Recombinant human MFG-E8 attenuates intestinal injury and mortality in severe whole body irradiation in rats.
Recombinant human MFG-E8 attenuates intestinal injury and mortality in severe whole body irradiation in rats.
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DOI：
10.1371/journal.pone.0046540
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Wang P
中科院分区：
文献类型：
--
作者：
Ajakaiye MA;Jacob A;Wu R;Yang WL;Nicastro J;Coppa GF;Wang P
急性放射综合征 (ARS) 的胃肠道 (GI) 综合征是由高剂量辐射后未成熟的实质干细胞耗尽引起的，并且会导致早期死亡。它与胃肠道严重的、不可修复的损伤和极低的生存率有关。由于核事故或袭击可能会导致意外的高水平辐射暴露，因此需要开发可行的全身辐射（WBI）缓解剂。因此，我们研究了重组人乳脂肪球-EGF 因子 8 (rhMFG-E8) 在减轻 WBI 后损伤中的作用。使用 Cesium-137 作为辐射源，将雄性 Sprague-Dawley 大鼠暴露于 10 Gy WBI。治疗组的动物每天皮下注射一次rhMFG-E8（166 µg/kg BW），第一次剂量在WBI后6小时给予。治疗3天后收集回肠的血液和组织样本。对一组单独的动物进行 7 天的治疗，并确定 21 天的死亡率。 rhMFG-E8 治疗在 21 天内将存活率从 31% 显着提高至 75%。此外，rhMFG-E8 治疗导致放射损伤肠粘膜损伤评分降低 36%，这与可见的组织学变化相对应。与假手术对照相比，WBI 诱导的动物中 MFG-E8 基因表达显着降低。与未处理的对照相比，rhMFG-E8 处理使 p53 和 p21 表达增加了 207% 和 84%。与此同时，抗凋亡细胞调节因子 Bcl-2 的表达增加了 80%。 p53 和 p21 水平与辐射损伤后生存率的提高相关。这些细胞调节剂在 DNA 损伤后阻止细胞，实现 DNA 修复并优化细胞存活。总而言之，这些结果表明 rhMFG-E8 通过最小化肠道细胞损伤和优化恢复来改善胃肠道综合征并提高 WBI 后的生存率。
The gastrointestinal (GI) syndrome component of acute radiation syndrome (ARS) results from depletion of immature parenchymal stem cells after high dose irradiation and contributes significantly to early mortality. It is associated with severe, irreparable damage in the GI tract and extremely low survival. There is a need for the development of viable mitigators of whole body irradiation (WBI) due to the possibility of unexpected high level radiation exposure from nuclear accidents or attacks. We therefore examined the effect of recombinant human milk fat globule-EGF factor 8 (rhMFG-E8) in mitigating damage after WBI. Male Sprague-Dawley rats were exposed to 10 Gy WBI using Cesium-137 as the radiation source. The animals in the treatment group received rhMFG-E8 (166 µg/kg BW) subcutaneously once a day with the first dose given 6 h after WBI. Blood and tissue samples from the ileum were collected after 3 days of treatment. A separate cohort of animals was treated for 7 days and the 21 day mortality rate was determined. Treatment with rhMFG-E8 significantly improved the survival from 31% to 75% over 21 days. Furthermore, rhMFG-E8 treatment resulted in a 36% reduction in the radiation injury intestinal mucosal damage score, corresponding to visible histological changes. MFG-E8 gene expression was significantly decreased in WBI-induced animals as compared to sham controls. Treatment with rhMFG-E8 increased p53 and p21 expression by 207% and 84% compared to untreated controls. This was accompanied by an 80% increase in the expression of anti-apoptotic cell regulator Bcl-2. p53 and p21 levels correlate with improved survival after radiation injury. These cell regulators arrest the cell after DNA damage and enable DNA repair as well as optimize cell survival. Taken together, these results indicate that rhMFG-E8 ameliorates the GI syndrome and improves survival after WBI by minimizing intestinal cell damage and optimizing recovery.
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影响因子：
3.7
作者：
Aziz M;Jacob A;Matsuda A;Wu R;Zhou M;Dong W;Yang WL;Wang P
通讯作者：
Wang P
影响因子：
3.4
作者：
Li Q;Martinez JD
通讯作者：
Martinez JD
DOI：
10.1073/pnas.76.5.2420
发表时间：
1979-01-01
影响因子：
11.1
作者：
DELEO, AB;JAY, G;OLD, LJ
通讯作者：
OLD, LJ
影响因子：
5.7
作者：
Matsuda, Akihisa;Jacob, Asha;Wang, Ping
通讯作者：
Wang, Ping
影响因子：
2.9
作者：
Andersen, MH;Berglund, L;Petersen, TE
通讯作者：
Petersen, TE