LIVER-LUNG INTERACTIONS FOLLOWING LIVER INJURY

越来越多的证据表明，肝损伤可加重或加重肺损伤。肝和肺中产生的细胞因子，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的表达增加涉及两种转录因子，核因子κ B（NF-κ B B）和CCAAT增强子结合蛋白β（C/EBP β，也称为NF-IL 6）的活化，并且在几种炎症状态中充分记录了活化。肝脏冷冻消融术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。这种反应的机制仍不明确。先前的研究表明，冷冻消融术在实验动物中产生的肝损伤导致NF-κ B的早期激活，随后在肝脏中释放TNF-α，然后在肺中激活NF-κ B，组织学结果与成人呼吸窘迫综合征中观察到的结果相似;肝切除术后没有这些事件。具体目标是：1）使用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在对肝脏冷冻消融的响应中的作用。2)确定改变肝脏中NF-κ B或C/EBP（P20）激活是否影响对冷冻消融的反应。这些研究的结果应导致增强对肝脏在SIRS传播中响应于直接肝损伤的作用的理解，并可能允许介质特异性策略来改善环境中的有害事件。

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.