Section of Pediatric Surgery, Department of Surgery, University of Michigan, Mott Children's Hospital, Ann Arbor, Michigan 48109-4211, USA.
J Surg Res. 2013 Sep;184(1):365-73. doi: 10.1016/j.jss.2013.03.089. Epub 2013 Apr 17.
Application of distractive forces to small bowel induces intestinal growth, or enterogenesis. This emerging area of research may provide treatment for short bowel syndrome. Glucagon-like peptide 2(GLP-2) has also been reported to induce small bowel growth after bowel resection. We hypothesized that exogenous GLP-2 will result in enhanced distraction-induced enterogenesis.
Distraction-induced model was performed in 10-wk-old C57BL/6 mice using osmotic forces with high molecular weight polyethylene glycol (PEG)-stretch. Four groups were studied: Control group (PEG-/GLP-2-); PEG-stretch (PEG+/GLP-2-); GLP-2 control (PEG-/GLP-2+); and GLP-2 stretch (PEG+/GLP-2+). GLP-2 was given via subcutaneous osmotic pump over the 5 d of experiment. Morphology was measured by histomicrography. Epithelial cell (EC) proliferation was measured with proliferating cell nuclear antigen immunofluorescent staining. Total intestinal growth and blood vessel volume was assessed with Micro computed tomography volumetry. Vascular endothelial growth factor, fibroblast growth factor 1 and 2, and platelet-derived growth factor were measured by reverse-transcriptase polymerase chain reaction.
EC proliferation increased significantly in all groups compared with controls, but was greatest in the GLP-2 stretch group. Diameter and length significantly increased in the PEG-stretch and GLP-2 stretch groups. Moreover, there was statistically greater diameter, crypt depth and EC proliferation in the GLP-2 stretch versus PEG-stretch groups. GLP-2 stretch vessel volume was greater than all other groups and was significantly increased compared with controls. The relative expression of platelet-derived growth factor increased significantly in the PEG-stretch group versus the Control group.
GLP-2 had an additive effect on EC proliferation, tissue growth, histomorphology, and vascularization. We also demonstrated a unique action of GLP-2, the enhancement of intestinal vascularization. The combination of enterogenesis and GLP-2 may yield an improved approach to treat short bowel syndrome.
对小肠施加牵拉力量会诱导肠生长，即肠发生。这一新兴研究领域可能为短肠综合征提供治疗方法。胰高血糖素样肽 2（GLP-2）在肠切除后也被报道能诱导小肠生长。我们假设外源性 GLP-2 将增强牵拉诱导的肠发生。
使用高分子量聚乙二醇（PEG）拉伸对 10 周龄 C57BL/6 小鼠进行牵拉诱导模型。研究了 4 组：对照组（PEG-/GLP-2-）；PEG 拉伸组（PEG+/GLP-2-）；GLP-2 对照组（PEG-/GLP-2+）；和 GLP-2 拉伸组（PEG+/GLP-2+）。在实验的 5 天中，通过皮下渗透泵给予 GLP-2。通过组织学显微镜测量形态。用增殖细胞核抗原免疫荧光染色测量上皮细胞（EC）增殖。通过 Micro CT 体视学评估总肠生长和血管体积。通过逆转录聚合酶链反应测量血管内皮生长因子、成纤维细胞生长因子 1 和 2 以及血小板衍生生长因子。
与对照组相比，所有组的 EC 增殖均显著增加，但 GLP-2 拉伸组增加最多。PEG 拉伸和 GLP-2 拉伸组的直径和长度均显著增加。此外，GLP-2 拉伸组的直径、隐窝深度和 EC 增殖均显著大于 PEG 拉伸组。GLP-2 拉伸组的血管体积大于其他所有组，与对照组相比显著增加。PEG 拉伸组的血小板衍生生长因子相对表达显著增加。
GLP-2 对 EC 增殖、组织生长、组织形态和血管生成具有附加作用。我们还证明了 GLP-2 的独特作用，即增强肠血管生成。肠发生和 GLP-2 的结合可能为治疗短肠综合征提供一种改进的方法。
