Franco-Gou Rosa, Roselló-Catafau Joan, Peralta Carmen
Hepatology Unit, Investigaciones Biomédicas de Barcelona August Pi i Sunyer, Consejo Superior de Investigaciones Científicas (IDIBAPS-CSIC), Barcelona, Spain.
Crit Care Med. 2006 May;34(5):1506-13. doi: 10.1097/01.CCM.0000215512.68930.A8.
This study examined the effect of ischemic preconditioning on pulmonary damage associated with reduced-size orthotopic liver transplantation (ROLT) and attempted to identify the underlying protective mechanisms.
Randomized and controlled animals study.
Experimental laboratory.
Male Sprague-Dawley rats.
Lung damage was evaluated in ROLT with or without preconditioning. Nitric oxide and interleukin (IL)-1 actions were altered pharmacologically.
IL-1, tumor necrosis factor (TNF)-alpha, soluble TNF receptors (sTNFR), and inflammatory response in lung were measured after ROLT. Our results indicate the involvement of IL-1 in the lung damage following ROLT. Ischemic preconditioning, mediated by nitric oxide, reduced IL-1 release and protected against lung damage. Nitric oxide synthesis inhibition in the preconditioned group led to increased IL-1 levels and increased lung damage following ROLT, whereas the addition of IL-1 receptor antagonist protected against the injurious effects of nitric oxide inhibition. In addition, nitric oxide pretreatment gave similar results in terms of IL-1alpha and lung protection to those found in preconditioning. The benefits to the lung attributable to IL-1 inhibition might be linked to the effect of this cytokine on sTNFR, an endogenous mechanism that modulates systemic TNF actions. In fact, strategies aimed at inhibiting IL-1 action, including IL-1 receptor antagonist, ischemic preconditioning, and nitric oxide donor, increased systemic sTNFR2 and decreased free TNF, following ROLT. Similarly, nitric oxide synthesis inhibition in the preconditioned group, which increased IL-1alpha and lung damage, reduced systemic sTNFR2 and increased free TNF levels. These injurious effects were avoided when IL-1 action was inhibited.
Ischemic preconditioning and pharmacologic strategies that simulate its benefits protected against lung damage in an experimental model of ROLT. Our results also suggest a potential relationship between nitric oxide, IL-1, and TNF/sTNF in the benefits of preconditioning on the lung damage associated with ROLT.
本研究探讨缺血预处理对减体积原位肝移植（ROLT）相关肺损伤的影响，并试图确定其潜在的保护机制。
随机对照动物研究。
实验实验室。
雄性Sprague-Dawley大鼠。
评估有或无预处理的ROLT中的肺损伤。通过药理学方法改变一氧化氮和白细胞介素（IL）-1的作用。
ROLT后测量肺组织中的IL-1、肿瘤坏死因子（TNF）-α、可溶性TNF受体（sTNFR）以及炎症反应。我们的结果表明IL-1参与了ROLT后的肺损伤。由一氧化氮介导的缺血预处理可减少IL-1释放并预防肺损伤。预处理组中一氧化氮合成抑制导致ROLT后IL-1水平升高和肺损伤加重，而添加IL-1受体拮抗剂可预防一氧化氮抑制的有害作用。此外，一氧化氮预处理在IL-1α和肺保护方面产生了与预处理相似的结果。IL-1抑制对肺的益处可能与该细胞因子对sTNFR的作用有关，sTNFR是一种调节全身TNF作用的内源性机制。事实上，旨在抑制IL-1作用的策略（包括IL-1受体拮抗剂、缺血预处理和一氧化氮供体）在ROLT后可增加全身sTNFR2并降低游离TNF水平。同样，预处理组中一氧化氮合成抑制增加了IL-1α和肺损伤，降低了全身sTNFR2并增加了游离TNF水平。当抑制IL-1作用时可避免这些有害影响。
缺血预处理以及模拟其益处的药理学策略在ROLT实验模型中可预防肺损伤。我们的结果还提示在预处理对ROLT相关肺损伤的益处方面，一氧化氮、IL-1和TNF/sTNF之间可能存在潜在关系。
