PMID- 16327493
OWN - NLM
STAT- MEDLINE
DCOM- 20060117
LR  - 20240412
IS  - 0003-4932 (Print)
IS  - 1528-1140 (Electronic)
IS  - 0003-4932 (Linking)
VI  - 242
IP  - 6
DP  - 2005 Dec
TI  - p38 mitogen-activated protein kinase-dependent chemokine production, leukocyte 
      recruitment, and hepatocellular apoptosis in endotoxemic liver injury.
PG  - 830-8, discussion 838-9
AB  - OBJECTIVE: To determine the role of p38 mitogen-activated protein kinase (MAPK) 
      signaling in endotoxin-induced liver injury. BACKGROUND: MAPKs have been reported 
      to play a potential role in regulating inflammatory responses, but the role of 
      p38 MAPK signaling in chemokine production, leukocyte recruitment, and 
      hepatocellular apoptosis in the liver of endotoxemic mice is not known. METHODS: 
      Endotoxin-induced leukocyte-endothelium interactions were studied by use of 
      intravital fluorescence microscopy in the mouse liver. Tumor necrosis 
      factor-alpha (TNF-alpha) and CXC chemokines, liver enzymes, and apoptosis were 
      determined 6 hours after endotoxin challenge. The specific p38 MAPK inhibitor SB 
      239063 was given immediately prior to endotoxin exposure. Phosphorylation and 
      activity of p38 MAPK were determined by immunoprecipitation and Western blot. 
      RESULTS: Endotoxin increased phosphorylation and activity of p38 MAPK in the 
      liver, which was markedly inhibited by SB 239063. Inhibition of p38 MAPK 
      signaling dose-dependently decreased endotoxin-induced leukocyte rolling, 
      adhesion, and sinusoidal sequestration of leukocytes. SB 239063 markedly reduced 
      endotoxin-induced formation of TNF-alpha and CXC chemokines in the liver. Indeed, 
      the endotoxin-provoked increase of liver enzymes and hepatocellular apoptosis 
      were abolished and sinusoidal perfusion was restored in endotoxemic mice treated 
      with SB 239063. CONCLUSIONS: This study demonstrates that p38 MAPK signaling 
      plays an important role in regulating TNF-alpha and CXC chemokine production in 
      endotoxemic liver injury and that inhibition of p38 MAPK activity abolishes 
      endotoxin-induced leukocyte infiltration as well as hepatocellular apoptosis. 
      These novel findings suggest that interference with the p38 MAPK pathway may 
      constitute a therapeutic strategy against septic liver damage.
FAU - Klintman, Daniel
AU  - Klintman D
AD  - Department of Surgery, Malmo University Hospital, Lund University, S-205 02 
      Malmo, Sweden.
FAU - Li, Xiang
AU  - Li X
FAU - Santen, Stefan
AU  - Santen S
FAU - Schramm, Rene
AU  - Schramm R
FAU - Jeppsson, Bengt
AU  - Jeppsson B
FAU - Thorlacius, Henrik
AU  - Thorlacius H
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Ann Surg
JT  - Annals of surgery
JID - 0372354
RN  - 0 (Chemokines, CXC)
RN  - 0 (Lipopolysaccharides)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
SB  - IM
MH  - Analysis of Variance
MH  - Animals
MH  - Apoptosis
MH  - Chemokines, CXC/*biosynthesis
MH  - Endotoxemia/immunology/*pathology
MH  - Leukocyte Rolling/drug effects/immunology
MH  - Lipopolysaccharides/pharmacology
MH  - Liver/blood supply/*injuries/pathology
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Microscopy, Fluorescence
MH  - Reperfusion Injury
MH  - Tumor Necrosis Factor-alpha/*biosynthesis
MH  - p38 Mitogen-Activated Protein Kinases/*physiology
PMC - PMC1409872
EDAT- 2005/12/06 09:00
MHDA- 2006/01/18 09:00
PMCR- 2006/06/01
CRDT- 2005/12/06 09:00
PHST- 2005/12/06 09:00 [pubmed]
PHST- 2006/01/18 09:00 [medline]
PHST- 2005/12/06 09:00 [entrez]
PHST- 2006/06/01 00:00 [pmc-release]
AID - 00000658-200512000-00010 [pii]
AID - 0000658-200512000-00010 [pii]
AID - 10.1097/01.sla.0000189132.86878.f7 [doi]
PST - ppublish
SO  - Ann Surg. 2005 Dec;242(6):830-8, discussion 838-9. doi: 
      10.1097/01.sla.0000189132.86878.f7.