Erythropoietin Protects against Necrotizing Enterocolitis of Newborn Rats by the Inhibiting Nitric Oxide Formation

Kumral, Abdullah; Baskın, Hüseyin; Duman, Nuray; Yılmaz, Osman; Tatlı, Mustafa Mansur; Özer, Erdener; Gökmen, Ali Necati; Genç, Şermin; Özkan, Hasan

doi:10.1159/000073642

Cited by 38 publications

(29 citation statements)

References 31 publications

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“…However, these studies have not identified the responsible mediators, examined NO levels in endothelial cells or identified a molecular mechanism to explain the recruitment of Cav1 to caveolae. Based on our findings it might be interesting to examine the role of sphingomyelinase in these and other clinically relevant situations [44,45] that are characterised by reduced NO production.…”

Section: Role Of No In Paf-induced Oedema Formationmentioning

confidence: 88%

Platelet-activating factor reduces endothelial nitric oxide production: role of acid sphingomyelinase

Yang¹,

Yin²,

Baumgärtner³

et al. 2009

Eur Respir J

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Platelet-activating factor (PAF) is a mediator of pulmonary oedema in acute lung injury that increases vascular permeability within minutes, partly through activation of acid sphingomyelinase (ASM). Since caveolae are rich in sphingomyelin and caveolin-1, which block endothelial nitric oxide (NO) synthase (eNOS) by direct binding, we examined the relationship between ASM, caveolin-1 and eNOS activity in the regulation of vascular permeability by PAF.In caveolar fractions from pulmonary vascular endothelial cells (isolated from perfused rat lungs) the abundance of caveolin-1 and eNOS increased rapidly after PAF perfusion. PAF treatment decreased endothelial NO (eNO) formation as assessed by in situ fluorescence microscopy. Restoration of eNO levels with PAPA-NONOate ((Z)-1-[N-(3-ammoniopropyl)-N-(npropyl)amino]diazen-1-ium-1,2-diolate) mitigated the PAF-induced oedema.PAF treatment increased the ASM activity in caveolar fractions and perfusion with ASM decreased eNO production. Pharmacological inhibition of the ASM pathway with imipramine, D609 or dexamethasone blocked the PAF-induced increase of caveolin-1 and eNOS in caveolae, and the decrease in eNO production and oedema formation.We conclude that PAF causes ASM-dependent enrichment of caveolin-1 in caveolae of endothelial cells, leading to decreased eNO production which contributes to pulmonary oedema formation. These findings suggest rapid reduction in eNO production as a novel mechanism in the regulation of vascular permeability.

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Section: Role Of No In Paf-induced Oedema Formationmentioning

confidence: 88%

Platelet-activating factor reduces endothelial nitric oxide production: role of acid sphingomyelinase

Yang¹,

Yin²,

Baumgärtner³

et al. 2009

Eur Respir J

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“…In premature rabbits exposed to hyperoxia, rhEPO decreased the plasma iron concentration and increased the ability of plasma to inhibit lipid peroxidation (7). In addition, EPO may increase the activity of protective enzymes of oxidative injury and modulate the production of nitric oxide, a major mediator of tissue injury (15,16).…”

