LIVER-LUNG INTERACTIONS FOLLOWING LIVER INJURY

越来越多的证据表明肝损伤可导致或加重肺损伤。肝脏和肺部产生的细胞因子，包括肿瘤坏死因子α (tnf - α)和白细胞介素-1(IL- 1)，与全身性炎症反应综合征（SIRS）的发病机制有关。动物实验已经证明它们能够引起急性肺损伤。编码这些细胞因子的基因表达增加涉及两种转录因子的激活，即核因子κ B （nf - κ B）和CCAAT增强子结合蛋白β (C/EBPbeta，也称为NF-IL6)，并且在几种炎症状态下激活已得到充分证明。肝脏冷冻消融是一种用于消除原发性和转移性肝脏肿瘤的非切除手术技术，当消融超过30-35%时与ARDS相关。这种反应的机制尚不明确。先前的研究表明，实验动物冻融造成的肝损伤引起NF-kappaB的早期激活，随后在肝脏中释放tnf - α，然后在肺部激活NF-kappaB，其组织学表现与成人呼吸窘迫综合征相似；这些事件均不发生在肝切除术后。具体目的是：1)利用tnf - α、IL-1和tnf - α /IL-1受体敲除转基因小鼠，确定近端细胞因子、tnf - α和IL-1在肝脏冷冻消融应答中的作用。2)确定改变肝脏NF-kappaB或C/EBP （P20）激活是否会影响对冷冻消融的反应。这些研究的结果将有助于加深对肝脏在直接肝损伤时SIRS传播中的作用的理解，并可能允许采用特定的介质策略来改善这种情况下的有害事件。

There is increasing evidence that liver injury can precipitate or exaggerate lung injury. Cytokines produced in the liver and lungs, including tumor necrosis factor alpha (TNF-alpha) and interleukin-1(IL- 1), are implicated in the pathogenesis of Systemic Inflammatory Response Syndrome (SIRS). Animal experiments have demonstrated them capable of precipitating acute lung injury. Increased expression of the genes encoding these cytokines involves activation of two transcription factors, nuclear factor kappa B (NF-kappa B) and CCAAT enhancer binding protein beta (C/EBPbeta, also known as NF-IL6) and activation is well-documented in several inflammatory states. Hepatic cryoablation, a non-resectional surgical technique used to eliminated primary and metastatic liver tumors, is associated with ARDS when more than 30-35% is ablated. The mechanisms of this response remain undefined. Previous studies have shown that liver injury produced by cryoablation in experimental animals caused an early activation of NF- kappaB, followed by TNF-alpha release in the liver and then NF-kappaB activation in the lungs with histologic findings similar to those seen in Adult Respiratory Distress Syndrome; none of these events follows hepatic resection. The specific aims are to: 1) To determine the role of the proximal cytokines, TNF-alpha and IL-1 in the response to hepatic cryoablation using TNF-alpha, IL-1, and TNF-alpha/IL-1 receptor knockout transgenic mice. 2) To determine if altering NF-kappaB or C/EBP (P20) activation in the liver affects the response to cryoablation. Results of these studies should lead to enhanced understanding of the liver's role in propagation of SIRS in response to direct liver injury and may permit mediator specific strategies to ameliorate deleterious events in the setting.