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Updated: Jun 25, 2026
Visualization of Neutrophil Extracellular Traps in Mesenteric Venules After Mesenteric Ischemia-Reperfusion Injury via Intravital Microscopy
Published on: September 27, 2024
p38 MAPK regulates ischemia-reperfusion-induced recruitment of leukocytes in the colon
Stefan Santén1, Andrada Mihaescu, Matthias W Laschke
1Department of Surgery, Malmö University Hospital, Lund University, Malmö, Sweden.
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.
Insights
p38 mitogen-activated protein kinase (MAPK) inhibition significantly reduced leukocyte rolling and adhesion in colonic ischemia-reperfusion (I/R) injury. This pathway also impacts TNF-alpha and P-selectin, suggesting a therapeutic target for I/R inflammation.
Area of Science:
- Molecular Biology
- Immunology
- Gastroenterology
Background:
- Ischemia-reperfusion (I/R) injury in the colon involves complex inflammatory processes.
- Leukocyte recruitment to the colonic vasculature is a key feature of I/R-induced inflammation.
- The role of p38 mitogen-activated protein kinase (MAPK) in this process requires further elucidation.
Purpose of the Study:
- To investigate the involvement of p38 MAPK in leukocyte recruitment during colonic I/R.
- To assess the impact of p38 MAPK inhibition on inflammatory mediators like TNF-alpha and P-selectin.
Main Methods:
- Utilized a mouse model of colonic I/R induced by superior mesenteric artery occlusion.
- Administered selective p38 MAPK inhibitors (SB 239063 and SKF 86002) prior to I/R.
- Quantified leukocyte-endothelial cell interactions using intravital fluorescence microscopy.
- Examined TNF-alpha production and P-selectin expression in vitro.
Main Results:
- Selective p38 MAPK inhibitors significantly reduced I/R-induced leukocyte rolling and adhesion by over 75%.
- Inhibition of p38 MAPK dose-dependently decreased mast cell-generated TNF-alpha production.
- Reduced TNF-alpha also led to decreased P-selectin expression and neutrophil adhesion on endothelial cells.
Conclusions:
- p38 MAPK plays a critical regulatory role in leukocyte rolling and adhesion in colonic I/R.
- Inhibiting p38 MAPK activity mitigates inflammation by reducing TNF-alpha and P-selectin-dependent leukocyte attachment.
- Targeting the p38 MAPK signaling pathway represents a promising therapeutic strategy for colonic I/R injury.
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