An example for successful immune modulation with L-arginine is the supplementation of low plasma levels during necrotizing enterocolitis (NEC), which has been shown to reduce the incidence and morbidity in clinical trials and animal studies. Immune modulation during sepsis needs to be stage-dependent, as early inflammation in newborns requires immune stimulation, whilst over-activation may induce a systemic inflammatory response syndrome (SIRS) with often fatal consequences. Especially during sepsis, L-arginine levels rapidly drop, defining sepsis as an “arginine-deprived state”. As L-arginine levels are lower in preterm infants, supplementation is common practice on neonatal intensive care units. On the other hand, L-arginine exerts anti-inflammatory effects on PMNs by reducing leukocyte activation and recruitment, partially through the downregulation of ICAM-1 on endothelial cells. By a similar mechanism, human natural-killer (NK) cells are suppressed by PMNs through L-arginine depletion. Interestingly, it was shown that L-arginine depletion through neutrophilic arginase secretion may locally suppress T-cell functions, and restoring L-arginine levels had a pro-inflammatory effect. Polymorphonuclear leukocytes (PMNs) express Arginase-1 (Arg-1) and inducible nitric oxide synthase (iNOS), which both catabolize L-arginine. For example, L-arginine limitation dampens Toll-like receptor 4 (TLR-4) signaling in macrophages, and the supplementation of L-arginine can restore TNF-α production in response to lipopolysaccharide (LPS). L-arginine, a conditionally essential amino acid for the fetus and neonate, is known to be involved in the regulation of various immune functions. This ontogenetic maturation may partially account for the high susceptibility to sepsis in preterm infants. In line, the expression of adhesion molecules such as P-selectin or ICAM-1 and the chemokine IL-8 increase with gestational age. found that the fetal leukocyte recruitment in preterm infants is heavily impaired and undergoes a maturation process during fetal development. The activation of β2 integrins such as LFA-1 (CD11a/CD18) and Mac-1 (CD11b/CD18) leads to binding with different endothelial ligands such as intercellular adhesion molecule 1 (ICAM-1), resulting in firm adhesion to the inflamed endothelium, which is followed by transmigration along a chemokine gradient. Circulating leukocytes are first captured and start rolling along the endothelial layer. Neutrophils are the first responders in bacterial sepsis, and the leukocyte recruitment cascade initiates the response of the innate immune system. Especially among very premature infants, the immaturity of the immune system contributes greatly to adverse outcome. The high susceptibility to infections and sepsis in preterm infants remains a major problem in neonatology, leading to high morbidity and mortality.
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