Tyrphostin AG126 Inhibits the Development of Postoperative Ileus Induced by Surgical Manipulation of the Murine Colon

Background: Manipulation of the bowel during abdominal surgery leads to a period of ileus, which is most severely manifested after procedures that directly involve the colon. Ileus is associated with the increased expression of pro-inflammatory cytokines and chemokines, a leukocytic infiltration into the muscularis, and the release of mediators from resident and infiltrating leukocytes that directly inhibit intestinal smooth muscle contractility. The phosphorylation of tyrosine residues on regulatory proteins by protein tyrosine kinases (PTK’s) occurs at multiple steps in the signaling cascades that regulate the expression of proinflammatory genes. Aim: To determine whether inhibition of PTK activity will attenuate the inflammatory response associated with colonic ileus, leading to improved function. Methods & Results: Using a rodent model of colonic postoperative ileus, we demonstrate that a single bolus injection of the PTK inhibitor tyrphostin AG-126 (15 mg/kg s.c.) prior to surgery significantly attenuates the surgically induced impairment of colonic contractility both in vivo and in vitro. The improvement in function was associated with a reduction in the magnitude of the inflammatory cell infiltrate and with a decrease in the transcription of the genes encoding the pro-inflammatory mediators interleukin (IL)-1 monocyte chemo attractant protein (MCP)-1, inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2. Furthermore, Tyrphostin AG-126 pretreatment significantly inhibited the activation of the multifactorial transcription factor NFB, which could form the basis for the reduction in pro-inflammatory mediator expression. Conclusions: These data demonstrate for the first time that inhibition of protein tyrosine kinase activity may represent a novel approach for the management of ileus in the clinical setting.