p38 MAPK regulates ischemia-reperfusion-induced recruitment of leukocytes in the colon.

Abstract

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.

CONCLUSION:

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.

• Authors: Stefan Santén, Andrada Mihaescu, Matthias W Laschke, Michael D Menger, Yousheng Wang, Bengt Jeppsson, Henrik Thorlacius
• Journal: Surgery (Surgery) Vol. 145 Issue 3 Pg. 303-12 (Mar 2009) ISSN: 1532-7361 [Electronic] United States
• PMID: 19231583 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Enzyme Inhibitors
• Imidazoles
• P-Selectin
• Pyrimidines
• Thiazoles
• Tumor Necrosis Factor-alpha
• 6-(4-fluorophenyl)-2,3-dihydro-5-(4-pyridinyl)imidazo(2,1-b)thiazole
• p38 Mitogen-Activated Protein Kinases
• SB 239063

Topics

• Animals
• Cell Adhesion (physiology)
• Colitis (metabolism, pathology)
• Colon (metabolism, pathology)
• Dose-Response Relationship, Drug
• Endothelial Cells (metabolism, pathology)
• Enzyme Inhibitors (pharmacology)
• Imidazoles (pharmacology)
• Leukocytes (pathology)
• Mast Cells (metabolism)
• Mice
• Mice, Inbred C57BL
• P-Selectin (metabolism)
• Pyrimidines (pharmacology)
• Reperfusion Injury (metabolism, pathology)
• Signal Transduction (physiology)
• Thiazoles (pharmacology)
• Tumor Necrosis Factor-alpha (metabolism)
• p38 Mitogen-Activated Protein Kinases (antagonists & inhibitors, metabolism)