Inhibition of p38 mitogen-activated protein kinase pathway as prophylaxis of postoperative ileus in mice.
OBJECTIVE
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.


CONCLUSIONS
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.
Wehner
Sven
S
Department of Surgery, University of Bonn, Bonn, Germany.
Straesser
Stefan
S
Vilz
Tim O
TO
Pantelis
Dimitrios
D
Sielecki
Thais
T
de la Cruz
Vidal F
VF
Hirner
Andreas
A
Kalff
Joerg C
JC
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D004195:Disease Models, Animal; D005769:Gastrointestinal Motility / Q000187:drug effects / Q000502:physiology; D006835:Hydrazones / Q000494:pharmacology*; D045823:Ileus / Q000378:metabolism / Q000517:prevention & control*; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D007579:Jejunal Diseases / Q000378:metabolism / Q000517:prevention & control*; D007583:Jejunum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016173:Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011183:Postoperative Complications; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000813:Anilides; D006146:Guanidines
D000894:Anti-Inflammatory Agents, Non-Steroidal; D006835:Hydrazones; D016173:Macrophage Colony-Stimulating Factor; D048055:Mitogen-Activated Protein Kinase 8; D009569:Nitric Oxide; D048051:p38 Mitogen-Activated Protein Kinases; C097256:semapimod; D000813:Anilides; D006146:Guanidines