Mucosal permeability after subclinical intestinal ischemia-reperfusion injury: An exploration of possible mechanisms

doi:10.1016/0022-3468(95)90133-7

Journal of Pediatric Surgery

Volume 30, Issue 4, April 1995, Pages 568-572

https://doi.org/10.1016/0022-3468(95)90133-7 Get rights and content

Abstract

Changes in mucosal permeability may be important in the etiology of necrotizing enterocolitis. The authors have previously shown that subclinical ischemia-reperfusion injury results in increased permeability in the rat intestine, and have partially characterized this phenomenon. In the present study the authors attempt to determine the mechanism by which these changes occur. Six-week-old rats underwent 10-minute superior mesenteric artery occlusion (SMAO) or sham, and mucosal permeability to ⁵¹CrEDTA was measured after 30 minutes. Rats were pretreated with saline, inhibitors of oxygen free radicals (superoxide dismutase + catalase, vitamin E, allopurinol, α-phenyl-N-tert butyl-nitrone), inhibitors of eicosanoids (indomethacin, quinacrine, diethylcarbamazine, 13-azaprostanoic acid), the putative cytoprotective agent prostaglandin E₂, or the inhibitor of neutrophil free radical production fructose 1–6 diphosphate. None of the agents significantly attenuated the increase in mucosal permeability caused by SMAO, although indomethacin and prostaglandin E₂ significantly exacerbated the permeability changes. To further explore the role of neutrophils, tissue myeloperoxidase was measured 30 minutes after SMAO. There was no significant difference in myeloperoxidase levels between sham and SMAO animals. These data suggest that the early increase in mucosal permeability after subclinical ischemia-reperfusion injury is not mediated by oxygen free radicals, eicosanoids, or neutrophils. The deleterious effect of indomethacin and prostaglandin E₂ suggests a possible protective role for the cyclooxygenase system, but further studies are necessary to elucidate this possibility.

References (53)

RM Kliegman
Models of the pathogenesis of necrotizing enterocolitis
J Pediatr
(1990)
AM Kosloske
A unifying hypothesis for pathogenesis and prevention of necrotizing enterocolitis
J Pediatr
(1990)
JC Langer et al.
Mucosal permeability to 51Cr EDTA following subclinical intestinal ischemia-reperfusion injury in the weanling rat
J Pediatr Surg
(1993)
JC Langer et al.
Increased mucosal permeability after ischemia-reperfusion injury is mediated by local tissue factors
J Pediatr Surg
(1992)
JC Langer et al.
Histamine does not mediate mucosal permeability changes after subclinical intestinal ischemia-reperfusion injury
J Pediatr Surg
(1993)
JC Langer et al.
Mucosal permeability in the immature rat intestine: Effects of ischemia-reperfusion, cold stress, hypoxia, and drugs
J Pediatr Surg
(1993)
JK Ramage et al.
Effect of immunological reactions on rat intestinal epithelium. Correlation of increased gut permeability to 51Cr-EDTA and ovalbumin during inflammation and anaphylaxis in the rat
Gastroenterology
(1988)
J Sun et al.
Fructose 1–6 diphosphate prevents intestinal ischemic reperfusion injury and death in rats
Gastroenterol
(1990)
BO Anderson et al.
Mechanisms of neutrophil-mediated tissue injury
J Surg Res
(1991)
PP Bradley et al.
Measurement of cutaneous inflammation: Estimation of neutrophil content with an enzyme marker
J Invest Dermatol
(1982)

DN Granger et al.

Xanthine oxidase inhibitors attenuate ischemia-induced vascular permeability changes in the cat intestine

Gastroenterol

(1986)

DN Granger et al.

Superoxide radicals in feline intestinal ischemia

Gastroenterology

(1981)

K Vohra et al.

Ischemic injury to newborn rabbit ileum: Protective role of human superoxide dismutase

J Pediatr Surg

(1989)

SM Megison et al.

Prolonged survival and decreased mucosal injury after low-dose enteral allopurinol prophylaxis in mesenteric ischemia

J Pediatr Surg

(1990)

T Mozes et al.

Role of PGF2-alpha in the superior mesenteric artery-induced shock

J Surg Res

(1989)

MF Brown et al.

The role of leukocytes in mediating injury of intestinal ischemia/reperfusion

J Pediatr Surg

(1990)

JC Langer et al.

Corticosteroids do not alter mucosal permeability after subclinical intestinal ischemia-reperfusion injury in the rat

Pediatr Surg Int

(1994)

VK Mittal et al.

Role of oxygen free radical scavengers in preservation of intestinal villi in the presence of ischemia

AL Tappel et al.

In vivo lipid peroxidation: Measurement via exhaled pentane and protection by vitamin E

JG Garcia et al.

Improved survival in intestinal ischemia by allopurinol not related to xanthineoxidase inhibition

J Surg Res

(1990)

EG Janzen et al.

The effect of phenyl tert-butyl nitrone (PBN) on CC14-induced rat liver injury detected by proton magnetic resonance imaging (MRI) in vivo and electron microscopy (EM)

Free Radic Res Commun

(1990)

JL Grosfeld et al.

