4-Phenylbutyrate Prevents Endoplasmic Reticulum Stress-Mediated Apoptosis Induced by Heatstroke in the Intestines of Mice
4-Phenylbutyrate Prevents Endoplasmic Reticulum Stress-Mediated Apoptosis Induced by Heatstroke in the Intestines of Mice
复制标题
4-苯基丁酸可预防小鼠肠道中暑引起的内质网应激介导的细胞凋亡
DOI：
10.1097/shk.0000000000001419
复制
发表时间：
2020-07-01
期刊：
影响因子：
3.1
通讯作者：
Su, Lei
中科院分区：
文献类型：
--
作者：
Cao, Yan;Liu, Zhifeng;Su, Lei
摘要目的：中暑可引起严重的肠道生理功能障碍。然而，这种情况的潜在机制是未知的，治疗策略是不可用的。在这项研究中，我们探讨了内质网（ER）应激信号在这一过程中的作用，并评估是否预处理小鼠与ER应激抑制剂可以减轻肠道损伤。方法：采用雄性小鼠建立中暑模型。小鼠在暴露于热应激之前用4-苯基丁酸（4-PBA）预处理。采用苏木精-伊红（H&E）染色和透射电镜观察小肠形态学变化。TUNEL法检测肠细胞凋亡。Western blot检测内质网应激相关蛋白和凋亡相关蛋白的表达。结果如下：与对照组相比，中暑小鼠肠组织出现明显的损伤和上皮细胞凋亡，并伴有内质网应激相关蛋白的表达明显增加。4-PBA能显著降低肠损伤评分和肠上皮细胞凋亡水平。此外，在4-PBA处理后，肠道ER应激相关蛋白GRP 78、PERK、p-eIF 2 α、ATF 4和CHOP的水平降低。结论：我们的研究结果表明，ER应激介导的细胞凋亡途径在热应激诱导的肠损伤过程中被激活。4-PBA能抑制中暑引起的肠道内质网应激，减轻肠道损伤。我们提供的证据表明，4-PBA的有益效果是密切相关的ER应激介导的细胞凋亡的抑制。这些发现表明，ER应激可能是中暑患者的一个新的治疗靶点。
ABSTRACT Objective: Heatstroke can induce serious physiological dysfunction in the intestine. However, the underlying mechanisms of this condition are unknown, and therapeutic strategies are not available. In this study, we explored the role of endoplasmic reticulum (ER) stress signaling in this process and assessed whether pretreating mice with an inhibitor of ER stress could alleviate intestinal damage. Methods: A heatstroke model was established in male mice. Mice were pretreated with 4-phenylbutyrate (4-PBA) before exposure to heat stress. Intestinal morphological changes were observed by hematoxylin and eosin (H&E) staining and transmission electron microscopy. The TUNEL assay was used to detect intestinal apoptosis. The expression of the ER stress-related proteins and apoptosis-related proteins was investigated by the Western blot assay. Results: Compared with control group, mice with heatstroke exhibited evidence of intestinal injury and epithelial apoptosis, accompanied by significantly increased expression of ER stress-related proteins in the intestines. The intestinal injury score and level of intestinal epithelial apoptosis were significantly reduced after administration of 4-PBA. Furthermore, the levels of the intestinal ER stress-related proteins GRP78, PERK, p-eIF2α, ATF4, and CHOP were decreased after 4-PBA treatment. Conclusions: Our results indicate that the ER stress-mediated apoptosis pathway is activated during heat stress-induced intestinal injury. 4-PBA can inhibit heatstroke-induced intestinal ER stress and attenuate intestinal injury. We provide evidence that the beneficial effect of 4-PBA is closely related to the inhibition of ER stress-mediated apoptosis. These findings suggest that ER stress may be a novel therapeutic target in patients with heatstroke.