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Early disturbance of microvascular function precedes chemotherapy-induced intestinal injury

Journal article
Authors Edvard Abel
Tor Ekman
Elisabet Warnhammar Finnborg
Ragnar Hultborn
Eva Jennische
Stefan Lange
Published in Dig Dis Sci
Volume 50
Issue 9
Pages 1729-33
ISSN 0163-2116 (Print)
Publication year 2005
Published at Institute of Selected Clinical Sciences, Department of Oncology
Institute of Anatomy and Cell Biology
Institute of Laboratory Medicine, Dept of Clinical Bacteriology
Pages 1729-33
Language en
Links www.ncbi.nlm.nih.gov/entrez/query.f...
Keywords Animals, Antineoplastic Agents, Phytogenic/*toxicity, Endothelium/pathology, Etoposide/*toxicity, Intestinal Mucosa/pathology, Intestines/*blood supply/*drug effects/pathology, Ion Channels/*drug effects, Male, Microcirculation, Permeability, Rats, Rats, Sprague-Dawley, Stem Cells/physiology
Subject categories Cancer and Oncology

Abstract

Intestinal injury 4-48 hr after cytotoxic therapy (etoposide phosphate, 100 mg/kg body weight [bw], intravenously [i.v.]) was studied in rats using ligated intestinal loops. Chromium-51 ethylenediaminetetraacetic acid ((51)Cr-EDTA) and rubidium-86 chloride ((86)RbCl) were deposited intraluminally to determine the extent of the increase in intestinal permeability and ion channel disruption. Evans Blue (EB) was used for detection of endothelial leakage. Intestinal morphology was documented. Endothelial dysfunction, as observed by an increased extravasation of EB, was evident already 4 hr after cytotoxic therapy. Intestinal epithelial injury, as observed by an increase in (51)Cr-EDTA permeation and a decrease in (86)Rb absorption, occurred after 48 hr. Finally, histology disclosed a reduced crypt cell proliferation, displayed as a decrease in Ki67-positive cells. The findings suggest that, in the development of intestinal injury after cytotoxic therapy, endothelial disruption is an early event, whereafter epithelial dysfunction and crypt stem cell arrest occur. This knowledge could be of importance in the design of future intervention trials.

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