Center for Perinatal Research, The Research Institute at Nationwide Children's Hospital, Department of Pediatric Surgery, Nationwide Children's Hospital, The Ohio State University College of Medicine, Columbus, OH, USA.
Surgery. 2011 Feb;149(2):276-83. doi: 10.1016/j.surg.2010.08.003. Epub 2010 Oct 20.
The aim of the current study was to determine whether overexpression of heparin-binding epidermal growth factor-like growth factor (HB-EGF) could protect the intestines from injury after hemorrhagic shock and resuscitation in mice.
Hemorrhagic shock and resuscitation was induced in HB-EGF transgenic and wild type mice. Cross-reacting material 197 (5 mg/kg) was administered to a subset of HB-EGF transgenic mice to block the overexpressed HB-EGF. Intestinal histologic injury scores, intestinal epithelial cell apoptosis indices, and gut barrier function were determined. The Student t test and 1-way analysis of variance were employed to compare the differences between groups.
All mice subjected to hemorrhagic shock and resuscitation had significantly increased intestinal histologic injury scores, apoptosis indices, and intestinal permeability compared with sham-operated mice. Compared with wild type mice, HB-EGF transgenic mice had significantly decreased histologic injury (mean injury grade 2.79 ± 0.84 vs 3.88 ± 1.43, P = .02), apoptosis indices (mean apoptosis index 8.77 ± 5.23 vs 17.91 ± 13.23, P = .03), and mucosal permeability (FITC-dextran 4 clearance 13.06 ± 5.67 vs 20.03 ± 7.81 nL/min/ m(2), P = .02) at 3 hours of reperfusion. HB-EGF transgenic mice subjected to hemorrhagic shock and resuscitation and treated with cross-reacting material 197 had a significantly increased histologic injury (mean injury grade 3.63 ± 1.00 vs 2.79 ± 0.84, P = .04) and mucosal permeability (FITC-dextran 4 clearance 22.87 ± 9.69 vs 13.06 ± 5.67 nL/min/cm2, P = .01) at 3 hours of reperfusion compared with non-cross-reacting material 197 treated transgenic mice, with no significant changes in apoptosis indices. Cross-reacting material 197 did not reverse the decreased apoptosis observed in HB-EGF transgenic mice subjected to hemorrhagic shock and resuscitation, which suggests that mechanisms in addition to decreased apoptosis may be responsible for the intestinal cytoprotective effects of endogenous HB-EGF overexpression.
Overexpression of HB-EGF increases resistance to hemorrhagic shock and resuscitation in mice.
本研究旨在确定肝素结合表皮生长因子样生长因子（HB-EGF）的过表达是否能保护小鼠在失血性休克和再灌注后的肠道免受损伤。
在 HB-EGF 转基因和野生型小鼠中诱导失血性休克和再灌注。用交叉反应物质 197（5mg/kg）处理部分 HB-EGF 转基因小鼠以阻断过表达的 HB-EGF。检测肠组织学损伤评分、肠上皮细胞凋亡指数和肠道屏障功能。采用学生 t 检验和单因素方差分析比较组间差异。
所有接受失血性休克和再灌注的小鼠与假手术组相比，肠组织学损伤评分、凋亡指数和肠道通透性均显著增加。与野生型小鼠相比，HB-EGF 转基因小鼠的组织学损伤显著减轻（平均损伤评分 2.79±0.84 比 3.88±1.43，P=0.02）、凋亡指数（平均凋亡指数 8.77±5.23 比 17.91±13.23，P=0.03）和黏膜通透性（FITC-右旋糖酐 4 清除率 13.06±5.67 比 20.03±7.81 nL/min/m2，P=0.02）在再灌注 3 小时时显著降低。接受失血性休克和再灌注并接受交叉反应物质 197 治疗的 HB-EGF 转基因小鼠的组织学损伤显著增加（平均损伤评分 3.63±1.00 比 2.79±0.84，P=0.04）和黏膜通透性（FITC-右旋糖酐 4 清除率 22.87±9.69 比 13.06±5.67 nL/min/cm2，P=0.01）在再灌注 3 小时时与未接受交叉反应物质 197 治疗的转基因小鼠相比显著增加，但凋亡指数无明显变化。交叉反应物质 197 不能逆转 HB-EGF 转基因小鼠在失血性休克和再灌注后观察到的凋亡减少，这表明除了凋亡减少之外，可能还有其他机制导致内源性 HB-EGF 过表达具有肠道细胞保护作用。
HB-EGF 的过表达可提高小鼠对失血性休克和再灌注的抵抗力。
