King R C, Laubach V E, Kanithanon R C, Kron A M, Parrino P E, Shockey K S, Tribble C G, Kron I L
Department of Surgery, University of Virginia Health Sciences Center, Charlottesville 22908, USA.
Ann Thorac Surg. 1998 Nov;66(5):1732-8. doi: 10.1016/s0003-4975(98)00991-6.
Cyclic guanosine monophosphate (cGMP) is a potent second messenger for the nitric oxide pathway in the pulmonary vasculature. Increased cytosolic cGMP levels elicit pulmonary vasodilatation resulting in decreased pulmonary vascular resistance and maximized pulmonary function after ischemia-reperfusion injury. We hypothesized that the addition of a membrane-permeable cGMP analogue (8-bromo-cGMP) to a Euro-Collins (EC) preservation solution would ameliorate pulmonary reperfusion injury better than prostaglandin E1 injection alone after prolonged hypothermic ischemia.
All lungs from New Zealand White rabbits (weight, 3 to 3.5 kg) were harvested en bloc, flushed with EC solution, and reperfused with whole blood for 30 minutes. Group 1 lungs (immediate control) were immediately reperfused. Group 2 lungs (control) were stored inflated at 4 degrees C for 18 hours before reperfusion. Groups 3 and 4 lungs were flushed with EC solution containing 200 micromol/L 8-bromo-cGMP and stored at 4 degrees C for 18 and 30 hours, respectively. Fresh, nonrecirculated venous blood was used to determine single-pass pulmonary venous-arterial oxygen gradients at 10-minute intervals. Assays for cGMP, cyclic adenosine monophosphate, nitric oxide synthase activity, and myeloperoxidase were performed on all lung tissue samples. Wet to dry weight ratios were determined after 2 weeks of passive desiccation.
Oxygenation (venous-arterial oxygen gradient), pulmonary artery pressure, pulmonary vascular resistance, and edema formation were significantly improved in groups 3 and 4 (addition of 8-bromo-cGMP to EC plus 18 or 30 hours of hypothermic ischemia). Hypothermic storage (groups 2, 3, and 4) decreased both nitric oxide synthase activity and myeloperoxidase levels compared with immediate reperfusion (group 1).
These results suggest that the addition of a membrane-permeable cGMP analogue to an EC pulmonary flush solution improves pulmonary function after prolonged storage compared with EC and prostaglandin (E1) preservation alone. The finding of myeloperoxidase reduced levels after hypothermic storage and subsequent reperfusion may suggest a more important role for pulmonary hemodynamic control in mitigating pulmonary reperfusion injury.
环磷酸鸟苷（cGMP）是肺血管中一氧化氮途径的一种强效第二信使。胞质cGMP水平升高会引起肺血管舒张，从而导致肺血管阻力降低，并使缺血再灌注损伤后的肺功能最大化。我们假设，在长时间低温缺血后，向Euro-Collins（EC）保存液中添加一种可透过细胞膜的cGMP类似物（8-溴-cGMP），比单独注射前列腺素E1能更好地改善肺再灌注损伤。
取新西兰白兔（体重3至3.5千克）的所有肺脏进行整块摘取，用EC溶液冲洗，并以全血再灌注30分钟。第1组肺脏（即刻对照组）即刻进行再灌注。第2组肺脏（对照组）在4℃充气保存18小时后再灌注。第3组和第4组肺脏分别用含200微摩尔/升8-溴-cGMP的EC溶液冲洗，并在4℃保存18小时和30小时。使用新鲜的、非循环的静脉血每隔10分钟测定一次单通道肺静脉-动脉氧梯度。对所有肺组织样本进行cGMP、环磷酸腺苷、一氧化氮合酶活性和髓过氧化物酶的检测。在被动干燥2周后测定湿重与干重之比。
第3组和第4组（向EC中添加8-溴-cGMP并进行18或30小时低温缺血）的氧合（静脉-动脉氧梯度）、肺动脉压、肺血管阻力和水肿形成均得到显著改善。与即刻再灌注（第1组）相比，低温保存（第2、3和4组）使一氧化氮合酶活性和髓过氧化物酶水平均降低。
这些结果表明，与单独使用EC和前列腺素（E1）保存相比，向EC肺冲洗液中添加一种可透过细胞膜的cGMP类似物可改善长时间保存后的肺功能。低温保存及随后再灌注后髓过氧化物酶水平降低这一发现可能表明肺血流动力学控制在减轻肺再灌注损伤中发挥着更重要的作用。
