Laffey J G, Tanaka M, Engelberts D, Luo X, Yuan S, Tanswell A K, Post M, Lindsay T, Kavanagh B P
The Lung Biology Programme, The Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada.
Am J Respir Crit Care Med. 2000 Dec;162(6):2287-94. doi: 10.1164/ajrccm.162.6.2003066.
Permissive hypercapnia, involving tolerance to elevated Pa(CO(2)), is associated with reduced acute lung injury (ALI), thought to result from reduced mechanical stretch, and improved outcome in ARDS. However, deliberately elevating inspired CO(2) concentration alone (therapeutic hypercapnia, TH) protects against ALI in ex vivo models. We investigated whether TH would protect against ALI in an in vivo model of lung ischemia-reperfusion (IR). Anesthetized open chest rabbits were ventilated (standard eucapnic settings), and were randomized to TH (FI(CO(2)) 0.12) versus control (FI(CO(2)) 0.00). Pa(CO(2)) and arterial pH values achieved in the TH versus CON groups were 101 +/- 3 versus 44.4 +/- 4 mm Hg and 7.10 +/- 0.03 versus 7.37 +/- 0.03, respectively. Following left lung ischemia and reperfusion, TH versus control was associated with preservation of lung mechanics, attenuation of protein leakage, reduction in pulmonary edema, and improved oxygenation. Indices of systemic protection included improved acid-base and lactate profile, in the absence of systemic hypoxemia. In the TH group, mean BALF TNF-alpha levels were 3.5% of CON levels (p < 0.01), and mean 8-isoprostane levels were 30% of CON levels (p = 0.02). Western blot analysis demonstrated reduced lung tissue nitrotyrosine in TH, indicating attenuation of tissue nitration. Finally, preliminary data suggest that TH may attenuate apoptosis following lung IR. We conclude that in the current model TH is protective versus IR lung injury and mechanisms of protection include preservation of lung mechanics, attenuation of pulmonary inflammation, and reduction of free radical mediated injury. If these findings are confirmed in additional models, TH may become a candidate for clinical testing in critical care.
允许性高碳酸血症，即对动脉血二氧化碳分压（Pa(CO₂)）升高的耐受，与急性肺损伤（ALI）减轻相关，这被认为是机械牵张减少所致，并改善了急性呼吸窘迫综合征（ARDS）的预后。然而，仅故意提高吸入二氧化碳浓度（治疗性高碳酸血症，TH）就能在体外模型中预防ALI。我们研究了TH在肺缺血再灌注（IR）的体内模型中是否能预防ALI。对麻醉的开胸兔进行通气（标准的正常碳酸血症设置），并随机分为TH组（吸入二氧化碳分数（FI(CO₂)）为0.12）和对照组（FI(CO₂)为0.00）。TH组与对照组所达到的Pa(CO₂)和动脉血pH值分别为101±3与44.4±4 mmHg以及7.10±0.03与7.37±0.03。左肺缺血再灌注后，TH组与对照组相比，肺力学得以保留，蛋白渗漏减轻，肺水肿减轻，氧合改善。全身保护指标包括酸碱和乳酸水平改善，且无全身低氧血症。在TH组中，支气管肺泡灌洗液（BALF）中肿瘤坏死因子-α（TNF-α）的平均水平为对照组水平的3.5%（p<0.01），8-异前列腺素的平均水平为对照组水平的30%（p = 0.02）。蛋白质印迹分析表明，TH组肺组织硝基酪氨酸减少，表明组织硝化作用减弱。最后，初步数据表明TH可能减轻肺IR后的细胞凋亡。我们得出结论，在当前模型中，TH对IR肺损伤具有保护作用，保护机制包括保留肺力学、减轻肺部炎症以及减少自由基介导的损伤。如果这些发现在其他模型中得到证实，TH可能成为重症监护临床测试的候选方法。
