Inhibition of MK2 shows promise for preventing postoperative ileus in mice

Abstract

BackgroundPostoperative ileus (POI) is a common iatrogenic complication caused by physical disturbances to the bowel during abdominal surgery. Inflammation contributes to the development of POI and leads to impaired intestinal motility. Mitogen-activated protein kinase-activated protein kinase 2 (MK2) plays an essential role in inflammation and is an established drug target for many inflammatory diseases. We evaluated the role of MK2 in POI and investigated whether MK2 inhibition will alleviate POI. Materials and methodsOne group of mice were sham operated as controls. In another two groups, POI was induced by intestinal manipulation, and in one of the groups, MK2 inhibitor was administered 1 h before intestinal manipulation. The bowel tissues were collected and analyzed using real-time reverse-transcriptase polymerase chain reaction, immunoblot, whole-mount histochemistry, immunofluorescence in muscularis, and functional analyses. ResultsBowel manipulation resulted in an upregulation of MK2 activation. Preoperative treatment with an MK2 inhibitor reduced the proinflammatory gene expression induced by intestinal manipulation, such as macrophage inflammatory protein-1α, tumor necrosis factor-α, interleukin-6, interleukin-1β, intercellular adhesion molecule-1, and monocyte chemotactic protein-1. MK2 inhibitor 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 ability. ConclusionsMK2 mediated the cellular inflammatory responses within the intestinal muscularis in a mouse model of POI. Inhibition of MK2 activity reduced recruitment of immune cells to the intestinal muscularis, preventing loss of intestine smooth muscle contractility. These findings suggest MK2 inhibition is a promising potential target for preventing POI.