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Am J Physiol Gastrointest Liver Physiol (October 15, 2009). doi:10.1152/ajpgi.00328.2009
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Research Article

Oral PEG 15-20 protects the intestine against radiation: role of lipid rafts

Vesta Valuckaite,1 Olga Zaborina,2 Jason Long,1 Martin Hauer-Jensen,3 Junru Wang,4 Christopher Holbrook,1 Alexander Zaborin,1 Kenneth Drabik,1 Mukta Katdare,1 Helena Mauceri,1 Ralph Weichselbaum,1 Millicent A Firestone,5 Ka Yee C. Lee,6 Eugene B. Chang,1 Jeffrey B. Matthews,7 and John C. Alverdy1,*

1University of Chicago 2 3University 4University of Arkansas for Medical Sciences and Surgical Service 5Argonne National Laboratory, Argonne 6The University of Chicago 7Univ. of chicago

Submitted 5 August 2009 ; revision received 8 October 2009 ; accepted in final form 8 October 2009

ABSTRACT

Intestinal injury following abdominal radiation therapy or accidental exposure remains a significant clinical problem that can result in varying degrees of mucosal destruction such as ulceration, vascular sclerosis, intestinal wall fibrosis, loss of barrier function, and even lethal gut-derived sepsis. We determined the ability of a high molecular weight polyethylene glycol based co-polymer, PEG 15-20, to protect the intestine against the early and late effects of radiation in mice and rats and determine its mechanism of action by examining cultured rat intestinal epithelia. Rats were exposed to fractionated radiation in an established model of intestinal injury whereby an intestinal segment is surgically placed into the scrotum and radiated daily. Radiation injury score was decreased in a dose-dependent manner in rats gavaged with 0.5 or 2.0 g/kg/day of PEG 15-20 (n=9-13/group, p<0.005). Complementary studies were performed in a novel mouse model of abdominal radiation followed by intestinal inoculation with Pseudomonas aeruginosa, a common pathogen that causes lethal gut-derived sepsis following radiation. Mice mortality was decreased by 40% in mice drinking 1% PEG 15-20 (n=10/group, p<0.001). In both models, oral PEG 15-20 was administered as a supplement in drinking water. Parallel studies were performed in cultured rat intestinal epithelial cells treated with PEG 15-20 prior to radiation. Results demonstrated that PEG 15-20 prevented radiation induced intestinal injury in rats, prevented apoptosis and lethal sepsis due to P. aeruginosa in mice, and protected cultured intestinal epithelial cells from apoptosis and microbial adherence and possible invasion. PEG 15-20 appeared to exert its protective effect via its binding to lipid rafts by preventing their coalescence- a hallmark feature in intestinal epithelial cells exposed to radiation.

Pseudomonas aeruginosa; gut-derived sepsis; apoptosis; radiation injury


* University of Chicago jalverdy{at}surgery.bsd.uchicago.edu






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