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.
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