LIVER-LUNG INTERACTIONS FOLLOWING LIVER INJURY

越来越多的证据表明，肝损伤可以加速或加重肺损伤。在全身炎症反应综合征(SIRS)的发病机制中，肝脏和肺产生的细胞因子，包括肿瘤坏死因子-α(TNF-α)和白介素1(IL-1)。动物实验证明，它们能够加速急性肺损伤。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-kappa B(NF-kappa B)和CCAAT增强子结合蛋白β(C/EBPbeta，也称为NF-IL6)的激活，并且在几种炎症状态下的激活是众所周知的。肝冷冻消融术是一种非切除的外科技术，用于消除原发和转移性肝肿瘤，当肝冷冻消融率超过30%-35%时与ARDS相关。这种反应的机制仍不清楚。先前的研究表明，冷冻消融对实验动物造成的肝损伤导致核因子-kappaB的早期激活，随后在肝脏中释放肿瘤坏死因子-α，然后在肺中激活核因子-kappaB，其组织学表现与成人呼吸窘迫综合征相似；这些事件都不是肝脏切除后发生的。本研究的具体目的是：1)利用肿瘤坏死因子α、白介素1和肿瘤坏死因子α/白介素1受体基因敲除转基因小鼠，研究近端细胞因子、肿瘤坏死因子α和白介素1在肝脏冷冻消融反应中的作用。2)确定改变肝脏中核因子-kappaB或C/EBP(P20)的激活是否影响冷冻消融的反应。这些研究的结果应该有助于更好地理解肝脏在SIRS的传播中的作用，以响应直接的肝损伤，并可能允许特定的介体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.