Istrefi ([email protected]}) Icko Gjorgoski ([email protected]}) Azem Lajçi Article type Research Submission date 13 January Acceptance date 27 [email protected] Zahide Istrefi1 Email: [email protected] Icko. Jul 31, e-mail: [email protected] D. Mihailović. Institute of .. Pesevska S, Nakova M, Gjorgoski I, Angelov N, Ivanovski K,. Nares S, Andreana S. Aug 1, e-mail: [email protected] D. Mihailović. Institute of .. Pesevska S, Nakova M, Gjorgoski I, Angelov N, Ivanovski K,. Nares S, Andreana S.
The relaxation values of TSM obtained from control tissues ranged from 1. The data ranged from 0. These data ranged from 0. The data ranged 0. Figure 8 Effect of in vivo L-citrulline supplementation on TSM relaxation in hyperoxia- exposed rat pups: Both of these processes complement each other in increasing airway hyperreactivity. Hyperoxia increases arginase activity, which limits the availability of L-arginine for NOS . In our recent publication we have shown that production of NO in airway smooth muscle cells is reduced in hyperoxia-exposed rat pups .
In a lung cell, L-arginine is used as a substrate for NOS and is obtained from different sources for the production of NO, including the recycling of L-citrulline .
We have observed that the supplementation of L—citrulline reversed the hyperoxia-induced impaired relaxation in both in vivo i. Since the systemic administration of L- citrulline via i. For this reason, oral or systemic administration of L-citrulline could be a better substitute for L-arginine as it bypasses the liver .
However, this pathway appears to play a key role once the NOS enzyme is blocked. Interestingly, L-citrulline supplementation fully restored the impaired relaxation caused by the blockage of NOS under basal conditions.
The effect of L-citrulline was more prominent particularly at higher voltages when an extra supply of NO is required to compensate the changes. Similar results were shown in the tracheal rings of guinea pigs .
In asthmatic patients, a decrease in plasma L-arginine levels and an increase in serum arginase activity was observed . Similarly, in the experimental BPD in neonatal rats, the plasma level of L-arginine was found to have decreased after hyperoxic exposure of animals , while arginase protein expression was upregulated in the airway epithelium, further depriving the adjacent ASM for L-arginine substrate.
Furthermore, Malleske et al. L-citrulline also plays a key role in the reversal of impaired relaxation during hyperoxia that creates an L-arginine limiting condition.
L-citrulline has been reported to be a noncompetitive inhibitor of arginase . Therefore, in hyperoxic conditions, L- citrulline appears to work through arginase inhibition rather than competition with NOS inhibitors as discussed above.
In a rat pup model of BPD, L-arginine becomes a limiting substrate and disrupts the NO- cGMP signaling pathway, due to the hyperoxia-induced upregulation of arginase activity. An increase of arginase activity has been linked to airway hyperreactivity under different conditions in different animal models, such as rat pups, mice, and guinea pigs, as well as in humans [34,35,].
In the perfused trachea of guinea pigs, it was demonstrated that increased arginase activity contributes to the airway hyperresponsiveness after early asthmatic reaction and deficiency of cNOS-derived NO . Therefore, in this study the role of L-citrulline recycling in the airways under in vitro and in vivo conditions of TSM obtained from hyperoxia exposed animals was studied.
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We have shown that after hyperoxic exposure, arginase activity increased in the experimental BPD model [4,32]. This model demonstrates that the raised levels of arginase activity, which compete with NOS for common substrate, contribute to the impairment of relaxation in most distal airways because of the decrease of NO production [4,32]. Since it has been shown that the limitation of L-arginine availability to NOS is involved in pathogenesis of several diseases involving NO deficiencies, L-arginine supplementation to the animals has been used to treat these disorders.
Although L-arginine supplementation in rat pups exposed to hyperoxia seems to normalize impaired relaxation of lung parenchymal strips, it further increased arginase activity, thus reducing the effectiveness of L-arginine therapy. In addition, oral L-arginine administration failed to reduce airway hyperresponsiveness in a murine model of allergic asthma  or in asthmatic patients .
