Sage Edouard, Mercier Olaf, Van den Eyden Frederic, de Perrot Marc, Barlier-Mur Anne Marie, Dartevelle Philippe, Eddahibi Saadia, Herve Philippe, Fadel Elie
UPRES EA2705, Laboratoire de Chirurgie Expérimentale, Hôpital Marie Lannelongue, Le Plessis Robinson, France.
Respir Res. 2008 Feb 12;9(1):19. doi: 10.1186/1465-9921-9-19.
Endothelial dysfunction is a major complication of pulmonary endarterectomy (PTE) that can lead to pulmonary edema and persistent pulmonary hypertension. We hypothesized that endothelial dysfunction is related to increased endothelial-cell (EC) death.
In piglets, the left pulmonary artery (PA) was ligated to induce lung ischemia then reimplanted into the main PA to reperfuse the lung. Animals sacrificed 5 weeks after ligation (n = 5), 2 days after reperfusion (n = 5), or 5 weeks after reperfusion (n = 5) were compared to a sham-operated group (n = 5). PA vasoreactivity was studied and eNOS assayed. EC apoptosis was assessed by TUNEL in the proximal and distal PA and by caspase-3 activity assay in the proximal PA. Gene expression of pro-apoptotic factors (thrombospondin-1 (Thsp-1) and plasminogen activator inhibitor 1 (PAI-1)) and anti-apoptotic factors vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) was investigated by QRT-PCR.
Endothelium-dependent relaxation was altered 5 weeks after ligation (p = 0.04). The alterations were exacerbated 2 days after reperfusion (p = 0.002) but recovered within 5 weeks after reperfusion. EC apoptosis was increased 5 weeks after PA ligation (p = 0.02), increased further within 2 days after reperfusion (p < 0.0001), and returned to normal within 5 weeks after reperfusion. Whereas VEGF and bFGF expressions remained unchanged, TSP and PAI-1 expressions peaked 5 weeks after ligation (p = 0.001) and returned to normal within 2 days after reperfusion.
Chronic lung ischemia induces over-expression of pro-apoptotic factors. Lung reperfusion is followed by a dramatic transient increase in EC death that may explain the development of endothelial dysfunction after PE. Anti-apoptotic agents may hold considerable potential for preventing postoperative complications.
内皮功能障碍是肺动脉内膜剥脱术（PTE）的主要并发症，可导致肺水肿和持续性肺动脉高压。我们推测内皮功能障碍与内皮细胞（EC）死亡增加有关。
在仔猪中，结扎左肺动脉（PA）以诱导肺缺血，然后将其重新植入主肺动脉以对肺进行再灌注。将结扎后5周（n = 5）、再灌注后2天（n = 5）或再灌注后5周（n = 5）处死的动物与假手术组（n = 5）进行比较。研究肺动脉血管反应性并检测内皮型一氧化氮合酶（eNOS）。通过TUNEL法在近端和远端肺动脉评估EC凋亡，并通过近端肺动脉中的半胱天冬酶-3活性测定进行评估。通过定量逆转录聚合酶链反应（QRT-PCR）研究促凋亡因子（血小板反应蛋白-1（Thsp-1）和纤溶酶原激活物抑制剂1（PAI-1））和抗凋亡因子血管内皮生长因子（VEGF）和碱性成纤维细胞生长因子（bFGF）的基因表达。
结扎后5周内皮依赖性舒张功能发生改变（p = 0.04）。再灌注后2天这些改变加剧（p = 0.002），但在再灌注后5周内恢复。肺动脉结扎后5周EC凋亡增加（p = 0.02），再灌注后2天内进一步增加（p < 0.0001），并在再灌注后5周内恢复正常。虽然VEGF和bFGF表达保持不变，但TSP和PAI-1表达在结扎后5周达到峰值（p = 0.001），并在再灌注后2天内恢复正常。
慢性肺缺血诱导促凋亡因子的过度表达。肺再灌注后EC死亡急剧短暂增加，这可能解释了PE后内皮功能障碍的发生。抗凋亡药物在预防术后并发症方面可能具有巨大潜力。
