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Experimental and Clinical Necrotizing Enterocolitis
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Paediatric Surgery.
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Necrotizing enterocolitis (NEC), a severe inflammatory disorder of the gastrointestinal tract with high morbidity and mortality, affects primarily preterm infants. The diagnosis represents a challenging task, and no biomarker has been found to aid early diagnosis with high accuracy. Microdialysis has been widely used to detect metabolites of anaerobic metabolism, enabling a local and early detection of ischemia. This thesis aims to evaluate the possibility of detecting intestinal ischemic stress in experimental and clinical  NEC, by use of rectal intraluminal microdialysis.

Intraluminal rectal microdialysis was performed on rats subjected to total intestinal ischemia. Metabolites of ischemia were detectable in both ileum and rectum, with raised glycerol concentrations and lactate/pyruvate ratios. Elevated concentrations of glycerol correlated to increasing intestinal histopathological injury.

Experimental early NEC was induced in newborn rat pups, by hypoxia/re-oxygenation treatment. Development of NEC was confirmed by histopathology. Elevated glycerol concentrations were detected by rectal microdialysis.

The genetic alterations following experimental NEC in rat pups were studied with microarray. Immunohistochemistry staining was performed for tight junction proteins claudin-1 and claudin-8. Several genes were altered in experimental NEC, mainly genes regulating tight junctions and cell adhesion. Immunohistochemistry revealed reduced expression of claudin-1.

A prospective study was conducted on preterm infants with a gestational age of less than 28 weeks. The infants were admitted to a neonatal intensive care unit, and observed during a 4-week period. Rectal microdialysis was performed twice a week, and blood was drawn for analysis of I-FABP. A total of 15 infants were included in the study, whereof four infants developed NEC, and 11 served as controls. Rectal glycerol and I-FABP displayed high concentrations, which varied considerably during the observation periods, both in NEC and controls. No differences in either glycerol or I-FABP concentrations were seen in the NEC-group vs. the controls.

In conclusion, rectal microdialysis can detect metabolites of intestinal ischemia, both in experimental and clinical NEC. Rectal microdialysis is safe and could provide a valuable non-invasive aid to detect hypoxia-induced intestinal damage or ischemic stress in extremely preterm infants. In this study however, it was not possible to predict the development of clinical NEC using microdialysis or I-FABP.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2013. , 47 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 898
Keyword [en]
Necrotizing, Enterocolitis, Ischemia, Microdialysis, Intraluminal, I-FABP
National Category
Surgery
Research subject
Pediatric Surgery
Identifiers
URN: urn:nbn:se:uu:diva-197754ISBN: 978-91-554-8655-6 (print)OAI: oai:DiVA.org:uu-197754DiVA: diva2:615556
Public defence
2013-05-30, Rosénsalen, Ing 95/96, NB, Akademiska Barnsjukhuset, Uppsala, 13:00 (Swedish)
Opponent
Supervisors
Available from: 2013-05-06 Created: 2013-04-03 Last updated: 2013-08-30Bibliographically approved
List of papers
1. Intestinal ischemia measured by intraluminal microdialysis
Open this publication in new window or tab >>Intestinal ischemia measured by intraluminal microdialysis
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2012 (English)In: Scandinavian Journal of Clinical and Laboratory Investigation, ISSN 0036-5513, E-ISSN 1502-7686, Vol. 72, no 1, 59-66 p.Article in journal (Refereed) Published
Abstract [en]

Objective.

To evaluate the possibility of detecting intestinal ischemia by intraluminal microdialysis and comparing the ileum and colon.

Methods.

The studies were performed on male Sprague-Dawley rats. In the fi rst part of the study, microdialysis catheters were placed in the sigmoid part of the colon and in the subcutaneous adipose tissue. In the second part of the study, microdialysis catheters were placed in the lumen of the ileum and the colon. The infrarenal aorta was clamped proximal to the cranial mesenteric artery. Microdialysate levels of glucose, lactate, pyruvate and glycerol were measured. Intestinal specimens were removed at the end of the ischemic period for microscopic evaluation.

Results.

Intraluminal microdialysis could detect early signs of ischemic injury in the ileum, as well as in the colon, with a marked increase of lactate, lactate/pyruvate ratio and glycerol. The increased levels of intraluminal glycerol showed a positive correlation to prolonged ischemia and to higher degrees of intestinal damage.

Conclusion.

Intraluminal measurement of glycerol is a good marker for intestinal ischemia. Intraluminal microdialysis in the colon is easily accessible through the rectum, and ay prove to be a valuable clinical tool for diagnosing intestinal ischemia.

Keyword
Intestinal, ischemia, microdialysis, intraluminal
National Category
Surgery
Research subject
Pediatric Surgery
Identifiers
urn:nbn:se:uu:diva-159807 (URN)10.3109/00365513.2011.629307 (DOI)000299283700009 ()22103734 (PubMedID)
Available from: 2011-12-07 Created: 2011-10-10 Last updated: 2017-12-08Bibliographically approved
2. Intraluminal intestinal microdialysis detects markers of hypoxia and cell damage in experimental necrotizing enterocolitis
Open this publication in new window or tab >>Intraluminal intestinal microdialysis detects markers of hypoxia and cell damage in experimental necrotizing enterocolitis
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2012 (English)In: Journal of Pediatric Surgery, ISSN 0022-3468, E-ISSN 1531-5037, Vol. 47, no 9, 1646-1651 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND/PURPOSE:

Necrotizing enterocolitis (NEC) represents one of the gravest complications in premature infants and carries significant morbidity and mortality. There is a great need for improved diagnostic methods to reduce the severity and incidence of NEC. The aim of the study was to investigate if intraluminal microdialysis can detect intestinal ischemia in newborn rats with induced experimental NEC.

