glucagon-like-peptide-2 and Acute-Disease

Acute graft-versus-host disease (aGVHD) is a life-threatening complication after allogeneic haematopoietic cell transplantation, with gastrointestinal (GI) tract involvement (GI aGVHD) being one of the leading causes of morbidity and mortality. Whilst systemic steroids are the standard first-line treatment for aGVHD, approximately 50% of patients become steroid refractory (SR), which is associated with poor outcomes. Existing options for SR-GVHD are limited, and there is a significant unmet need for new non-immunosuppressive treatment approaches in patients with GI aGVHD. Here, we review newer concepts in the pathogenesis of GI aGVHD and present the evidence for the role of glucagon-like peptide 2 (GLP-2) in maintaining and protecting GI epithelial cells, including the enterocytes, intestinal stem cells and Paneth cells, which are direct targets of aGVHD. Finally, we discuss the therapeutic rationale for GLP-2 treatment as a tissue regeneration approach and the potential use of the novel GLP-2 analogue apraglutide as an adjunctive treatment for GI aGVHD.

Topics: Acute Disease; Glucagon-Like Peptide 2; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Steroids; Transplantation, Homologous

Intestinal adaptation is the natural compensatory mechanism that occurs when the bowel is lost due to trauma. The adaptive responses, such as crypt cell proliferation and increased nutrient absorption, are critical in recovery, yet poorly understood. Understanding the molecular mechanism behind the adaptive responses is crucial to facilitate the identification of nutrients or drugs to enhance adaptation. Different approaches and models have been described throughout the literature, but a detailed descriptive way to essentially perform the procedures is needed to obtain reproducible data. Here, we describe a method to estimate important endpoints and proliferative markers of small intestinal injury and compensatory hyperproliferation using a model of chemotherapy-induced mucositis in mice. We demonstrate the detection of proliferating cells using a cell cycle specific marker, as well as using small intestinal weight, crypt depth, and villus height as endpoints. Some of the critical steps within the described method are the removal and weighing of the small intestine and the rather complex software system suggested for the measurement of this technique. These methods have the advantages that they are not time-consuming, and that they are cost-effective and easy to carry out and measure.

Topics: Acute Disease; Adaptation, Physiological; Animals; Antineoplastic Agents; Biomarkers; Body Weight; Bromodeoxyuridine; Cell Proliferation; Disease Models, Animal; Endpoint Determination; Female; Glucagon-Like Peptide 1; Glucagon-Like Peptide 2; Intestinal Mucosa; Intestine, Small; Mice, Inbred C57BL; Mucositis

To investigate the protective effect of glucagon-like peptide 2 (GLP-2) on intestinal barrier dysfunction in severe acute pancreatitis and to explore the putative mechanism of this effect.. Thirty rats were randomly divided into 3 groups. Group 1 received sham operation. Severe acute pancreatitis was induced in group 2 and group 3 via retrograde injection of 3% sodium taurocholate to the pancreatic duct. Rats in group 3 were peritoneally injected with GLP-2. Intestinal barrier dysfunction was characterized by the histological measurements and concentration of plasma diamine oxidase. The tissue sections of ileum were collected for the detection of proliferating cell nuclear antigen protein and apoptosis.. Glucagon-like peptide 2 administration improved the ileal mucosal injury, which was also demonstrated by the histological score of ileal mucosa. The concentration of diamine oxidase was decreased in rats with acute pancreatitis treated with GLP-2. Acute pancreatitis-induced epithelial cell apoptosis was partly prevented by GLP-2. Immunohistochemical staining of proliferating cell nuclear antigen protein was increased in group 3 compared with that in group 2.. Results from this study suggest that GLP-2 has a protective effect on intestinal barrier dysfunction in rats with severe acute pancreatitis via mechanisms closely involving promotion of cell growth and inhibition of intestinal epithelial cell apoptosis.

Topics: Acute Disease; Amine Oxidase (Copper-Containing); Animals; Apoptosis; Cell Proliferation; Epithelial Cells; Glucagon-Like Peptide 2; Ileum; Intestinal Mucosa; Pancreatitis; Proliferating Cell Nuclear Antigen; Rats; Rats, Wistar

To investigate the influence of glucagon-like peptide-2 (GLP-2) on intestinal lymphocyte homing receptor-integrin alpha 4 beta 7 and homing ligand-intestinal mucosal addressin cell adhesion molecule-1 (MAdCAM-1) in mice with acute pancreatitis (AP).. A total of 96 mice were divided into three groups randomly (n=32 in each group): AP group, GLP-2 group and control group. Murine AP model was reproduced by intraperitoneal injection of caerulein and lipopolysaccharides (LPS). GLP-2 (250 microg/kg) was injected intraperitoneally at 15 minutes after the establishment of model, then it was injected twice a day for 3 days in GLP-2 group, while the mice in control group received normal saline instead. Mice were sacrificed at 6, 12, 24 and 48 hours after reproduction of AP, and tissue specimens were harvested. Integrin alpha 4 beta 7 positive peripheral blood lymphocytes were determined by flow cytometry. The expression of MAdCAM-1 in the terminal ileum mucosa and Peyer patch was measured by immunohistochemistry. Same observations were also done in the control and GLP-2 groups.. Compared with control group, integrin alpha 4 beta 7 positive lymphocyte in peripheral blood and the expression of MAdCAM-1 in the terminal ileum mucosa and Peyer patch were significantly reduced at 6, 12, 24 and 48 hours in AP mice (all P<0.05). Integrin alpha 4 beta 7 positive lymphocyte and the expression of MAdCAM-1 were markedly higher in GLP-2 group than those in AP group (all P<0.05), but were lower in GLP-2 group than those in control group (all P>0.05).. Administration of GLP-2 may restore expression of integrin alpha 4 beta 7 and MAdCAM-1, promote lymphocyte homing to intestine, thus improve the immunological function of intestine.

Topics: Acute Disease; Animals; Disease Models, Animal; Glucagon-Like Peptide 2; Immunoglobulins; Integrins; Intestinal Mucosa; Intestines; Lymphocytes; Mice; Mucoproteins; Pancreatitis; Random Allocation

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