p38 MAPK regulates ischemia-reperfusion-induced recruitment of leukocytes in the colon.
BACKGROUND
Our objective was to examine the role of p38 mitogen-activated protein kinase (MAPK) in ischemia-reperfusion (I/R)-induced recruitment or leukocytes in the colon.


METHODS
C57/Bl6 mice were subjected to 30 minutes of ischemia by clamping the superior mesenteric artery followed by 2 hours of reperfusion. Animals were pretreated with the selective p38 MAPK inhibitors SB 239063 and SKF 86002 before induction of I/R. Leukocyte-endothelium interactions were quantified by use of intravital fluorescence microscopy. Additionally, the role of p38 MAPK in mast cell-generated tumor necrosis factor-alpha (TNF-alpha) as well as neutrophil adhesion and P-selectin expression were examined in vitro.


RESULTS
SB 239063 and SKF 86002 decreased both I/R-provoked leukocyte rolling and adhesion by > 75%. Inhibition of p38 MAPK decreased dose-dependently the mast cell generated TNF-alpha production as well as TNF-alpha-induced expression of P-selectin and neutrophil adhesion on endothelial cells.


CONCLUSIONS
We conclude that p38 MAPK regulates leukocyte rolling and adhesion in colonic I/R. Moreover, inhibition of p38 MAPK activity decreases formation of TNF-alpha and P-selectin-dependent leukocyte attachment to activated endothelial cells. Thus, our findings suggest that interference with the p38 MAPK signaling pathway could be an effective strategy to protect against I/R-induced inflammation in the colon.
Santén
Stefan
S
Department of Surgery, Malmö University Hospital, Lund University, Malmö, Sweden.
Mihaescu
Andrada
A
Laschke
Matthias W
MW
Menger
Michael D
MD
Wang
Yousheng
Y
Jeppsson
Bengt
B
Thorlacius
Henrik
H
D000818:Animals; D002448:Cell Adhesion / Q000502:physiology; D003092:Colitis / Q000378:metabolism / Q000473:pathology; D003106:Colon / Q000378:metabolism* / Q000473:pathology*; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D007962:Leukocytes / Q000473:pathology*; D008407:Mast Cells / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D019007:P-Selectin / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D015427:Reperfusion Injury / Q000378:metabolism* / Q000473:pathology*; D015398:Signal Transduction / Q000502:physiology; D013844:Thiazoles / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
D004791:Enzyme Inhibitors; D007093:Imidazoles; D019007:P-Selectin; D011743:Pyrimidines; D013844:Thiazoles; D014409:Tumor Necrosis Factor-alpha; C052026:6-(4-fluorophenyl)-2,3-dihydro-5-(4-pyridinyl)imidazo(2,1-b)thiazole; D048051:p38 Mitogen-Activated Protein Kinases; C406525:SB 239063