Department of Anesthesiology, Affiliated Hospital of Zunyi Medical University, Zunyi, 563000, China; Department of Anesthesiology, Affiliated Hospital of Chengdu University, Chengdu, 610081, China.
Guizhou Key Laboratory of Anesthesia and Organ Protection, Zunyi Medical University, Zunyi, 563000, China.
Biomed Pharmacother. 2018 Oct;106:747-754. doi: 10.1016/j.biopha.2018.06.125. Epub 2018 Jul 11.
Apoptosis is a cellular mechanism contributing to cardiac surgery using cardiopulmonary bypass (CPB)-induced lung injury. The ubiquitous PI3K/Akt pathway regulates proliferation, apoptosis and differentiation by controlling a broad range of target proteins including NF-κB and GSK-3β. The roles of the PI3K/Akt/NF-κB and PI3K/Akt/GSK-3β pathways in CPB-related lung injury are unclear.
Seventy-two male Sprague-Dawley rats were assigned into sham, CPB, Wortmannin (Wtn) and insulin-like growth factor-I (IGF-I) groups (n = 18, each). Six subjects per group were evaluated at each of three time points: Prior to CPB (T1); opening of the left hilus pulmonis (T2); and 90 min after CPB (T3). Arterial blood specimens were obtained at each time point to test respiratory and oxygenation indices. Left lung tissues were processed for H&E and TUNEL staining. Western blot was employed to evaluate protein levels and activities of Akt, phospho-Akt (p-Akt), GSK-3β, phospho-GSK-3β (p-GSK-3β) and nuclear NF-κB.
Lung ischemia/reperfusion and CPB caused notable lung injury, as evidenced by lung functional decline and pathological deterioration, accompanied by increases in apoptosis and expression levels of p-Akt, p-GSK-3β and nuclear NF-κB in lungs (all P < 0.05 vs. Sham). At T3, Wtn-treated CPB subjects showed worsened lung function and pathological lung structures, as well as apoptosis in lungs (all P < 0.05 vs. CPB); additionally, Wtn inhibited Akt phosphorylation and slightly, but significantly increased expression of nuclear NF-κB (both P < 0.001 vs. CPB). Conversely, treatment of subjects with IGF-I increased Akt phosphorylation (P < 0.001 vs. CPB), inhibited expression of nuclear NF-κB (P = 0.008 vs. CPB), improved lung function and tissue morphology (both P < 0.05 vs. CPB), and reduced apoptosis in lungs (P < 0.001 vs. CPB). Neither Wtn nor IGF-I did alter GSK-3β phosphorylation levels (P = 0.836 and P = 0.669 vs. CPB, respectively).
The PI3K/Akt/NF-κB pathway played a role in CPB-related lung injury, possibly through mediating apoptosis in lungs. GSK-3β, a signaling effector that also participated in CPB-induced apoptosis in lungs, but was not regulated by the PI3K/Akt pathway in this context.
细胞凋亡是一种参与体外循环（CPB）诱导肺损伤的细胞机制。普遍存在的 PI3K/Akt 通路通过控制包括 NF-κB 和 GSK-3β 在内的广泛的靶蛋白，调节增殖、凋亡和分化。PI3K/Akt/NF-κB 和 PI3K/Akt/GSK-3β 通路在 CPB 相关肺损伤中的作用尚不清楚。
72 只雄性 Sprague-Dawley 大鼠被分为假手术、CPB、渥曼青霉素（Wtn）和胰岛素样生长因子-I（IGF-I）组（n=18，每组）。每组 6 只动物在三个时间点进行评估：CPB 前（T1）；左肺门开放时（T2）；CPB 后 90 分钟（T3）。在每个时间点采集动脉血标本，以检测呼吸和氧合指数。左肺组织进行 H&E 和 TUNEL 染色。采用 Western blot 法检测 Akt、磷酸化 Akt（p-Akt）、GSK-3β、磷酸化 GSK-3β（p-GSK-3β）和核 NF-κB 的蛋白水平和活性。
肺缺血再灌注和 CPB 导致明显的肺损伤，表现为肺功能下降和病理恶化，同时肺组织中凋亡和 p-Akt、p-GSK-3β 和核 NF-κB 的表达水平增加（均 P<0.05 与 Sham 组相比）。在 T3 时，Wtn 处理的 CPB 组肺功能恶化，肺结构病理恶化，肺组织凋亡（均 P<0.05 与 CPB 组相比）；此外，Wtn 抑制 Akt 磷酸化，轻度但显著增加核 NF-κB 的表达（均 P<0.001 与 CPB 组相比）。相反，IGF-I 处理组增加 Akt 磷酸化（P<0.001 与 CPB 组相比），抑制核 NF-κB 的表达（P=0.008 与 CPB 组相比），改善肺功能和组织形态（均 P<0.05 与 CPB 组相比），并减少肺组织中的凋亡（P<0.001 与 CPB 组相比）。Wtn 和 IGF-I 均未改变 GSK-3β 的磷酸化水平（P=0.836 和 P=0.669 与 CPB 组相比）。
PI3K/Akt/NF-κB 通路在 CPB 相关肺损伤中发挥作用，可能通过介导肺组织中的凋亡。GSK-3β 是一种信号效应物，也参与 CPB 诱导的肺组织凋亡，但在这种情况下不受 PI3K/Akt 通路调节。
