The purpose of this application is to investigate the role of citrulline in preventing or mitigatin acute lung injury (ALI) in patients with severe sepsis. The urea/NO cycle plays an integral role in severe sepsis pathophysiology, a disease with high morbidity and mortality characterized by uncontrolled systemic inflammation and oxidative stress leading to organ dysfunction. Inflammation results in plasma citrulline deficiency which leads to arginine deficiency and uncoupling of nitric oxide synthase (NOS). NOS, in its natural coupled form, utilizes arginine as substrate for producing NO and citrulline. When uncoupled, NOS preferentially produces superoxide radicals (O2-) which react with NO to form peroxynitrite and other reactive oxygen species (ROS). These ROS stimulate monocytes to produce and release additional pro-inflammatory cytokines, further propagating and prolonging the inflammatory cascade. These free radicals also interact with endothelial cells, especially in the lung, via lipid peroxidation causing altered membrane fluidity and function and the clinical picture of ALI. In sepsis, NOS also increases production of NO resulting in systemic vasodilation and worsening inflammation, which along with the increased oxidative stress contributes to the development of organ dysfunction, especially ALI. The body needs regulated NOS activity to maintain homeostasis. Citrulline, by serving as both substrate for arginine and feedback inhibitor of NOS, can re-establish urea/NO cycle homeostasis, reduce inflammation and oxidative stress and prevent or mitigate ALI in severe sepsis. We hypothesize that citrulline administration will safely restore homeostasis of NOS by increasing both plasma citrulline and arginine levels. This restored homeostasis will result in reduced production of nitric oxide and oxidative stress, thereby preventing development and/or progression of ALI and other organ failures and improving clinical outcomes in patients with severe sepsis.
The specific aims of this application are to demonstrate that administration of IV citrulline to severely septic patients will 1) increase both plasma citrulline and arginine levels and reduce oxidative stress and production of NO in patients;2) be safe and not exacerbate vasomotor instability and/or hypotension;and 3) improve clinical outcomes, including prevention of both the development and progression of ALI. Vanderbilt University Medical Center, through its several ICUs, will provide the environment to conduct a randomized, placebo-controlled clinical trial investigating the effects of IV citrulline n patients with severe sepsis. Laboratory resources are available to investigate changes in biochemical responses, including plasma levels of amino acids, nitric oxide metabolites, and inflammatory cytokines. Isoprostanes, isofurans, and nitrotyrosine from urine and breath condensate will be measured as markers of oxidative stress. Safety will be closely monitored, especially vasomotor stability as measured by vasopressor dependency index and net fluid balance. P/F and S/F ratios and lung injury score will be compared to evaluate the extent of ALI. Differences in clinical outcomes, including organ dysfunction, ventilator time, and survival will also be evaluated.
Currently treatments for severe sepsis resulting in acute lung injury are limited with none that prevent the development of acute lung injury. Urea cycle dysfunction is a key part of the inflammatory and oxidative stress cascades leading to acute lung injury in severely septic patients. Administration of the amino acid citrulline can re-establish autoregulation of nitric oxie synthase and homeostasis of the urea cycle, reduce inflammation and oxidative stress, and prevent or mitigate organ dysfunction, especially injury to the lungs, in these patients.
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