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Proinflammatory role of leukocyte-derived Egr-1 in the development of murine postoperative ileus.

ABSTRACT: Early growth response gene-1 (Egr-1) is an important inflammatory transcription factor. We hypothesize that leukocyte-derived Egr-1 plays a key inflammatory role in causing postoperative ileus.Wild-type, Egr-1 knockout, and chimera mice (constructed by irradiation followed by injection with Egr-1(+/+) or Egr-1(-/-) bone marrow) were subjected to surgical manipulation of the gastrointestinal tract to induce ileus. Reverse-transcription polymerase chain reaction, Western blot, and immunohistochemistry quantified and localized Egr-1. Lumenal transit of nonabsorbable fluorescein isothiocyanate-labeled dextran and in vitro organ bath techniques measured functional gastrointestinal motility. Inflammatory mediator expressions were measured by Griess reaction, enzyme-linked immunosorbent assay, and multiplex Luminex assay.Intestinal manipulation rapidly and significantly induced Egr-1 messenger RNA and protein within the inflamed muscularis externa. Egr-1 was colocalized early to smooth muscle and enteric neurons and later in extravasated monocytes after surgery when postoperative ileus was functionally prominent. The functional severity of postoperative ileus was significantly ameliorated in mice deficient in Egr-1(-/-) and chimera wild-type mice transplanted with Egr-1(-/-) bone marrow, whereas knockout mice with Egr-1(+/+) bone marrow again displayed significant ileus. Motility was mechanistically associated in Egr-1(-/-) gene deficiency with a down-regulation in the release of nitric oxide, prostanoids, monocyte chemoattractant protein-1, macrophage inflammatory protein-1alpha, interleukin-6, interleukin-1, and granulocyte colony-stimulating factor, as well as a decrease in the recruitment of leukocytes into the manipulated muscle wall of the intestine compared with wild-type mice.Leukocyte-derived Egr-1 plays an early critical inflammatory role in the initiation of the postoperative inflammatory response, which leads to a prolonged decreased in gastrointestinal motility after intestinal surgery.

SUBMITTER: Schmidt J

PROVIDER: S-EPMC3319384 | biostudies-literature | 2008 Sep

REPOSITORIES: biostudies-literature

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Proinflammatory role of leukocyte-derived Egr-1 in the development of murine postoperative ileus.

Schmidt Joachim J Stoffels Burkhard B Moore Beverley A BA Chanthaphavong R Savanh RS Mazie Abigail R AR Buchholz Bettina M BM Bauer Anthony J AJ

Gastroenterology 20080604 3

<h4>Background & aims</h4>Early growth response gene-1 (Egr-1) is an important inflammatory transcription factor. We hypothesize that leukocyte-derived Egr-1 plays a key inflammatory role in causing postoperative ileus.<h4>Methods</h4>Wild-type, Egr-1 knockout, and chimera mice (constructed by irradiation followed by injection with Egr-1(+/+) or Egr-1(-/-) bone marrow) were subjected to surgical manipulation of the gastrointestinal tract to induce ileus. Reverse-transcription polymerase chain re ...[more]

PMID: 18652830

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Project description:IntroductionIntestinal manipulation (IM) during abdominal surgery results in intestinal inflammation leading to hypomotility or ileus. Mast cell activation is thought to play a crucial role in the pathophysiology of postoperative ileus (POI). However, this conclusion was mainly drawn using mast cell-deficient mouse models with abnormal Kit signaling. These mice also lack interstitial cells of Cajal (ICC) resulting in aberrant gastrointestinal motility even prior to surgery, compromising their use as model to study POI. To avoid these experimental weaknesses we took advantage of a newly developed knock-in mouse model, Cpa3(Cre/+) , devoid of mast cells but with intact Kit signaling.DesignThe role of mast cells in the development of POI and intestinal inflammation was evaluated assessing gastrointestinal transit and muscularis externa inflammation after IM in two strains of mice lacking mast cells, i.e. Kit(W-sh/W-sh) and Cpa3(Cre/+) mice, and by use of the mast cell stabilizer cromolyn.ResultsKit(W-sh/W-sh) mice lack ICC networks and already revealed significantly delayed gastrointestinal transit even before surgery. IM did not further delay intestinal transit, but induced infiltration of myeloperoxidase positive cells, expression of inflammatory cytokines and recruitment of monocytes and neutrophils into the muscularis externa. On the contrary, Cpa3(Cre/+) mice have a normal network of ICC and normal gastrointestinal. Surprisingly, IM in Cpa3(Cre/+) mice caused delay in gut motility and intestinal inflammation as in wild type littermates mice (Cpa3(+/+) ). Furthermore, treatment with the mast cell inhibitor cromolyn resulted in an inhibition of mast cells without preventing POI.ConclusionsHere, we confirm that IM induced mast cell degranulation. However, our data demonstrate that mast cells are not required for the pathogenesis of POI in mice. Although there might be species differences between mouse and human, our results argue against mast cell inhibitors as a therapeutic approach to shorten POI.

Project description:Study designRetrospective observational study of a cohort of consecutive patients.ObjectivesPostoperative ileus (POI) is associated with a variety of adverse effects. Although the incidence of and risk factors for POI following spinal surgery have been reported, the frequency and pathology of POI after spinal corrective surgery for adult spinal deformity (ASD) are still largely unknown. The study objectives were to: (1) clarify the prevalence and clinical significance of POI, (2) elucidate the risk factors for POI, (3) determine radiographically which preoperative and/or postoperative spinal parameters predominantly influence the risk of POI after spinal corrective surgery for ASD.MethodsWe included data from 144 consecutive patients who underwent spinal corrective surgery. Perioperative medical complications and clinical information were extracted from patient electronic medical records. Preoperative radiographic parameters and changes in radiographic parameters after surgery were compared between patients with and without POI. Multivariate logistic regression analyses were performed to clarify potential risk factors for POI.ResultsPOI developed in 25/144 (17.4%) patients and was the most common complication in the present study. The frequencies of smoking, gastroesophageal reflux disease, and lateral lumbar interbody fusion (LLIF), as well as the duration of surgery were significantly greater in the group with POI versus the group without POI. Among radiographic parameters, only the change in thoracolumbar kyphosis (TLK) from before to after surgery was significantly larger in the group with POI. Multivariate logistic regression analysis showed that male sex, LLIF and large changes in TLK from before to after surgery were significantly associated with the development of POI.ConclusionsThese results suggested that LLIF and large corrections in TLK were independent risk factors for POI after ASD surgery. When patients with ASD have large TLK preoperatively, and it is determined that a large correction is needed, physicians must be aware of the potential for occurrence of POI.

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Proinflammatory role of leukocyte-derived Egr-1 in the development of murine postoperative ileus.

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Proinflammatory role of leukocyte-derived Egr-1 in the development of murine postoperative ileus.

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