The Protective Effects of Glucagon-like Peptide -2 on Intestinal Barrier Function of Doxorubicin Chemotherapy in Rats
|School||Dalian Medical University|
|Keywords||glucagon-like peptide-2 chemotherapy doxorubicin gut barrier|
Purpose: Chemotherapy is an important cancer treatment adjunct, but its damage to the intestinal mucosa is a common cause of gastrointestinal side effects of chemotherapy. Serious damage can lead to intestinal mucosal barrier dysfunction. Clinical manifestations of mucosal barrier injury is mucositis, diarrhea, ulcers, abdominal pain, malnutrition, and even lead to bacteremia, septic shock, multiple organ dysfunction. Mucositis is a common reason for delayed chemotherapy, resulting in prolonged cycles of chemotherapy, significantly increased the risk of infection and bleeding, resulting in cancer mortality. Also increase the economic burden of health care, we can see it have clinical significance that mucosal injury prevention research and effective solutions to the intestinal barrier damage caused by chemotherapy.Glucagon-like peptide -2 (GLP-2) is the recent discovery of the intestinal epithelial specific growth factor, is the product of the intestinal endocrine L cells of glucagon after the original gene-specific expression. Distinguished from other polypeptide growth factors is that GLP-2 is in the role of intestinal specificity. Some studies of foreign countries suggest that GLP-2 can promote the growth of normal intestinal mucosa, and enhance intestinal barrier function, and verified in animal models can promote repair and healing of mucosal in injury inflammatory bowel disease, short bowel syndrome, intestinal ischemia, radiation enteritis and pancreatitis. There are also a study found that GLP-2 on intestinal mucosa of mice transplanted with the role of promoting recovery and growth; also found that GLP-2 studies the effect was stronger than the other growth factor. At present GLP-2 treatment of ulcerative colitis and short bowel syndrome were carried outⅡandⅢclinical trials. It shows that the advantages of GLP-2 in intestinal mucosal injury prevention and control diseases in a good clinical application.Adriamycin is a widely used clinical chemotherapeutic drugs, a variety of tumors have a strong sensitivity to it, but also often accompanied by side effects of intestinal damage. And the more increasing doses of chemotherapy in the pursuit of clinical efficacy, the more aggravated the mucosal damage. In this experiment, high-dose chemotherapy with adriamycin induced model to assess the GLP-2 to chemotherapy in rats barrier function of intestinal mucosa and to verify the protective effect of Glp-2, and explore new prevention and treatment methods of chemotherapy-induced intestinal mucosal injury.Methods: Male Wistar rats inbred 24 and weighing between 220-250g were randomly divided into 4 groups, n=6. A group: control group (Control); B group: GLP -2 control group (GLP-2); C group: chemotherapy with adriamycin (ADM); D group: Adriamycin chemotherapy + GLP -2 treatment group (ADM + GLP-2). Daily weigh the rats for each group. On group D and B group rats were administrated with GLP-2, GLP-2 dissolved in 0.01mol / L PBS, according to 250μg/kg/d, 2 times a day by subcutaneous injection, continuous 3 days. On group C Group D of intraperitoneal chemotherapy, doxorubicin dissolved in saline, at 20mg/kg, on the first day of intraperitoneal injection. On control group of injection of PBS with the same amount of glp-2 buffer, 2 times daily by subcutaneous injection for 3 days. On the 4th day, after weighing for each group, all rats were sacrificed, blood samples were measured in blood collected diamine oxidase (DAO) content; aseptic bacterial culture of mesenteric lymph nodes, 37℃for 48 hours, calculate each gram of tissue in the colony forming unit (CFU) compared the bacterial translocation; making small intestine tissue, chemical detection of small intestinal mucosa of malondialdehyde (MDA) and myeloperoxidase (MPO) content; small intestine tissue paraffin sections HE staining and measurement of the small intestine morphology and intestinal villous height, crypt depth; compared before and after treatment in each group changes in body weight in rats.Results:1, The weight of each group before and after treatment comparison: Four groups of rats showed decreased body weight, C group weight loss was significantly higher than A group, body weight decreased (21.25±6.44g vs. 4.27±10.44g, P <0.05); D group weight loss was significantly higher than A group, body weight decreased significantly (18.43±4.32g vs. 4.27±10.44g, P <0.05); The weight loss of D group was less than C group’s, but the difference not significant.2, Comparison of morphology among the groups: C group of small intestine villus height and crypt depth were significantly lower than A group (villus height:143.92±24.13μm vs. 231.95±83.81μm, P <0.05; crypt depth:51.12±16.28μm vs. 85.36± 33.22μm, P <0.05), D group and B group than C group was significantly higher villus height (253.24±17.45μm and 251.27±63.33μm vs.143.92±24.13μm, P <0.01). D group and B group than C group of crypt depth was significantly better (84.17±5.85μm and 89.83±16.01μm vs. 51.12±16.28μm, P <0.05).3, Comparison of the content of plasma diamine oxidase (DAO) among the groups: C group of DAO levels compared with A group’s were significantly higher (85.12±14.78 U/L vs. 63.15±22.64 U/L, P <0.01) , ADM + GLP-2 group of DAO content compared with C group’s was significantly lower (56.07±12.26 U/L vs. 85.12±14.78U/L, P <0.05).4, Comparison of each group in the small intestinal mucosa malondialdehyde (MDA) content: C group of MDA levels than A group and B group’s were significantly higher (1.83±0.57 nmol / mgprot vs. 0.42±0.06 nmol / mgprot and 0.40±0.37 nmol / mgprot, P <0.01), D group of MDA levels were significantly lower than C group’s (0.74±0.49nmol/mgprot vs. 1.83±0.57nmol/mgprot, P <0.01).5, Comparison of each group in small intestinal myeloperoxidase (MPO) activity: C group of MPO activity compared with A group and B group’s were significantly higher (0.78±0.29 units/g-wet-film vs. 0.24±0.16 units/g-wet-film and 0.28±0.08 units/g-wet-film, P <0.01), D group of MPO activity was significantly lower than C group’s (0.47±0.09 units/g-wet-film vs. 0.78±0.29 units/g-wet-film, P <0.05).6, Each group of bacteria ectopic mesenteric lymph nodes compared: C group of bacterial culture of mesenteric lymph node bacterial colony forming unit (CFU) than A group and B group’s were significantly higher (38.33±20.41 vs. 10.00±10.00 and 13.33±5.77, P <0.05), CFU number of D group than C group’s was significantly lower (7.50±9.57 vs. 38.33±20.41, P <0.01).Conclusion: 1, High-dose intraperitoneal injection of adriamycin induced body weight decreased significantly, GLP-2 could reduced that adriamycin on the impact of weight loss, but the difference was not significant. 2, GLP-2 reduced intestinal mucosa damage by chemotherapy in rats. 3, GLP-2 reduced back to chemotherapy rat intestinal inflammation. 4, GLP-2 has a protective effect of mechanical barriers on doxorubicin chemotherapy ileum.