutrophils and proinflammatory compounds in plasma. Gene expression of CXC chemokines and tumor... (More)
- Excessive neutrophil recruitment is a major feature in septic lung damage although the signaling mechanisms behind pulmonary infiltration of neutrophils in sepsis remain elusive. In the present study, we hypothesized that Rac1 might play an important role in pulmonary neutrophil accumulation and tissue injury in abdominal sepsis. Male C57BL/6 mice were treated with Rac1 inhibitor NSC23766 (5 mg/kg) before cecal ligation and puncture (CLP). Bronchoalveolar lavage fluid and lung tissue were collected for the quantification of neutrophil recruitment and edema and CXC chemokine formation. Blood was collected for the determination of Mac-1 on neutrophils and proinflammatory compounds in plasma. Gene expression of CXC chemokines and tumor necrosis factor alpha was determined by quantitative reverse transcription-polymerase chain reaction in alveolar macrophages. Rac1 activity was increased in lungs from septic animals, and NSC23766 significantly decreased pulmonary activity of Rac1 induced by CLP. Administration of NSC23766 markedly reduced CLP-triggered neutrophil infiltration, edema formation, and tissue damage in the lung. Inhibition of Rac1 decreased CLP-induced neutrophil expression of Mac-1 and pulmonary formation of CXC chemokines. Moreover, NSC23766 abolished the sepsis-evoked elevation of messenger RNA levels of CXC chemokines and tumor necrosis factor alpha in alveolar macrophages. Rac1 inhibition decreased the CLP-induced increase in plasma levels of high mobility group protein B1 and interleukin 6, indicating a role of Rac1 in systemic inflammation. In conclusion, our results demonstrate that Rac1 signaling plays a key role in regulating pulmonary infiltration of neutrophils and tissue injury via regulation of chemokine production in the lung and Mac-1 expression on neutrophils in abdominal sepsis. Thus, targeting Rac1 activity might be a useful strategy to protect the lung in abdominal sepsis. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/3734303
- author
- Hwaiz, Rundk
LU
; Hasan, Zirak
LU
; Rahman, Milladur
LU
; Zhang, Su
LU
; Palani, Karzan
LU
; Syk, Ingvar
LU
; Jeppsson, Bengt
LU
and Thorlacius, Henrik
LU
- organization
- publishing date
- 2013
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Journal of Surgical Research
- volume
- 183
- issue
- 2
- pages
- 798 - 807
- publisher
- Elsevier
- external identifiers
-
- wos:000321737300047
- pmid:23545410
- scopus:84880299117
- pmid:23545410
- ISSN
- 1095-8673
- DOI
- 10.1016/j.jss.2013.02.045
- language
- English
- LU publication?
- yes
- id
- 47213e5b-ce54-4d51-83dd-c749b91efa2d (old id 3734303)
- alternative location
- http://www.ncbi.nlm.nih.gov/pubmed/23545410?dopt=Abstract
- date added to LUP
- 2016-04-01 10:10:32
- date last changed
- 2022-04-27 19:21:15
@article{47213e5b-ce54-4d51-83dd-c749b91efa2d,
abstract = {{Excessive neutrophil recruitment is a major feature in septic lung damage although the signaling mechanisms behind pulmonary infiltration of neutrophils in sepsis remain elusive. In the present study, we hypothesized that Rac1 might play an important role in pulmonary neutrophil accumulation and tissue injury in abdominal sepsis. Male C57BL/6 mice were treated with Rac1 inhibitor NSC23766 (5 mg/kg) before cecal ligation and puncture (CLP). Bronchoalveolar lavage fluid and lung tissue were collected for the quantification of neutrophil recruitment and edema and CXC chemokine formation. Blood was collected for the determination of Mac-1 on neutrophils and proinflammatory compounds in plasma. Gene expression of CXC chemokines and tumor necrosis factor alpha was determined by quantitative reverse transcription-polymerase chain reaction in alveolar macrophages. Rac1 activity was increased in lungs from septic animals, and NSC23766 significantly decreased pulmonary activity of Rac1 induced by CLP. Administration of NSC23766 markedly reduced CLP-triggered neutrophil infiltration, edema formation, and tissue damage in the lung. Inhibition of Rac1 decreased CLP-induced neutrophil expression of Mac-1 and pulmonary formation of CXC chemokines. Moreover, NSC23766 abolished the sepsis-evoked elevation of messenger RNA levels of CXC chemokines and tumor necrosis factor alpha in alveolar macrophages. Rac1 inhibition decreased the CLP-induced increase in plasma levels of high mobility group protein B1 and interleukin 6, indicating a role of Rac1 in systemic inflammation. In conclusion, our results demonstrate that Rac1 signaling plays a key role in regulating pulmonary infiltration of neutrophils and tissue injury via regulation of chemokine production in the lung and Mac-1 expression on neutrophils in abdominal sepsis. Thus, targeting Rac1 activity might be a useful strategy to protect the lung in abdominal sepsis.}},
author = {{Hwaiz, Rundk and Hasan, Zirak and Rahman, Milladur and Zhang, Su and Palani, Karzan and Syk, Ingvar and Jeppsson, Bengt and Thorlacius, Henrik}},
issn = {{1095-8673}},
language = {{eng}},
number = {{2}},
pages = {{798--807}},
publisher = {{Elsevier}},
series = {{Journal of Surgical Research}},
title = {{Rac1 signaling regulates sepsis-induced pathologic inflammation in the lung via attenuation of Mac-1 expression and CXC chemokine formation.}},
url = {{http://dx.doi.org/10.1016/j.jss.2013.02.045}},
doi = {{10.1016/j.jss.2013.02.045}},
volume = {{183}},
year = {{2013}},
}