Comparative effects of indomethacin, prostaglandin E1, and ibuprofen on bowel ischemia

J Pediatr Surg

(1983)

T Otamiri et al.

Phospholipase A2 inhibition prevents mucosal damage associated with small intestinal ischaemia in rats

Gut

(1988)

W Hsueh et al.

Platelet-activating factor-induced ischemic bowel necrosis: An investigation of secondary mediators in its pathogenesis

Am J Pathol

(1986)

C Lancaster et al.

Intestinal lesions produced by prednisolone: Prevention (cytoprotection) by 16,16-dimethyl prostaglandin E2

Am J Physiol

(1978)

GB Bulkley

Free radicals and other reactive oxygen metabolites: Clinical relevance and the therapeutic efficacy of antioxidant therapy

Surgery

(1993)

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HT and postconditioning with SEV influence the expression and activity of several small intestinal proteins that are possibly involved in intestinal I/R-mediated events following successful cardiopulmonary resuscitation.
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Background. Pathophysiological mechanisms and ways to intervene on intestinal barrier dysfunction following small intestinal ischaemia and prolonged reperfusion are still not fully clarified.
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It has been postulated that subclinical I/R injury to the intestine may result in increased mucosal permeability to noxious intraluminal proteins and bacteria, leading to bacterial translocation. Langer et al7,15 suggested that the increased mucosal permeability after the subclinical I/R injury led to bacterial translocations. They have used a weaning rat model to show that I/R injury results in an early reversible increasing mucosal permability to 51Cr EDTA, but they did not study bacterial translocation.7
Background/Purpose: The purpose of this study was to evaluate the detection of bacterial translocation after subclinical ischemia reperfusion injuries in rats with the polymerase chain reaction (PCR) technique. Methods: Six-week-old weaning rats were divided into 3 groups. (1) Experiment rats (n = 20) were gavaged with 10¹⁰ Escherichia coli followed by superior mesentery artery occluded for 10 minutes, then reperfused for 30 minutes. (2) Control rats (n = 20) received bacterial gavage. (3) Group 3 were sham rats (n = 20). After the procedure, 3 mL of blood was obtained from the portal vein. The terminal ileum and mesenteric lymph node (MLN) near the terminal ileum were removed. E coli DNA was detected in blood and MLN samples by PCR, and histological changes were examined. Results: E coli DNA detection in ischemia-reperfusion (I/R) group animals was 6 of 20 (30%) in the MLN and 2 of 20 (10%) in the blood. PCR was negative in all the rats in the control group and in the sham group (P <.05). There were no significant differences in the histological examination of rat intestines. Conclusion: These data suggest that subclinical intestinal I/R injury results in bacterial translocation. Also, PCR is a highly sensitive and rapid method to detect the presence of microbial DNA. J Pediatr Surg 35:41-43. Copyright © 2000 by W.B. Saunders Company.
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Since we have shown that orally administered IL-6 can reduce or eliminate bacterial translocation in hemorrhagic shock models,5,8,9 a detailed investigation of cellular events in the intestine after hemorrhage was carried out using the electron-dense marker HRP. HRP has been widely used to document blood flow and permeability in a number of models.13,14 The data presented in this report show that orally administered IL-6 restores intestinal circulation and reduces leakage of marker from the lumen to the circulation after hemorrhage.
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^☆: Supported by Medical Research Council of Canada Grant No. MA-10878.

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Mucosal permeability after subclinical intestinal ischemia-reperfusion injury: An exploration of possible mechanisms☆

Abstract

J Pediatr

J Pediatr

J Pediatr Surg

J Pediatr Surg

J Pediatr Surg

J Pediatr Surg

Gastroenterology

Gastroenterol

J Surg Res

J Invest Dermatol

Gastroenterol

Gastroenterology

J Pediatr Surg

J Pediatr Surg

J Surg Res

J Pediatr Surg

Corticosteroids do not alter mucosal permeability after subclinical intestinal ischemia-reperfusion injury in the rat

Pediatr Surg Int

Role of oxygen free radical scavengers in preservation of intestinal villi in the presence of ischemia

In vivo lipid peroxidation: Measurement via exhaled pentane and protection by vitamin E

Improved survival in intestinal ischemia by allopurinol not related to xanthineoxidase inhibition

J Surg Res

The effect of phenyl tert-butyl nitrone (PBN) on CC14-induced rat liver injury detected by proton magnetic resonance imaging (MRI) in vivo and electron microscopy (EM)

Free Radic Res Commun

Comparative effects of indomethacin, prostaglandin E1, and ibuprofen on bowel ischemia

J Pediatr Surg

Phospholipase A2 inhibition prevents mucosal damage associated with small intestinal ischaemia in rats

Gut

Platelet-activating factor-induced ischemic bowel necrosis: An investigation of secondary mediators in its pathogenesis

Am J Pathol

Intestinal lesions produced by prednisolone: Prevention (cytoprotection) by 16,16-dimethyl prostaglandin E2

Am J Physiol

Free radicals and other reactive oxygen metabolites: Clinical relevance and the therapeutic efficacy of antioxidant therapy

Surgery