Hepatic Urea Cycle Dysfunction and Acute Lung Injury

在以往的联合临床和生化人群研究中，我们发现尿素循环的基线功能对接受逐步剂量化疗和骨髓移植(BMT)的患者具有重要的预后意义。基础功能差与BMT后肝和肺损伤的可能性增加以及死亡风险增加有关。此外，循环功能的限速酶氨基甲酰磷酸合成酶-1(CPS-1)的常见多态与显著降低肝损伤的发生率、急性肺损伤的缓解和提高存活率相关。尿素循环功能在化疗期间和内毒素血症后调节肝脏和肺生理的机制仍不完全清楚。因此，我们提出了一系列相关研究，以了解尿素循环在肝肺相互作用中的作用。在具体目标1中，对小鼠模型的研究旨在确定尿素循环功能受损(遗传、药物或饮食诱导)是否调节内毒素血症后的肝和肺功能障碍。我们的初步数据显示，在鸟氨酸转氨甲基酶(一种关键的线粒体尿素循环酶)基因缺陷的小鼠中，内毒素诱导的肺和肝脏脂质过氧化增加。特殊目的2使用类似的策略来检查增强的尿素循环功能对内毒素血症后肺和肝脏功能障碍的影响。特异体3研究了在原位灌流猪肝肺制剂中，调节肝脏尿素循环功能、肝脏和肺对内毒素的生化和分子反应的影响。我们的数据表明，尿素循环中间产物的增加有复杂的影响，但明显减少急性肺脂质过氧化。这些协调一致的实验将为肝肺相互作用的关键机制提供新的见解，这些机制可能适合于治疗操作。

In previous combined clinical and biochemical population studies, we have found that baseline function of the urea cycle has important prognostic significance for patients receiving escalated dose chemotherapy and bone marrow transplantation (BMT). Inferior baseline function is associated with an increased likelihood of liver and lung injury and an increased risk of death after BMT Furthermore, a common polymorphism of carbamyl phosphate synthetase-1 (CPS-1), the rate limiting enzyme for cycle function, is associated with a markedly reduced incidence of liver injury, resolution of acute lung injury if it occurs, and improved survival. The mechanisms by which urea cycle function modulates liver and lung physiology during chemotherapy and following endotoxemia remain incompletely understood. We therefore propose a series of related studies at understanding the role of the urea cycle in liver-lung interaction. In Specific Aim 1, studies in a murine model are aimed at determining whether impaired urea cycle function (genetic, pharmacologic, or dietary induced) modulates liver and lung dysfunction following endotoxemia. Our preliminary data demonstrates increased endotoxin-induced pulmonary and hepatic lipid peroxidation in mice genetically deficient in ornithine transcarbamylase, a key mitochondrial urea cycle enzyme. Specific Aim 2 uses similar strategies to examine the effects of augmented urea cycle function on lung and liver dysfunction after endotoxemia. Specific 3 examines the effects of modulating hepatic urea cycle function, biochemical and molecular responses of liver and lung to endotoxin in an in situ perfused porcine liver-lung preparation. Our data suggests that augmentation of urea cycle intermediates have complex effects, but clearly reduce acute pulmonary lipid peroxidation . These concerted experiments will lend new insight into key mechanisms of liver-lung interaction that may be amenable to therapeutic manipulation.