METHODS:

The studies were performed on 1-day-old Sprague-Dawley rat pups. Experimental NEC was induced using hypoxia/reoxygenation treatment. Microdialysis catheters were rectally inserted and placed in the rectosigmoid part of the colon. Microdialysate levels of glucose, lactate, pyruvate, and glycerol were measured. Intestinal specimens were collected at the end of the experiments for microscopic evaluation.

RESULTS:

Intraluminal microdialysis revealed signs of intestinal hypoxia and cellular damage, with a marked increase of lactate and glycerol. Microscopic evaluation confirmed intestinal damage in the NEC group.

CONCLUSION:

Intraluminal microdialysis can detect intestinal hypoxic stress and mucosal cell membrane decay in a rat model of NEC. Intestinal intraluminal microdialysis is easily accessible through the rectum and may be a useful noninvasive complement to other methods in the assessment of NEC.

National Category
Surgery
Research subject
Pediatric Surgery
Identifiers
urn:nbn:se:uu:diva-183821 (URN)10.1016/j.jpedsurg.2012.03.086 (DOI)000308810400013 ()22974600 (PubMedID)
Available from: 2012-11-01 Created: 2012-11-01 Last updated: 2017-12-07Bibliographically approved
3. Genes regulating tight junctions and cell adhesion are altered in early experimental necrotizing enterocolitis
Open this publication in new window or tab >>Genes regulating tight junctions and cell adhesion are altered in early experimental necrotizing enterocolitis
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2013 (English)In: Journal of Pediatric Surgery, ISSN 0022-3468, E-ISSN 1531-5037, Vol. 48, no 11, 2308-2312 p.Article in journal (Refereed) Published
Abstract [en]

Background/purpose:

Necrotizing enterocolitis (NEC) represents one of the gravest complications in preterm infants and carries significant morbidity and mortality. Increased intestinal permeability may play an important role in the pathogenesis of NEC. In this study we investigated the genes regulating structural proteins such as tight junctions (TJ) and cell adhesion in a neonatal rat model of early NEC, as well as the expression of TJ proteins by immunohistochemistry staining.

Methods:

The studies were performed on Sprague-Dawley rat pups. Experimental NEC was induced using hypoxia/reoxygenation treatment on day 1 after birth. Intestinal specimens from the ileum were obtained, mRNA was purified and the transcriptome was analyzed using microarray. Immunohistochemistry staining was performed for TJ proteins.

Results:

We found several TJ genes such as claudins 1, 8, 14, 15 and gap junction protein to be affected. Immunohistochemistry staining for TJ protein claudin-1 revealed decreased levels in experimental NEC compared to controls. Alterations in genes involved in the inflammatory response was confirmed, along with several genes regulating proteins used as biomarkers for NEC.

Conclusion:

This study indicates that tight junctions and cell adhesion may play a critical role in the pathogenesis of early experimental NEC. Better understanding of the pathogenesis of NEC may lead to novel strategies for the prevention and treatment of NEC.

National Category
Surgery Basic Medicine
Research subject
Pediatric Surgery; Pathology
Identifiers
urn:nbn:se:uu:diva-197750 (URN)10.1016/j.jpedsurg.2013.06.027 (DOI)000327140800022 ()
Note

De två sista författarna delar sistaförfattarskapet.

Available from: 2013-04-03 Created: 2013-04-03 Last updated: 2017-12-06Bibliographically approved
4. Intestinal intraluminal glycerol and plasma I-FABP levels in preterm infants with necrotizing enterocolitis
Open this publication in new window or tab >>Intestinal intraluminal glycerol and plasma I-FABP levels in preterm infants with necrotizing enterocolitis
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2016 (English)In: Clinics in Surgery, Vol. 1, no 1085, 1-6 p.Article in journal (Refereed) Published
Abstract [en]

Background/Purpose: Necrotizing enterocolitis (NEC) is highly associated with prematurity and is characterized by bowel necrosis and multi-organ failure. There is a strong need for improved diagnostic methods to reduce the significant morbidity and mortality associated with NEC. The aim of this single centre prospective study was to investigate the possibility to detect early signs of NEC, by using rectal intraluminal microdialysis and plasma intestinal fatty acid binding protein (I-FABP) in preterm infants admitted to a level III neonatal intensive care unit.

Methods: The study was performed on extremely preterm infants with a gestational age of less than 28 weeks. During a 4-week period after birth, rectal intraluminal microdialysate levels of glucose, lactate, pyruvate and glycerol were measured, and plasma was collected for I-FABP analysis. Infants not developing NEC served as controls.

 Results: Microdialysis revealed signs of intestinal hypoxic or ischemic damage and cell membrane degradation, with a marked increase of both intraluminal glycerol and plasma I-FABP in infants developing NEC, as well as in infants suffering from other complications. The microdialysate levels of glucose, lactate and pyruvate were too low to be evaluated in this setting. All infants tolerated the microdialysis well without any complications.

Conclusion: Elevated levels of intraluminal glycerol and plasma I-FABP suggests mucosal cell membrane degradation and hypoxic or ischemic damage in preterm infants developing NEC, as well as in preterm infants suffering from other complications such as volvulus, sepsis or respiratory distress. However, it was not possible to predict development of NEC before clinical diagnosis using these markers. 

National Category
Surgery
Research subject
Pediatric Surgery
Identifiers
urn:nbn:se:uu:diva-197752 (URN)
Available from: 2013-04-03 Created: 2013-04-03 Last updated: 2017-01-04

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