Hepatic Urea Cycle Dysfunction and Acute Lung Injury

在之前的临床和生化人群联合研究中，我们发现尿素循环的基线功能对接受加大剂量化疗和骨髓移植（BMT）的患者具有重要的预后意义。较差的基线功能与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，循环功能限速酶磷酸氨甲酰合成酶-1 （ps -1）的常见多态性与肝损伤发生率显著降低、急性肺损伤（如果发生）的消退和生存率提高有关。尿素循环功能在化疗期间和内毒素血症后调节肝和肺生理的机制尚不完全清楚。因此，我们提出了一系列相关的研究，以了解尿素循环在肝-肺相互作用中的作用。在Specific Aim 1中，小鼠模型的研究旨在确定内毒素血症后尿素循环功能受损（遗传、药理学或饮食诱导）是否会调节肝和肺功能障碍。我们的初步数据表明，在鸟氨酸转氨基甲酰基酶（一种关键的线粒体尿素循环酶）基因缺陷的小鼠中，内毒素诱导的肺部和肝脏脂质过氧化增加。特异性目标2使用类似的策略来检查内毒素血症后尿素循环功能增强对肺和肝功能障碍的影响。特异性3研究了原位灌注猪肝-肺制剂中调节肝尿素循环功能、肝和肺对内毒素的生化和分子反应的影响。我们的数据表明，尿素循环中间体的增加具有复杂的作用，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，这些机制可能适用于治疗操作。

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.