Abstract
(1) Background: L-arginine is a complex modulator of immune functions, and its levels are known to decrease under septic conditions. L-arginine may suppress leukocyte recruitment in vivo; however, little is known about the gestational age-specific effects of L-arginine on leukocyte recruitment in preterm infants. We now asked whether L-arginine alters leukocyte recruitment in preterm and term neonates. (2) Methods: Leukocytes were isolated from preterm (28 + 0 to 32 + 6 weeks of gestation) and term (>37 weeks of gestation) newborns as well as from healthy adults. After incubation with 10 µg/mL L-arginine, we assessed leukocyte rolling and adhesion in dynamic microflow chamber experiments and leukocyte transmigration in fluorescence assays. In addition, we measured the expression of inducible nitric oxide synthase (iNOS) and Arginase 1 (Arg-1) in neutrophils by flow cytometry. (3) Results: Leukocyte rolling, adhesion, and transmigration increased with gestational age. Leukocyte rolling, adhesion, and transmigration were decreased by L-arginine in term-born infants and adults. Preterm leukocytes showed no change in recruitment upon L-arginine exposure. Leukocyte adhesion after L-arginine exposure reached similar levels among all groups. In line, the expression of iNOS and Arg-1 was similar in all three age groups. (4) Conclusion: L-arginine dampens the ex vivo recruitment capacity of leukocytes from term-born infants, whereas no effect was seen in premature infants. As levels of iNOS and Arg-1 in neutrophils remain ontogenetically unchanged, the anti-inflammatory effect of L-arginine on the leukocyte recruitment cascade needs further investigation. These results add to the controversial debate of L-arginine supplementation in premature infants in sepsis.
Highlights
The high susceptibility to infections and sepsis in preterm infants remains a major problem in neonatology, leading to high morbidity and mortality [1]
We measured the expression of inducible nitric oxide synthase and Arginase 1 (Arg-1) in neutrophils by flow cytometry
Neutrophils are the first responders in bacterial sepsis, and the leukocyte recruitment cascade initiates the response of the innate immune system [4,5]
Summary
The high susceptibility to infections and sepsis in preterm infants remains a major problem in neonatology, leading to high morbidity and mortality [1]. The expression of adhesion molecules such as P-selectin or ICAM-1 and the chemokine IL-8 increase with gestational age [9,10]. This ontogenetic maturation may partially account for the high susceptibility to sepsis in preterm infants [11]. 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 [13]. L-arginine exerts anti-inflammatory effects on PMNs by reducing leukocyte activation and recruitment [15], partially through the downregulation of ICAM-1 on endothelial cells [16]. In order to eliminate systemic pro- or anti-inflammatory effects of L-arginine, we used ex vivo flow chamber assays to assess peripheral PMNs from premature infants, term-born infants, and adults
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