Department of Cardiac Surgery, Lanzhou University Second Hospital, Lanzhou University, Lanzhou, Gansu, China; Second Clinical Medical College, Lanzhou University, Lanzhou, Gansu, China.
Department of Anesthesiology, Lanzhou University Second Hospital, Lanzhou University, Lanzhou, Gansu, China.
J Heart Lung Transplant. 2022 Oct;41(10):1391-1400. doi: 10.1016/j.healun.2022.06.005. Epub 2022 Jul 23.
The preferred configuration for bridging patients with respiratory failure while awaiting lung transplantation is venovenous extracorporeal membrane oxygenation (VV ECMO). However, the protective effect of VV ECMO on the lung, as well as the underlying mechanisms, are still unknown.
We investigated the role of VV ECMO in preventing lung injury in vivo using a rat model. Additionally, the effects of Hippo/YAP signaling on alveolar epithelial type II cells (AT2)-mediated alveolar epithelial recovery in VV ECMO rats were also investigated. In the bronchoalveolar lavage fluid (BALF) and lung tissue, RNA sequencing, lung injury, edema, and cytokine expression were evaluated.
VV ECMO significantly improved severe hypoxemia, reduced lung edema, and inflammatory response, and altered alveolar epithelial function, as indicated by reduced protein concentrations in BALF. This was associated with Hippo/YAP signaling activation, according to RNA sequencing analysis. Furthermore, we discovered that after VV ECMO, AT2 cells proliferated and differentiated, and this increase in AT2 cell activity was correlated to the increased nuclear expression of YAP, which is critical for alveolar epithelial recovery from lung injury. During VV ECMO, verteporfin-induced YAP inhibition and the loss of the oxygenator delayed lung alveolar epithelial recovery and led to a prolonged inflammatory response.
These findings suggest that VV ECMO protects against lung injury by activating the Hippo/YAP signaling pathway. Strategies aimed at increasing YAP activity in AT2 cells could thus aid alveolar epithelial recovery, making VV ECMO easier for lung transplantation.
在等待肺移植期间，为呼吸衰竭患者搭桥的首选方案是静脉-静脉体外膜肺氧合（VV ECMO）。然而，VV ECMO 对肺的保护作用及其潜在机制尚不清楚。
我们使用大鼠模型研究了 VV ECMO 在预防肺损伤中的作用。此外，还研究了 Hippo/YAP 信号通路在 VV ECMO 大鼠中对肺泡上皮细胞 II 型（AT2）介导的肺泡上皮恢复的影响。在支气管肺泡灌洗液（BALF）和肺组织中，评估了 RNA 测序、肺损伤、水肿和细胞因子表达。
VV ECMO 可显著改善严重低氧血症、减少肺水肿和炎症反应，并改变肺泡上皮功能，BALF 中蛋白浓度降低。根据 RNA 测序分析，这与 Hippo/YAP 信号通路的激活有关。此外，我们发现 VV ECMO 后 AT2 细胞增殖和分化，而这种 AT2 细胞活性的增加与 YAP 的核表达增加有关，YAP 对于肺损伤后肺泡上皮的恢复至关重要。在 VV ECMO 期间，verteporfin 诱导的 YAP 抑制和氧气供应器的丢失延迟了肺肺泡上皮的恢复，并导致炎症反应延长。
这些发现表明，VV ECMO 通过激活 Hippo/YAP 信号通路来保护肺免受损伤。因此，增加 AT2 细胞中 YAP 活性的策略可能有助于肺泡上皮恢复，使 VV ECMO 更有利于肺移植。
