Our previous studies indicated that calcitonin gene-related peptide (CGRP) alleviates hyperoxia-induced lung injury and suggested the possible involvement of autophagy in this process. Herein, we aimed to further explore the potential involvement of tumor protein p53 (TP53) and autophagy in the mode of action of CGRP against hyperoxia-induced lung injury in vitro and in vivo. The study conducted tests on type II alveolar epithelial cells (AECII) and rats that were subjected to hyperoxia treatment or combined treatment of hyperoxia with CGRP, CGRP inhibitor, rapamycin (an autophagy agonist), 3-methyladenine (3-MA, an autophagy inhibitor), TP53 silencing/inhibitor (pifithrin-α), or expression vector/activator (PRIMA-1 (2,2-bis(hydroxymethyl)-3-quinuclidinone)) and their corresponding controls. We found that oxidative stress, apoptosis, and autophagy were all increased by hyperoxia treatment in vitro. However, treating AECII cells with CGRP reversed hyperoxia-induced oxidative stress and apoptosis but further promoted autophagy. In addition, the combined treatment with rapamycin or TP53 silencing with CGRP promoted the effect of CGRP, while contrary results were obtained with combined therapy with 3-MA or TP53 overexpression. In vivo, the number of hyperoxia-induced autophagosomes was promoted in the lung tissue of neonatal rats. Furthermore, hyperoxia increased the expression levels of AMP-activated protein kinase (AMPK) alpha 1 (also known as protein kinase AMP-activated catalytic subunit alpha 1 (PRKAA1)) but inhibited TP53 and mechanistic target of rapamycin (MTOR); these expression trends were regulated by CGRP treatment. In conclusion, we showed that CGRP can attenuate hyperoxia-induced lung injury in neonatal rats by enhancing autophagy and regulating the TP53/AMPK/MTOR crosstalk axis.

我们之前的研究表明降钙素基因相关肽（CGRP）可以减轻高氧诱导的肺损伤，并表明自噬可能参与这一过程。在此，我们的目的是在体外和体内进一步探讨肿瘤蛋白p53（TP53）和自噬在CGRP对抗高氧诱导的肺损伤的作用模式中的潜在参与。该研究对II型肺泡上皮细胞（AECII）和接受高氧治疗或与CGRP、CGRP抑制剂、雷帕霉素（一种自噬激动剂）、3-甲基腺嘌呤（3-MA，一种自噬抑制剂）联合高氧治疗的大鼠进行了测试)、TP53 沉默/抑制剂 (pifithrin-α) 或表达载体/激活剂 (PRIMA-1 (2,2-双(羟甲基)-3-奎宁环酮)) 及其相应的对照。我们发现体外高氧处理会增加氧化应激、细胞凋亡和自噬。然而，用 CGRP 处理 AECII 细胞可逆转高氧诱导的氧化应激和细胞凋亡，但进一步促进自噬。此外，雷帕霉素或TP53沉默与CGRP联合治疗可促进CGRP的作用，而与3-MA或TP53过表达联合治疗则获得相反的结果。在体内，新生大鼠肺组织中高氧诱导的自噬体数量增加。此外，高氧增加了 AMP 激活蛋白激酶 (AMPK) α 1（也称为蛋白激酶 AMP 激活催化亚基 α 1 (PRKAA1)）的表达水平，但抑制了 TP53 和雷帕霉素（MTOR）的机制靶点；这些表达趋势受到 CGRP 处理的调节。总之，我们发现 CGRP 可以通过增强自噬和调节 TP53/AMPK/MTOR 串扰轴来减轻新生大鼠高氧诱导的肺损伤。