The Study Of P38/MK2Inhibitor In Preventing Postoperative Ileus

Objective:Postoperative ileus (POI) is a common iatrogenic complication caused by physical disturbances to the bowel during abdominal surgery. Aseptic inflammation contributes to the development of POI and leads to impaired intestinal motility. Mitogen-activated protein kinase-activated protein kinase2(MK2) plays an essential role in inflammation and is an established drug target for many inflammatory diseases. In this study, we evaluated the role of MK2in POI and investigated whether inhibition of MK2alleviated POI.Materials and Methods:Mice were sham operated as controls; POI was induced by intestinal manipulation; MK2inhibitor was administered lhr before intestinal manipulation. Bowel tissues were collected and analyzed by the following tests:Western Blotting to test the expression of MK2; real-time reverse-transcriptase polymerase chain reaction to test the expression of the proinflammatory gene; whole-mount histochemistry and immunofluorescence to test the infiltrating cells in muscularis; mechanical activity recording and intestinal transit measurement to test the intestinal function.Results:Bowel manipulation resulted in an upregulation of MK2activation. Preoperatively treatment of MK2inhibitor reduced the proinflammatory gene expression induced by intestinal manipulation, such as macrophage inflammatory protein-la (MIP-lα), tumor necrosis factor a (TNFa), interleukin-6(IL-6), interleukin-1β (IL-1β), intercellular adhesion molecule1(ICAM-1) and monocyte chemotactic protein-1(MCP-1). MK2inhibitor administration significantly reduced the number of myeloperoxidase-positive polymorphonuclear neutrophils, mast cells and monocyte-derived macrophages that infiltrated the muscularis and prevented the surgically induced reduction in bowel smooth muscle contractility and gastrointestinal transit (GIT) ability. Conclusions:MK2mediates cellular inflammatory responses within the intestinal muscularis in mouse model of POI.Inhibition of MK2activity reduced recruitment of immune cells to the intestinal muscularis, preventing loss of intestine smooth muscle contractility. Theses suggested MK2is a promising potential target of preventing POI.