Barr M L, Carey J N, Nishanian G P, Roberts R F, Sakamaki Y, Darbinian S H, Starnes V A
Department of Surgery, University of Southern California School of Medicine, Los Angeles 90033, USA.
J Thorac Cardiovasc Surg. 1998 Mar;115(3):631-6; discussion 636-7. doi: 10.1016/S0022-5223(98)70328-9.
Research in lung transplant preservation has generally focused on free radicals and enzyme release from neutrophils, parenchymal cells, macrophages, and endothelium. The lung has a large resident population of mast cells that, when activated, release potent inflammatory mediators. We hypothesized that adding an inhibitor of mast cell degranulation, lodoxamide tromethamine (10 micromol/L), to Euro-Collins and University of Wisconsin preservation solutions, would decrease lung preservation injury.
Rat lungs were isolated, flushed with the respective solution, and stored at 4 degrees C for 6 or 12 hours. The lungs were reperfused with fresh blood and ventilated with 100% oxygen. Alveolar-arterial oxygen difference, oxygen tension, capillary filtration coefficient, and compliance were determined.
After 6 hours of ischemic storage: lodoxamide tromethamine-enhanced Euro-Collins solution decreased alveolar-arterial oxygen difference from 539 to 457 (p = 0.004), increased oxygen tension from 119 to 205 mm Hg (p = 0.006), and decreased capillary filtration coefficient from 3.9 to 2.0 (p < 0.001); lodoxamide tromethamine-enhanced University of Wisconsin solution decreased alveolar-arterial oxygen difference from 546 to 317 (p < 0.001), increased oxygen tension from 166 to 335 mm Hg (p < 0.001), and decreased capillary filtration coefficient from 3.0 to 1.7 (p < 0.001). After 12 hours of ischemic storage, lodoxamide tromethamine-enhanced Euro-Collins solution decreased alveolar-arterial oxygen difference from 588 to 485 (p < 0.001), increased oxygen tension from 100 to 161 mm Hg (p = 0.012), decreased capillary filtration coefficient from 6.2 to 2.6 (p < 0.001), and increased compliance from 0.12 to 0.21 (p < 0.001); lodoxamide tromethamine-enhanced University of Wisconsin solution decreased alveolar-arterial oxygen difference from 478 to 322 (p < 0.001), increased oxygen tension from 214 to 335 mm Hg (p < 0.001), decreased capillary filtration constant from 4.2 to 2.0 (p < 0.001), and increased compliance from 0.20 to 0.25 (p < 0.001).
Addition of lodoxamide tromethamine to Euro-Collins or University of Wisconsin solution results in a marked decrease in lung reperfusion injury as demonstrated by increased oxygenation, decreased microvascular permeability, and increased compliance. These results are relevant as Euro-Collins and University of Wisconsin solutions are the most common clinically used lung preservation solutions. This study also highlights the deleterious role of resident mast cells in preservation injury.
肺移植保存研究通常聚焦于中性粒细胞、实质细胞、巨噬细胞和内皮细胞释放的自由基及酶。肺中有大量常驻肥大细胞，激活后会释放强效炎症介质。我们推测，在欧洲柯林斯液（Euro-Collins）和威斯康星大学保存液中添加肥大细胞脱颗粒抑制剂——三甲噻庚胺氯苯吡胺（lodoxamide tromethamine，10微摩尔/升），会减轻肺保存损伤。
分离大鼠肺脏，用相应溶液冲洗，于4℃保存6或12小时。用新鲜血液对肺进行再灌注，并给予100%氧气通气。测定肺泡-动脉氧分压差、氧张力、毛细血管滤过系数和顺应性。
缺血保存6小时后：添加三甲噻庚胺氯苯吡胺的欧洲柯林斯液使肺泡-动脉氧分压差从539降至457（p = 0.004），氧张力从119毫米汞柱升至205毫米汞柱（p = 0.006），毛细血管滤过系数从3.9降至2.0（p < 0.001）；添加三甲噻庚胺氯苯吡胺的威斯康星大学保存液使肺泡-动脉氧分压差从546降至317（p < 0.001），氧张力从166毫米汞柱升至335毫米汞柱（p < 0.001），毛细血管滤过系数从3.0降至1.7（p < 0.001）。缺血保存12小时后，添加三甲噻庚胺氯苯吡胺的欧洲柯林斯液使肺泡-动脉氧分压差从588降至485（p < 0.001），氧张力从100毫米汞柱升至161毫米汞柱（p = 0.012），毛细血管滤过系数从6.2降至2.6（p < 0.001），顺应性从0.12升至0.21（p < 0.001）；添加三甲噻庚胺氯苯吡胺的威斯康星大学保存液使肺泡-动脉氧分压差从478降至322（p < 0.001），氧张力从214毫米汞柱升至335毫米汞柱（p < 0.001），毛细血管滤过常数从4.2降至2.0（p < 0.001），顺应性从0.20升至0.25（p < 0.001）。
在欧洲柯林斯液或威斯康星大学保存液中添加三甲噻庚胺氯苯吡胺可显著减轻肺再灌注损伤，表现为氧合增加、微血管通透性降低和顺应性增加。鉴于欧洲柯林斯液和威斯康星大学保存液是临床上最常用的肺保存液，这些结果具有重要意义。本研究还突出了常驻肥大细胞在保存损伤中的有害作用。
