glucagon-like-peptide-2 and Enteritis

Radiation-induced acute intestinal injury after abdominal and pelvic irradiation is a common and serious problem in the clinical setting. Glucagon-like peptide-2 (GLP-2), a 33-amino acid peptide, exerts diverse effects related to the regulation of gastrointestinal growth and function. However, GLP-2 is relatively unstable in vivo. The aim of the present study was to improve GLP-2 stability in vivo and to evaluate its therapeutic effect on acute radiation enteritis. We generated long-lasting intestinal protection peptides by conjugating human GLP-2 (hGLP-2) peptides to polyethyleneglycol (PEG) to produce mPEGylation hGLP-2 (Mono-PEG-hGLP-2) through an enzymatic site-specific transglutamination reaction. Mono-PEG-hGLP-2 synthesized under optimal reaction conditions and separated by one-step ion-exchange chromatography was found to be resistant to degradation in vitro. Pretreatment with Mono-PEG-hGLP-2 reduced the severity of radiation-induced intestinal injury, oxidative stress, and the expression of NF-κB in rats with irradiation-induced acute radiation enteritis. The enhanced biological potency of Mono-PEG-hGLP-2 highlights its potential as a therapeutic agent for intestinal diseases.

Topics: Animals; Antioxidants; Enteritis; Glucagon-Like Peptide 2; Humans; Inflammation Mediators; Interleukin-2; Intestine, Small; Male; Malondialdehyde; Polyethylene Glycols; Radiation Injuries; Rats, Sprague-Dawley; Temperature; Time Factors; Tumor Necrosis Factor-alpha

Glucagon-like peptide-2 (GLP-2) is an intestinal growth-promoting hormone used to treat short bowel syndrome. GLP-2 promotes intestinal growth through a mechanism that involves both IGF-1 and the intestinal-epithelial IGF-1 receptor (IE-IGF-1R). GLP-2 also enhances intestinal barrier function, but through an unknown mechanism. We therefore hypothesized that GLP-2-enhanced barrier function requires the IE-IGF-1R and is mediated through alterations in expression and localization of tight junction proteins. Conditional IE-IGF-1R-null and control mice were treated with vehicle or degradation-resistant Gly(2)-GLP-2 for 10 days; some animals also received irinotecan to induce enteritis. Mice were then examined for gastrointestinal permeability to 4-kDa fluorescein isothiocyanate-dextran, jejunal resistance using Ussing chambers, tight junction structure by electron microscopy, and expression and localization of tight junction proteins by immunoblot and immunohistofluorescence, respectively. GLP-2 treatment decreased permeability to 4-kDa fluorescein isothiocyanate-dextran and increased jejunal resistance (P <.05-.01), effects that were lost in IE-IGF-1R-null mice. Electron microscopy did not reveal major structural changes in the tight junctions in any group of animals. However, the tight junctional proteins claudin-3 and -7 were upregulated by GLP-2 in control (P <.05-.01) but not null mice, whereas IE-IGF-1R deletion induced a shift in occludin localization from apical to intracellular domains; no changes were observed in expression or distribution of claudin-15 and zona occludins-1. Finally, in irinotecan-induced enteritis, GLP-2 normalized epithelial barrier function in control (P < .05) but not knockout animals. In conclusion, the effects of GLP-2 on intestinal barrier function are dependent on the IE-IGF-1R and involve modulation of key components of the tight junctional complex.

Topics: Animals; Claudin-3; Claudins; Enteritis; Glucagon-Like Peptide 2; Intestinal Mucosa; Intestines; Mice; Mice, Knockout; Permeability; Receptor, IGF Type 1; Tight Junctions; Up-Regulation

Acute and/or chronic radiation enteritis can develop after radiotherapy for pelvic cancers. Experimental and clinical observations have provided evidence of a role played by acute mucosal disruption in the appearance of late effects. The therapeutic potential of acute administration of glucagon-like peptide-2 (GLP-2) against acute and chronic intestinal injury was investigated in this study.. Intestinal segments were surgically exteriorized and exposed to 16.7 or 19 Gy X-rays. The rats were treated once daily with vehicle or a protease-resistant GLP-2 derivative for 14 days before irradiation, with or without 7 days of GLP-2 after treatment. Macroscopic and microscopic observations were made 2 and 15 weeks after radiation exposure.. In the control animals, GLP-2 induced an increase in intestinal mucosal mass, along with an increase in villus height and crypt depth. GLP-2 administration before and after irradiation completely prevented the acute radiation-induced mucosal ulcerations observed after exposure to 16.7 Gy. GLP-2 treatment strikingly reduced the late radiation damage observed after 19 Gy irradiation. Microscopic observations revealed an improved organization of the intestinal wall and an efficient wound healing process, especially in the smooth muscle layers.. GLP-2 has a clear therapeutic potential against both acute and chronic radiation enteritis. This therapeutic effect is mediated through an increased mucosal mass before tissue injury and the stimulation of still unknown mechanisms of tissue response to radiation damage. Although these preliminary results still need to be confirmed, GLP-2 might be a way to limit patient discomfort during radiotherapy and reduce the risk of consequential late effects.

Topics: Acute Disease; Animals; Chronic Disease; Drug Evaluation, Preclinical; Enteritis; Glucagon-Like Peptide 2; Intestinal Mucosa; Intestine, Small; Male; Radiation Injuries, Experimental; Rats; Rats, Wistar

Glucagon-like peptide 2 (GLP-2) is a recently identified intestinal epithelium-specific growth factor that has been shown to reduce the severity of inflammatory disorders of the intestine in rodent models. We hypothesized that GLP-2 administration would be beneficial in chemotherapy-induced enteritis either by preventing injury or by promoting recovery.. Rats received no drug (control), chemotherapy alone [5-fluorouracil (5-FU), 190 mg/kg, ip] (Chemo), 5-FU followed by 3 days of GLP-2 analog (ALX-0600, 0.1 microg, sc twice daily) (CH-G), or GLP-2 analog for 6 days prior to 5-FU and for 3 days afterward (G-CH-G). Animals were pair fed. Rats received 5-bromo-2-deoxyuridine (Br-dU, 50 mg/kg, 2.5 h prior to sacrifice on Day 3 postchemotherapy) for immunohistochemical assessment of cellular proliferation.. Chemotherapy induced significant reductions in body weight, villus height, and crypt depth compared with controls. Intestinal wet weight, villus height, and crypt depth were significantly higher for the CH-G group compared with the Chemo group. The CH-G group also showed a significant improvement in villus height compared with the G-CH-G group. Crypt depth, but not jejunal wet weight or villus height, was significantly improved in the G-CH-G group compared with the Chemo group. The percentage of Br-dU-labeled cells in the intestinal crypts did not differ among the groups.. These results suggest, for the first time, that GLP-2 treatment initiated after chemotherapy administration enhances intestinal recovery. In contrast, GLP-2 treatment initiated prior to chemotherapy administration to prevent injury has less beneficial effect. GLP-2 administration may be beneficial to patients suffering from chemotherapy-induced enteritis.

Topics: Animals; Antimetabolites, Antineoplastic; Body Weight; Bromodeoxyuridine; Enteritis; Fluorouracil; Glucagon-Like Peptide 2; Glucagon-Like Peptides; Intestinal Mucosa; Jejunum; Male; Morbidity; Peptides; Rats; Rats, Sprague-Dawley