Section: Discussionmentioning

confidence: 99%

Effects of Erythropoietin on Hyperoxic Lung Injury in Neonatal Rats

et al. 2005

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Pulmonary oxygen toxicity is believed to play a prominent role in the lung injury that leads to the development of bronchopulmonary dysplasia (BPD). To determine whether human recombinant erythropoietin (rhEPO) treatment reduces the risk of developing BPD, we investigated the effect of rhEPO treatment on the histopathologic changes seen in hyperoxia-induced lung injury of BPD. Twenty-five rat pups were divided into four groups: air-exposed control group (n ϭ 5), hyperoxia-exposed placebo group (n ϭ 7), hyperoxia-exposed rhEPO-treated group (n ϭ 6), and air-exposed rhEPO-treated group (n ϭ 7). Measurement of alveolar surface area, quantification of secondary crest formation, microvessel count, evaluation of alveolar septal fibrosis, and smooth muscle actin immunostaining were performed to assess hyperoxia-induced changes in lung morphology. Treatment of hyperoxia-exposed animals with rhEPO resulted in a significant increase in the mean alveolar area, number of secondary crests formed, and the microvessel count in comparison with hyperoxia-exposed placebo-treated animals. There was significantly less fibrosis in rhEPO-treated animals. However, treatment of hyperoxia-exposed animals with rhEPO did not result in a significant change in smooth muscle content compared with hyperoxia-exposed placebo treated animals. Our results suggest treatment with rhEPO during hyperoxia exposure is associated with improved alveolar structure, enhanced vascularity, and decreased fibrosis. Therefore, we conclude that treatment of preterm infants with EPO might reduce the risk of developing BPD. Despite the improvements in preventing acute respiratory disease in preterm infants, the incidence of BPD remains largely unchanged. The pathophysiology of BPD has been extensively studied for several decades, and pulmonary oxygen toxicity is believed to play a prominent role in the lung injury process that leads to the development of BPD (1). Histopathologic characteristics of the lung injury in BPD are lack of increased complexity (a decrease in alveolarization), abnormal capillary morphology, and an interstitium with variable cellularity/fibroproliferation (2).The treatment goals of BPD focus on minimizing ongoing injury, reducing inflammation, maintaining adequate oxygenation, and facilitating lung growth. A number of groups have used antioxidants to prevent BPD without any significant benefit (3). Corticosteroids facilitate extubation and decrease neonatal respiratory support and oxygen exposure. However, these short-term benefits are achieved at the expense of serious neonatal complications such as poor brain and somatic growth, and substantially worse neuromotor and developmental outcomes in early childhood (4). Therefore, investigating the effectiveness of new strategies in the treatment of BPD is of great interest.EPO is a 30.4-kD glycoprotein that regulates the rate of red blood cell production, through binding to its specific cell surface receptors. It has been used for many years to treat anemia of prematurity (5,6). In addition, in...

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“…Recent Cochrane analyses of early [77] and late [52] rEPO usage concluded that there was a reduction in the number and volume of RBCT but the clinical significance was questioned. Other hypotheses include: (1) protection against ischaemia/reperfusion injury in adult rats [78], (2) preservation of the intestinal barrier function in a rat NEC model [79], (3) inhibition of nitric oxide production [80], and (4) reduction of inflammatory mediators and apoptosis [81]. A recent human study in China [82] showed that in 94 infants with NEC, those treated with rEPO ( n = 52) compared to controls ( n = 42) had significantly lower levels of TNF-α and IL-6 and a significantly lower death and complication rate ( p < 0.05).…”

Section: Anaemia Blood Transfusion and Necmentioning

confidence: 99%

Red Blood Cell Transfusion in Preterm Infants: Current Evidence and Controversies

2018

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The current evidence regarding the indication, advantages and risks of red blood cell transfusion (RBCT) for preterm infants is discussed. This is an important area in Neonatology to be examined given that 90% of extremely low birth weight infants receive RBCT and many controversies remain regarding when to transfuse and the risks of RBCT. The various treatment thresholds and guidelines used are presented and we compare the short-term clinical benefits of liberal and restrictive RBCT in preterm infants; the majority of these are equivocal and sadly long-term outcome data is limited. The latest evidence on how anaemia and blood transfusion affect organ perfusion in preterm infants is presented. This is important when trying to establish the optimal trigger threshold for RBCT in preterm infants, especially because the knowledge about the adaptive physiological responses to anaemia in very low birth weight infants and the effects of RBCT at various levels of anaemia is also inadequate. Further research into the physiological adaptive response to anaemia of varying degrees and to RBCT at different levels of anaemia in preterm infants of different gestational and post-natal ages is needed before we can conclusively guide the optimal timing and trigger thresholds for RBCT in preterm infants.

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Erythropoietin Protects against Necrotizing Enterocolitis of Newborn Rats by the Inhibiting Nitric Oxide Formation

Cited by 38 publications

References 31 publications

Platelet-activating factor reduces endothelial nitric oxide production: role of acid sphingomyelinase

Platelet-activating factor reduces endothelial nitric oxide production: role of acid sphingomyelinase

Effects of Erythropoietin on Hyperoxic Lung Injury in Neonatal Rats

Red Blood Cell Transfusion in Preterm Infants: Current Evidence and Controversies

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