Tyrphostin AG 126 inhibits development of postoperative ileus induced by surgical manipulation of murine colon

Abstract

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 proinflammatory 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. Phosphorylation of tyrosine residues on regulatory proteins by protein tyrosine kinases (PTKs) occurs at multiple steps in the signaling cascades that regulate the expression of proinflammatory genes. The purpose of this study was to determine whether inhibition of PTK activity will attenuate the inflammatory response associated with colonic ileus and lead to improved function. 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 sc) before surgery significantly attenuates the surgically induced impairment of colonic contractility both in vivo and in vitro. Improvement in function was associated with a reduction in magnitude of inflammatory cell infiltrate and with a decrease in transcription of genes encoding proinflammatory mediators IL-1beta and monocyte chemoattractant protein (MCP)-1, inducible nitric oxide synthase, and cyclooxygenase-2. Furthermore, tyrphostin AG 126 pretreatment significantly inhibited activation of multifactorial transcription factor NF-kappaB, which could form the basis for reduction in proinflammatory mediator expression. These data demonstrate for the first time that inhibition of PTK activity may represent a novel approach for management of ileus in the clinical setting.

Cholinergic giant migrating contractions in conscious mouse colon assessed by using a novel noninvasive solid-state manometry method: modulation by stressors

“…Another condition known to influence colonic motility is abdominal surgery that induces a postoperative ileus in humans and experimental animals including in mice (40). Postoperative colonic ileus in mice has been studied primarily by using gastrointestinal transit assays (43) and in one study by recording intracolonic pressure in awake restrained mice (40). We provide here evidence that both low-amplitude phasic contractions and high-amplitude GMCs are inhibited following abdominal surgery and 1-min cecal palpation in mice.…”

“…Since in the present study we could not reliably attribute pressures below the 10 mmHg level to colonic contractile pressures, we took the 10 mmHg as the detectable threshold and added the 15 mmHg rise, as defined by Croci et al (10), and considered pressures over 25 mmHg as the threshold for defining an excursion in the pressure trace as a GMC. Although several studies identified and described CMMC as the main contractile pattern in isolated mouse colon (12,47), there is so far only one study that reported colonic contractility in awake mice (40). In contrast, GMC has been described to be the main propulsive contraction in the colon of several species in conscious state, including in rats and humans (25,55).…”

“…Contractions after the first 20 min are decreased to low levels with the overall colonic activity remaining the same for 40 min and even beyond the 60 min in few of the recordings made (data not shown). Another condition known to influence colonic motility is abdominal surgery that induces a postoperative ileus in humans and experimental animals including in mice (40). Postoperative colonic ileus in mice has been studied primarily by using gastrointestinal transit assays (43) and in one study by recording intracolonic pressure in awake restrained mice (40).…”

“…The latter consisted of Fos immunohistochemistry of the colonic longitudinal muscle myenteric plexus (LMMP) whole mount preparation as in our previous studies (63). We further validated the miniature pressure transducer solid-state manometry in conscious mice by assessing the time course of changes in the pattern of colonic contractions associated with abdominal surgery known to cause colonic ileus in mice (40).…”

Proinflammatory Role of Leukocyte-Derived Egr-1 in the Development of Murine Postoperative Ileus

“…Gastrointestinal transit was measured in Egr-1 +/+ , Egr-1 −/− and bone marrow transplanted animals 24 hours postoperatively with and without intestinal surgical manipulation by evaluating the intestinal distribution of the aboral transit of the non-absorbable tracer, fluorescein isothiocyanate-labeled dextran with an average molecular mass of 70 kDa (FD70), as previously described 7,12,19 .…”