Growth hormone releasing hormone (GHRH) antagonists enhance endothelial barrier function and counteract the LPS-induced lung endothelial hyperpermeability, the cardinal feature of the acute respiratory distress syndrome (ARDS). The unfolded protein response (UPR) is a multifaceted molecular mechanism, strongly involved in tissue defense against injury. The current study introduces the induction of UPR by GHRH antagonists, since those peptides induced several UPR activation markers, including the inositol-requiring enzyme-1α (IRE1α), the protein kinase RNA-like ER kinase (PERK), and the activating transcription factor 6 (ATF6). On the other hand, the GHRH agonist MR-409 exerted the opposite effects. Furthermore, GHRH antagonists counteracted the kifunensine (UPR suppressor)-induced lung endothelial barrier dysfunction. Our observations suggest that UPR mediates, at least in part, the protective effects of GHRH antagonists in the lung microvasculature. To the best of our knowledge; this is the first study to provide experimental evidence in support of the hypothesis that UPR induction is a novel mechanism by which GHRH antagonists oppose severe human disease, including ARDS.

生长激素释放激素 (GHRH) 拮抗剂可增强内皮屏障功能并抵消 LPS 诱导的肺内皮渗透性过高，这是急性呼吸窘迫综合征 (ARDS) 的主要特征。未折叠蛋白反应 (UPR) 是一种多方面的分子机制，强烈参与组织防御损伤。目前的研究介绍了 GHRH 拮抗剂对 UPR 的诱导，因为这些肽诱导了几种 UPR 激活标记，包括需要肌醇的酶 1α (IRE1α)、蛋白激酶 RNA 样 ER 激酶 (PERK) 和激活转录因子6 (ATF6)。另一方面，GHRH 激动剂 MR-409 发挥了相反的作用。此外，GHRH 拮抗剂可以抵消 kifunensine（UPR 抑制剂）诱导的肺内皮屏障功能障碍。我们的观察表明，UPR 至少部分介导了 GHRH 拮抗剂在肺微血管系统中的保护作用。据我们所知；这是第一项提供实验证据以支持UPR诱导是GHRH拮抗剂对抗严重人类疾病（包括ARDS）的新机制的假设的研究。