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Critical role of p38 mitogen-activated protein kinase signaling in septic lung injury.

Asaduzzaman, Muhammad; Wang, Yusheng LU and Thorlacius, Henrik LU (2008) In Critical Care Medicine 36(2). p.482-488
Abstract
OBJECTIVE: Leukocyte-mediated tissue damage is a key feature in septic lung injury, although the signaling mechanisms behind pulmonary recruitment of leukocytes remain elusive. The aim of the present study was to define the role of p38 mitogen-activated protein kinase (MAPK) signaling in septic lung injury. DESIGN: Prospective experimental study. SETTING: University hospital research unit. SUBJECTS: Male C57BL/6 mice. INTERVENTIONS: Pulmonary edema, bronchoalveolar infiltration of leukocytes, levels of myeloperoxidase, and CXC chemokines were determined 6 and 24 hrs after cecal ligation and puncture (CLP). The specific p38 MAPK inhibitors SB 239063 and SKF 86002 were given immediately before CLP induction. Phosphorylation and activity of... (More)
OBJECTIVE: Leukocyte-mediated tissue damage is a key feature in septic lung injury, although the signaling mechanisms behind pulmonary recruitment of leukocytes remain elusive. The aim of the present study was to define the role of p38 mitogen-activated protein kinase (MAPK) signaling in septic lung injury. DESIGN: Prospective experimental study. SETTING: University hospital research unit. SUBJECTS: Male C57BL/6 mice. INTERVENTIONS: Pulmonary edema, bronchoalveolar infiltration of leukocytes, levels of myeloperoxidase, and CXC chemokines were determined 6 and 24 hrs after cecal ligation and puncture (CLP). The specific p38 MAPK inhibitors SB 239063 and SKF 86002 were given immediately before CLP induction. Phosphorylation and activity of p38 MAPK were determined by immunoprecipitation and Western blot. MEASUREMENTS AND MAIN RESULTS: CLP induced clear-cut pulmonary damage characterized by edema formation, leukocyte infiltration, and increased levels of CXC chemokines in the lung. Moreover, CLP increased phosphorylation and activity of p38 MAPK in the lung, which was markedly inhibited by SB 239063. Interestingly, inhibition of p38 MAPK signaling protected against CLP-induced lung damage and edema. Indeed, both SB 239063 and SKF 86002 decreased CLP-induced leukocyte recruitment in the bronchoalveolar space and formation of CXC chemokines in the lung. CONCLUSIONS: Our data demonstrate that p38 MAPK signaling constitutes a key role in regulating CXC chemokine production in septic lung injury and that inhibition of p38 MAPK activity abolishes pulmonary infiltration of leukocytes as well as lung edema. These novel findings suggest that targeting the p38 MAPK signaling pathway may pave the way for a new therapeutic strategy against lung injury in polymicrobial sepsis. (Less)
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organization
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type
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published
subject
keywords
Animals Chemokines, CXC/metabolism* Chemotaxis, Leukocyte/physiology* Disease Models, Animal Male Mice Mice, Inbred C57BL Phosphorylation Pulmonary Edema/etiology* Pulmonary Edema/metabolism Pulmonary Edema/pathology Sepsis/complications* Sepsis/metabolism Sepsis/pathology Signal Transduction/physiology* p38 Mitogen-Activated Protein Kinases/physiology*
in
Critical Care Medicine
volume
36
issue
2
pages
482 - 488
publisher
Lippincott Williams & Wilkins
external identifiers
  • pmid:18091546
  • wos:000252794000016
  • scopus:38549145342
ISSN
1530-0293
DOI
10.1097/01.CCM.0B013E31816204FA
language
English
LU publication?
yes
id
e0d0b744-ca9b-4571-8237-dd41dffeece4 (old id 1035102)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/18091546?dopt=Abstract
date added to LUP
2008-02-28 08:53:46
date last changed
2017-06-18 04:45:10
@article{e0d0b744-ca9b-4571-8237-dd41dffeece4,
  abstract     = {OBJECTIVE: Leukocyte-mediated tissue damage is a key feature in septic lung injury, although the signaling mechanisms behind pulmonary recruitment of leukocytes remain elusive. The aim of the present study was to define the role of p38 mitogen-activated protein kinase (MAPK) signaling in septic lung injury. DESIGN: Prospective experimental study. SETTING: University hospital research unit. SUBJECTS: Male C57BL/6 mice. INTERVENTIONS: Pulmonary edema, bronchoalveolar infiltration of leukocytes, levels of myeloperoxidase, and CXC chemokines were determined 6 and 24 hrs after cecal ligation and puncture (CLP). The specific p38 MAPK inhibitors SB 239063 and SKF 86002 were given immediately before CLP induction. Phosphorylation and activity of p38 MAPK were determined by immunoprecipitation and Western blot. MEASUREMENTS AND MAIN RESULTS: CLP induced clear-cut pulmonary damage characterized by edema formation, leukocyte infiltration, and increased levels of CXC chemokines in the lung. Moreover, CLP increased phosphorylation and activity of p38 MAPK in the lung, which was markedly inhibited by SB 239063. Interestingly, inhibition of p38 MAPK signaling protected against CLP-induced lung damage and edema. Indeed, both SB 239063 and SKF 86002 decreased CLP-induced leukocyte recruitment in the bronchoalveolar space and formation of CXC chemokines in the lung. CONCLUSIONS: Our data demonstrate that p38 MAPK signaling constitutes a key role in regulating CXC chemokine production in septic lung injury and that inhibition of p38 MAPK activity abolishes pulmonary infiltration of leukocytes as well as lung edema. These novel findings suggest that targeting the p38 MAPK signaling pathway may pave the way for a new therapeutic strategy against lung injury in polymicrobial sepsis.},
  author       = {Asaduzzaman, Muhammad and Wang, Yusheng and Thorlacius, Henrik},
  issn         = {1530-0293},
  keyword      = {Animals
Chemokines,CXC/metabolism*
Chemotaxis,Leukocyte/physiology*
Disease Models,Animal
Male
Mice
Mice,Inbred C57BL
Phosphorylation
Pulmonary Edema/etiology*
Pulmonary Edema/metabolism
Pulmonary Edema/pathology
Sepsis/complications*
Sepsis/metabolism
Sepsis/pathology
Signal Transduction/physiology*
p38 Mitogen-Activated Protein Kinases/physiology*},
  language     = {eng},
  number       = {2},
  pages        = {482--488},
  publisher    = {Lippincott Williams & Wilkins},
  series       = {Critical Care Medicine},
  title        = {Critical role of p38 mitogen-activated protein kinase signaling in septic lung injury.},
  url          = {http://dx.doi.org/10.1097/01.CCM.0B013E31816204FA},
  volume       = {36},
  year         = {2008},
}