Inhibition of p38 mitogen-activated protein kinase pathway as prophylaxis of postoperative ileus in mice
Sven Wehner1, Stefan Straesser, Tim O Vilz
1Department of Surgery, University of Bonn, Bonn, Germany.
Background & Aims:
Postoperative ileus, an iatrogenic complication of abdominal surgery, is mediated by severe inflammation of the tunica muscularis. Macrophages that reside in the muscularis have important roles in initiating the inflammation. We investigated whether activation of the p38 mitogen-activated protein kinase (MAPK) and stress-activated protein kinase is involved in the genesis of postoperative ileus, and whether p38-MAPK inhibition by the macrophage-specific inhibitor semapimod prevents intestinal dysmotility.
Methods:
Postoperative ileus was induced by intestinal manipulation of the small bowel in mice. Protein kinase phosphorylation was assessed by immunoblotting of muscularis externa preparations. Proinflammatory gene expression was quantified by real-time polymerase chain reaction. Myeloperoxidase histochemistry for neutrophils was performed in jejunal segments. Nitric oxide production was measured by Griess reaction in smooth-muscle organ culture supernatants. Jejunal contractility was assessed within an organ bath setup. Intestinal motility was analyzed by gastrointestinal and colonic transit measurements.
Results:
High levels of p38-MAPK and stress-activated protein kinase phosphorylation were observed immediately after intestinal manipulation. Semapimod treatment led to a significant decrease of p38-MAPK phosphorylation in macrophages; proinflammatory gene expression of macrophage inflammatory protein-1alpha, interleukin-6, monocyte chemoattractant protein-1, and intercellular adhesion molecule-1; and neutrophil infiltration. Furthermore, semapimod completely abrogated nitric oxide production within the tunica muscularis. Subsequently, semapimod prevented the suppression of smooth muscle contractility and small intestinal and colonic motility after intestinal manipulation.
Conclusion:
A single preoperative semapimod administration prevents intestinal macrophage activation and subsequent gastrointestinal dysmotility induced by abdominal surgery. Semapimod inhibits p38-MAPK and nitric oxide production in macrophages, making it a promising strategy for prophylaxis of postoperative ileus.
Insights
A drug called semapimod, which inhibits p38-MAPK and nitric oxide in macrophages, can prevent postoperative ileus. This study shows semapimod prevents intestinal dysmotility after abdominal surgery.
Area of Science:
- Gastroenterology
- Surgical Complications
- Immunology
Background:
- Postoperative ileus is a common complication of abdominal surgery, characterized by inflammation of the tunica muscularis.
- Macrophages in the muscularis play a key role in initiating this inflammation.
Purpose of the Study:
- To investigate the role of p38 mitogen-activated protein kinase (MAPK) and stress-activated protein kinase in postoperative ileus.
- To determine if semapimod, a p38-MAPK inhibitor, can prevent intestinal dysmotility.
Main Methods:
- Postoperative ileus was induced in mice via intestinal manipulation.
- p38-MAPK and stress-activated protein kinase phosphorylation were measured.
- Proinflammatory gene expression, neutrophil infiltration, and nitric oxide production were assessed.
- Intestinal contractility and motility were analyzed.
Main Results:
- Intestinal manipulation led to increased p38-MAPK and stress-activated protein kinase phosphorylation.
- Semapimod treatment reduced p38-MAPK phosphorylation, proinflammatory gene expression, and neutrophil infiltration.
- Semapimod abrogated nitric oxide production and prevented the suppression of smooth muscle contractility and intestinal motility.
Conclusions:
- Preoperative semapimod administration prevents macrophage activation and gastrointestinal dysmotility post-surgery.
- Semapimod's inhibition of p38-MAPK and nitric oxide offers a promising strategy for preventing postoperative ileus.
