Arginine depletion is a phenomenon observed in septic patients, and is associated with greater mortality as its severity increases. Among numerous other functions, arginine is the precursor for the signaling molecule nitric oxide that plays a central role in immunity, in the control of blood pressure, and in the regulation of the microcirculation and tissue perfusion. Although the mechanism responsible for the depletion and fate of arginine has yet to be identified, arginine supplementation has been proposed to restore arginine availability. However, it is not clear if arginine supplementation is always effective or beneficial, because it can result in hyperproduction of nitric oxide and contribute to hypotension, cardio depression and vascular hyporeactivity in septic shock. Supplementing with citrulline, the precursor for the endogenous synthesis of arginine, has the potential to be more effective than arginine supplementation, but may also result in excessive nitric oxide production. An alternative approach that simultaneously addresses the depletion of arginine and hyperproduction of nitric oxide is the use of ADI-PEG 20. This pegylated bacterial enzyme catalyzes the conversion of arginine into citrulline, which can be re-utilized by the citrulline `recycling pathway'. This pathway provides intracellular arginine to sustain most processes that require this amino acid, but at the same time modulating the hyperproduction of nitric oxide during sepsis. Our central hypothesis is that sepsis causes dysregulation of arginine metabolism resulting in plasma arginine depletion and contributing to macro- and microcirculatory failure that leads to organ dysfunction. The objectives of the proposed research are to elucidate the mechanisms of ARG depletion in pediatric swine models of sepsis and evaluate different strategies to restore ARG availability, prevent hypotension and mitigate tissue injury. To test our central hypothesis and attain our objectives we propose the following specific aims:
Specific Aim1 : Quantify the disposal rate of arginine by the liver and the pathways involved in its utilization in swine models of sepsis.
Specific Aim2 : Determine arginine availability in septic pigs supplemented with citrulline or arginine and its effect on nitric oxide production, blood pressure, protein synthesis and markers of tissue injury.
Specific Aim3 : Determine arginine availability and cardiovascular function, including blood pressure and tissue markers of hypoxia during sepsis in ADI-PEG 20-arginine-depleted pigs. To achieve these aims we will use methicillin- resistant S. aureus and pathogenic E. Coli swine models of sepsis-induced multiple organ dysfunction. A multitracer stable isotope protocol will be used to quantify whole body and hepatic arginine metabolism, and the analysis of the relevant enzymes and transporters will provide the molecular basis for the changes observed. Blood pressure, plasma metabolites, and markers of organ function and tissue injury will be analyzed to determine the effect of the different interventions on cardiovascular function, tissue perfusion and organ injury.

Public Health Relevance

The results of the studies proposed will elucidate how arginine depletion affects the pathophysiology of sepsis-induced multiorgan dysfunction and provide the basis for new recommendations on arginine and citrulline supplementation during this critical illness.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM108940-05A1
Application #
10053138
Study Section
Integrative Nutrition and Metabolic Processes Study Section (INMP)
Program Officer
Dunsmore, Sarah
Project Start
2014-08-01
Project End
2024-06-30
Budget Start
2020-07-10
Budget End
2021-06-30
Support Year
5
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Baylor College of Medicine
Department
Pediatrics
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Mohammad, Mahmoud A; Didelija, Inka C; Stoll, Barbara et al. (2018) Citrulline Generation Test: What Does It Measure? JPEN J Parenter Enteral Nutr :
Marini, Juan C; Agarwal, Umang; Robinson, Jason L et al. (2017) The intestinal-renal axis for arginine synthesis is present and functional in the neonatal pig. Am J Physiol Endocrinol Metab 313:E233-E242
Marini, Juan C; Agarwal, Umang; Didelija, Inka C et al. (2017) Plasma Glutamine Is a Minor Precursor for the Synthesis of Citrulline: A Multispecies Study. J Nutr 147:549-555
Didelija, Inka C; Mohammad, Mahmoud A; Marini, Juan C (2017) Ablation of Arginase II Spares Arginine and Abolishes the Arginine Requirement for Growth in Male Mice. J Nutr 147:1510-1516
Agarwal, Umang; Didelija, Inka C; Yuan, Yang et al. (2017) Supplemental Citrulline Is More Efficient Than Arginine in Increasing Systemic Arginine Availability in Mice. J Nutr 147:596-602
Marini, Juan C (2016) Interrelationships between glutamine and citrulline metabolism. Curr Opin Clin Nutr Metab Care 19:62-6
Marini, Juan C (2015) Protein requirements: are we ready for new recommendations? J Nutr 145:5-6
Marini, Juan C; Agarwal, Umang; Didelija, Inka C (2015) Dietary arginine requirements for growth are dependent on the rate of citrulline production in mice. J Nutr 145:1227-31
Marini, Juan C; Didelija, Inka Cajo (2015) Arginine depletion by arginine deiminase does not affect whole protein metabolism or muscle fractional protein synthesis rate in mice. PLoS One 10:e0119801
Marini, Juan C; Didelija, Inka C; Fiorotto, Marta L (2014) Extrarenal citrulline disposal in mice with impaired renal function. Am J Physiol Renal Physiol 307:F660-5