Oral PEG 15-20 protects the intestine against radiation: role of lipid rafts.
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 copolymer, PEG 15-20, to protect the intestine against the early and late effects of radiation in mice and rats and to 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 per 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 (P. 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). Parallel studies were performed in cultured rat intestinal epithelial cells treated with PEG 15-20 before radiation. Results demonstrated that PEG 15-20 prevented radiation-induced intestinal injury in rats, prevented apoptosis and lethal sepsis attributable 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.
Valuckaite
Vesta
V
Bioengineering Institute for Advanced Surgery and Endoscopy, University of Chicago, Illinois 60637, USA.
Zaborina
Olga
O
Long
Jason
J
Hauer-Jensen
Martin
M
Wang
Junru
J
Holbrook
Christopher
C
Zaborin
Alexander
A
Drabik
Kenneth
K
Katdare
Mukta
M
Mauceri
Helena
H
Weichselbaum
Ralph
R
Firestone
Millicent A
MA
Lee
Ka Yee
KY
Chang
Eugene B
EB
Matthews
Jeffrey
J
Alverdy
John C
JC
D000284:Administration, Oral; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001422:Bacterial Adhesion / Q000187:drug effects; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D007082:Ileum / Q000187:drug effects* / Q000382:microbiology / Q000473:pathology / Q000528:radiation effects; D007410:Intestinal Diseases / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000382:microbiology / Q000473:pathology / Q000528:radiation effects; D008297:Male; D021962:Membrane Microdomains / Q000187:drug effects* / Q000378:metabolism / Q000382:microbiology / Q000528:radiation effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008970:Molecular Weight; D011092:Polyethylene Glycols / Q000008:administration & dosage*; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000472:pathogenicity; D011833:Radiation Injuries, Experimental / Q000382:microbiology / Q000473:pathology / Q000517:prevention & control*; D011837:Radiation-Protective Agents / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018805:Sepsis / Q000382:microbiology / Q000517:prevention & control*; D013997:Time Factors; D014774:Virulence / Q000187:drug effects
D011837:Radiation-Protective Agents; D011092:Polyethylene Glycols; D002784:Cholesterol