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

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 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.

Phosphate-Containing Polyethylene Glycol Polymers Prevent Lethal Sepsis by Multidrug-Resistant Pathogens

“…Whether Pi-PEG interacts with bacterial membranes and affects bacterial membrane signal transduction to the cytosol is unknown and will require further inquiry. However, we have previously shown that PEG 15-20 interacts with epithelial membrane lipid rafts, key structures involved in signal transduction, preventing dysregulation of barrier function and apoptosis (13). Bacteria also have membrane lipid microdomains to which Pi-PEG might bind and affect signaling.…”

“…The parent polymer in this study, PEG 15-20 (commercial name of a polymer purchased from Aldrich) was chosen because of previous work demonstrating its ability to protect the intestinal epithelium (13,22). This polymer consists of ϳ9-kDa PEG arms appended to a bis-phenol A moiety at the center of the polymer chain, giving an ABA structure wherein the B group is small but very hydrophobic and A groups are hydrophilic homopolymers (see Fig.…”

“…The rationale for delivering phosphate is based on the conserved response of a wide variety of microbes that express virulence and a lethal phenotype when the phosphate supply is limited (7)(8)(9)(10)(11)(12). We covalently bonded phosphate (P i ) onto PEG 15-20, a high-molecular-weight polymer with an ABA structure (A is hydrophilic and B is hydrophobic) that we previously demonstrated distributes along the entire intestinal axis and remains functionally durable in mouse intestine (13,14). As the data below demonstrate, Pi-PEG 15-20 combines the effect of inorganic phosphate and a specific ABA polymer, resulting in effective inhibition of the multidirectional signaling between microbes, pathogens, and the host response, such that lethal sepsis due to multidrug-resistant pathogens present in the gut is prevented.…”

“…NMR was performed on a Bruker DMX 500 NMR apparatus. 1 H-NMR data were recorded at 500 MHz, 13 C data were recorded at 125 MHz, and 31 P data were recorded at 202 MHz. Synthesis of other phosphorylated polymers.…”

Animal models of intestinal fibrosis: new tools for the understanding of pathogenesis and therapy of human disease

“…PEG 15-20, a high-molecular-weight polyethylene glycolbased copolymer, prevents radiation-induced intestinal injury in rats and also displays an antifibrotic effect (134), and treatment of TNBS murine colitis with the pentoxifilline metabolite M-1 has been reported to significantly reduce colon weight, thickness, and total collagen content (103). Biological films or gels containing hyaluronan, modified chitosan-dextran, or carboxymethyl chitosan have been used with some success in preventing or decreasing intra-abdominal adhesions abrasion and anastomosis models in rats (23,69,99,139).…”