309 - Citrulline and ADIPEG-20 Reduce Inflammatory Cytokines in a Porcine Model of Acute Sepsis
Saturday, April 29, 2023
3:30 PM – 6:00 PM ET
Poster Number: 309 Publication Number: 309.205
Caitlin E. Vonderohe, Baylor College of Medicine, Houston, TX, United States; Barbara Stoll. Stoll, Children's Nutrition Research Center, Houston, TX, United States; Inka Didelija, Baylor College of Medicine, Houston, TX, United States; Trung Nguyen, Baylor College of Medicine/Texas Children's Hospital, Houston, TX, United States; Yava Jones-Hall, Texas A&M, College Station, TX, United States; Douglas Burrin, USDA-ARS Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX, United States
Instructor Baylor College of Medicine Houston, Texas, United States
Background: Arginine is a conditionally essential amino acid that is depleted in critically ill or surgical patients. Sepsis is considered an arginine-deficient state, and depletion of plasma arginine is associated with greater mortality in adult and pediatric patients. Arginine is not only used for protein synthesis, but is also a precursor for important signaling compounds like nitric oxide (NO). However, direct supplementation of arginine can result in excessive production of NO, which can contribute to hypotension and vascular hypo-reactivity observed in septic shock. Pegylated arginine deiminase (ADIPEG20) reduces plasma arginine and generates citrulline that can be transported intracellularly to generate local arginine and NO, without resulting in hypotension, while maintaining microvascular patency. Objective: The objective of this study was to give citrulline and ADIPEG20 to a pediatric model of acute endotoxic sepsis to assess if pigs maintain tissue arginine availability without excessive NO production, preventing hypotensive shock and maintaining microvascular circulation. Design/Methods: Twenty, 3 week old crossbred pigs were implanted with jugular and carotid catheters as well as telemetry devices in the femoral artery to measure blood pressure, body temperature, heart rate, and respiration rate. Pigs allowed to recover from surgery then assigned to one of three treatments prior to undergoing a 5 hr lipopolysaccharide (LPS) infusion protocol. Six control (CTL) pigs underwent the protocol, 7 pigs (ADI) received an injection of ADIPEG 24 hrs prior to LPS infusion, and 8 pigs (CIT) received ADIPEG 24 hrs prior to LPS infusion and 250 mg/Kg citrulline intravenously 24 hrs prior to LPS infusion. Pigs were monitored throughout LPS infusion and tissue was harvested at the end of the protocol. Results: Plasma IL1-B, IL-6, IL-8, and TNF-α levels were lower in ADI and CIT than CTL pigs. Mean arterial pressure in all groups decreased from 90 mmHg to 60 mmHg within one hour of LPS infusion, but there were no significant differences between treatment groups throughout the LPS infusion protocol. Semi-quantitative assessment of histopathologic lesions associated with endotoxemia was similar across treatments. Plasma arginine levels decreased and remained low in CIT and ADI pigs compared to CTL pigs, but tissue arginine levels in liver and kidney were similar across all treatments.
Conclusion(s): ADIPEG and citrulline supplementation failed to ameliorate hypotension associated with acute endotoxic sepsis in pigs, but reduced pro-inflammatory cytokines and spared tissue arginine levels.
