HIF-1α triggers ER stress and CHOP-mediated apoptosis in alveolar epithelial cells, a key event in pulmonary fibrosis
HIF-1α triggers ER stress and CHOP-mediated apoptosis in alveolar epithelial cells, a key event in pulmonary fibrosis
复制标题
DOI：
10.1038/s41598-018-36063-2
复制
发表时间：
2018-12-18
影响因子：
4.6
通讯作者：
Boncoeur, Emilie
中科院分区：
文献类型：
--
作者：
Delbrel, Eva;Soumare, Abdoulaye;Boncoeur, Emilie
肺泡上皮细胞(AECs)的内质网应激被认为是肺纤维化(PF)中细胞功能障碍的关键事件。然而，导致特发性肺纤维化(IPF)血管内皮细胞内质网应激和随后的未折叠蛋白反应(UPR)通路的机制仍不清楚。我们假设肺泡低氧微环境可能通过低氧诱导因子-1α(HIF-1α)产生内质网应激和血管内皮细胞凋亡。结合体外、体内和体外实验，我们研究了低氧对UPR通路和内质网应激诱导的细胞凋亡的影响，进而探讨了低氧、HIF-1α、UPR与细胞凋亡的关系。HIF-1α和促凋亡的内质网应激标志物C/EBP同源蛋白(CHOP)在博莱霉素处理的小鼠和IPF肺的增生性AEC中共表达，而在对照组中未见表达。低氧暴露大鼠肺或原代大鼠血管内皮细胞可诱导HIF-1α、CHOP和细胞凋亡标志物的表达。在原代血管内皮细胞中，低氧激活了UPR通路。药物内质网应激抑制剂和药物抑制或沉默HIF-1α均可阻止缺氧诱导的CHOP上调和细胞凋亡。有趣的是，HIF-1α在常氧AEC中的过表达增加了UPR途径、转录因子的活性和CHOP的表达。这些结果表明，缺氧和HIF-1α可触发内质网应激和CHOP介导的血管内皮细胞凋亡，提示它们在IPF的发生发展中具有潜在的作用。
Endoplasmic Reticulum (ER) stress of alveolar epithelial cells (AECs) is recognized as a key event of cell dysfunction in pulmonary fibrosis (PF). However, the mechanisms leading to AECs ER stress and ensuing unfolded protein response (UPR) pathways in idiopathic PF (IPF) remain unclear. We hypothesized that alveolar hypoxic microenvironment would generate ER stress and AECs apoptosis through the hypoxiainducible factor-1 alpha (HIF-1 alpha). Combining ex vivo, in vivo and in vitro experiments, we investigated the effects of hypoxia on the UPR pathways and ER stress-mediated apoptosis, and consecutively the mechanisms linking hypoxia, HIF-1 alpha, UPR and apoptosis. HIF-1 alpha and the pro-apoptotic ER stress marker C/EBP homologous protein (CHOP) were co-expressed in hyperplastic AECs from bleomycin-treated mice and IPF lungs, not in controls. Hypoxic exposure of rat lungs or primary rat AECs induced HIF-1 alpha, CHOP and apoptosis markers expression. In primary AECs, hypoxia activated UPR pathways. Pharmacological ER stress inhibitors and pharmacological inhibition or silencing of HIF-1 alpha both prevented hypoxia-induced upregulation of CHOP and apoptosis. Interestingly, overexpression of HIF-1 alpha in normoxic AECs increased UPR pathways transcription factors activities, and CHOP expression. These results indicate that hypoxia and HIF-1 alpha can trigger ER stress and CHOP-mediated apoptosis in AECs, suggesting their potential contribution to the development of IPF.