This failure might be because of the presystemic elimination of L-arginine by increased intestinal or hepatic arginase activity . In contrast, L-citrulline is not taken up by the liver, but is metabolized predominantly in the kidney to L-arginine and could be considered as a masked precursor of L-arginine bypassing the liver , thus providing plenty of substrate for NO-cGMP signaling pathway .
The benefits of oral administration of L-citrulline have been shown in many diseases. Oral administration of L-citrulline in patients suffering from sickle cell disease raised the decreased plasma levels of L-arginine without any toxicity . Furthermore, L-citrulline decreased pulmonary hypertension after surgery in patients with congenital heart disease , and it also reduced blood pressure response to cold stress .
Recently, Cormio et al. Another study revealed that supplementation of L-citrulline prevents hyperoxia-induced lung injury in newborn rats . L-citrulline also ameliorates development of pulmonary hypertension and increases NO production in piglets exposed to chronic hypoxia . These studies provide evidence that support the use of L-citrulline as a therapy in diseases characterized by NO deficiency.
We recognize that this model under in vitro conditions has limitations, as it is isolated from systemic circulation and lacks the connections from central nervous system, which also affect the physiology of airways. Conclusion This study demonstrates that the prolonged hyperoxic exposure to new born rats causes impaired relaxation of tracheal smooth muscle.
Supplementation of L-citrulline in vitro and in vivo reverses hyperoxia-induced attenuated relaxant responses of rat pup TSM in L- arginine limiting conditions.
However, L—citrulline has no effect on relaxation in basal conditions when L-arginine is not a limiting factor. The evidence originated from this study suggests that supplementation with L-citrulline may have higher potential than L-arginine as a therapeutic use for preterm infants at risk for increased airway reactivity.
SIAZ participated in designing the study, carried out a part of experiments, and contributed to finalizing the manuscript. MM substantially participated in experiments and revised the manuscript.
HS performed the in vivo experiments. ZI assisted in the experiments, analyzed the data, supervised the statistics, and contributed to the manuscript. IG contributed to the study design, data interpretation, and final revision of the manuscript. AL advised during the experiments and contributed to finalizing the manuscript. MJ conceived the study and participated in its design and direction, as well as preparing the manuscript.
All authors read and approved the final draft of the manuscript. Bronchial lability and responsiveness in school children born very preterm. Chronic conditions, functional limitations and special health care needs of school-aged children born with extremely low-birth-weight in the 's. Role of brain- derived neurotrophic factor in hyperoxia-induced enhancement of contractility and impairment of relaxation in lung parenchyma.
Chronic O2 exposure enhances vascular and airway smooth muscle contraction in the newborn but not adult rat. J Appl Physiol Recovery of airway structure and function after hyperoxic exposure in immature rats.
Hyperoxia impairs airway relaxation in immature rats via a cyclic AMP-mediated mechanism. Role of endogenous nitric oxide in hyperoxia-induced airway hyperreactivity in maturing rats. Short-term mechanical ventilation increases airway reactivity in rat pups. Pediatr Res L-citrulline attenuates arrested alveolar growth and pulmonary hypertension in oxygen-induced lung injury in newborn rats.
Regulation of lower airway function. In Fetal and Neonatal Physiology. Nitric oxide synthase isoform expression in the developing lung epithelium. Am J Physiol Inhaled nitric oxide attenuates hyperoxic lung injury in lambs. Inhaled ethyl nitrite prevents hyperoxia-impaired postnatal alveolar development in newborn rats.Mr and Mrs with Outlander stars Caitriona Balfe and Sam Heughan
Inhaled nitric oxide in preterm infants undergoing mechanical ventilation. N Engl J Med Inhaled nitric oxide in premature infants with the respiratory distress syndrome.
Nitric oxide and cyclic GMP in cell signaling and drug development. Plasma membrane transporters for arginine. J Nutr Regulation of enzymes of the urea cycle and arginine metabolism. Annu Rev Nutr Arginine metabolism and the synthesis of nitric oxide in the nervous system. Prog Neurobiol Almost all about citrulline in mammals.
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