Sepsis: An Arginine Deficiency State?

Yvette C. Luiking, PhD; Martijn Poeze, MD, PhD; Cornelis H. Dejong, MD, PhD; Graham Ramsay, MD, PhD; Nicolaas E. Deutz, MD, PhD

Crit Care Med. 2004;32(10) 

In This Article

Arginine Metabolism in Sepsis

In this section, we will shortly review the metabolism of arginine in general and describe in more detail arginine metabolism in sepsis. Subsequently, we will analyze how these changes in arginine metabolism in sepsis are related to clinical symptoms and functional effects.

Arginine is a semi-essential amino acid, which is mainly synthesized endogenously in the proximal renal tubule by conversion of citrulline to arginine (Fig. 1).[5,6,7,8,9] Citrulline is mainly derived from intestinal conversion of arterial (mainly muscle derived) and luminal glutamine through the glutamate-to-ornithine pathway,[6,10,11,12,13] and about 83% of the intestinal release of citrulline is taken up by the kidneys.[6] Under normal conditions, this pathway contributes about 10-15% to whole-body arginine production.[13,14] Besides endogenous production from citrulline, arginine is also available from protein breakdown and food intake, with the jejunum as the major site of intestinal absorption.

Metabolic pathways of arginine. Pathways are compartmentalized to different organs and to cytosolic and mitochondrial locations. ASS, argininosuccinate synthase; ASL, argininosuccinate lyase; ODC, ornithine decarboxylase; OTC, ornithine carbamoyltransferase; NO, nitric oxide; NOS, nitric oxide synthase. Partly derived from van de Poll et al.,[12] Wu and Morris,[18] Flynn et al.,[20] and Luiking and Deutz.[70]

Four major metabolic pathways for arginine exist (refer to Morris,[15] Kelm,[16] Boger and Bode-Boger,[17] Wu and Morris,[18] Cynober et al.,[19] and Flynn et al.[20] for recent reviews). First, arginine is degraded to urea and ornithine by isoforms of the enzyme arginase. Type I cytosolic arginase is expressed in the liver and is involved in detoxification of ammonia and urea synthesis, and type II mitochondrial arginase is expressed at low levels in extrahepatic tissues and is involved in synthesis of ornithine, proline, and glutamate.[21] Via ornithine and the polyamines, arginine is important for cell growth and differentiation[22] and for synthesis of connective tissue. Due to the arginase activity in the intestinal mucosa (type II arginase), approximately 40% of arginine absorbed from the intestinal lumen is degraded in the first pass.[23] A second metabolic pathway of arginine is the synthesis of nitric oxide (NO) by isoforms of the enzyme NO synthase (NOS) with concomitant formation of citrulline.[24,25] Basically, three isoforms of NOS exist. NO synthesized by NOS-1 (neuronal NOS) and NOS-3 (endothelial NOS) enzymes acts as a neurotransmitter and as vasodilator, respectively.[25] NO synthesized by NOS-2 (inducible NOS) at high levels has immunoregulatory functions, such as control or killing of infectious pathogens, modulation of cytokine production, and T-helper cell development, and has cytoprotective action as a free radical scavenger[26] when induced by elevated circulating cytokine concentrations (mainly tumor necrosis factor-α, and interleukin-1, interleukin-6, and interleukin-8) or microbial products (e.g., lipopolysaccharide) during inflammatory processes.[24,25,27,28,29] This has led to the suggestion that arginine could have a great potential as an immunomodulator[30,31] and may prove useful in catabolic conditions such as severe sepsis.[32] Apart from the arginase and NO breakdown route, a large part of arginine is used for protein synthesis and hence disappears from the circulation, and arginine is also involved in the biosynthesis of creatine (the precursor of creatinine) and the synthesis of agmatine.[18] Under normal conditions, about 1.2% of plasma arginine production is used for NO synthesis, whereas this percentage is about 15% for urea synthesis.[14] Arginine metabolism is highly compartmentalized, which is due to the fact that the enzymes involved in arginine metabolism are expressed to a different extent in the various organs involved.[18] Finally, arginine stimulates secretion of several hormones.[33]

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