Molecular Mechanisms for Regulating Postnatal Ductus Arteriosus Closure

Hung, Yu-Chi; Yeh, Jwu‐Lai; Hsu, Jong‐Hau

doi:10.3390/ijms19071861

Cited by 40 publications

(34 citation statements)

References 89 publications

(96 reference statements)

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“…Increased O 2 tension and decreased prostaglandin E 2 levels immediately after birth are the main pathophysiological mechanisms of ductal constriction. 9 Besides these, other unrevealed factors may contribute to appropriate closure of DA. Therefore, underlying molecular factors that oppose ductal constriction must be elucidated for early and effective intervention, particularly in extremely preterm infants.…”

Section: Discussionmentioning

confidence: 99%

Do Calcium and Potassium Levels Influence Ductal Patency in Preterm Infants?

et al. 2019

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Objective We investigated the relationship of serum potassium (K+) and ionized calcium (iCa2+) levels with the persistence of ductus arteriosus. Study Design This retrospective cohort study included infants with birth weight < 1,500 g and gestational age < 32 weeks. Serum K+ and iCa2+ levels at the 1st and 48th hour of life were measured from samples. The difference between the two levels was calculated for both serum K+ (ΔK+) and iCa2+ (ΔCa2+). These values were compared between hemodynamically significant patent ductus arteriosus (hsPDA) and non-hsPDA. Results Of 1,322 hospitalized preterm nonates, 1,196 were included in the study. Mean serum K+ levels at the 1st and 48th hour were higher and iCa2+ levels at the 1st and 48th hour were lower in hsPDA and non-hsPDA, respectively (p < 0.001). Ionized ΔCa2+ (–0.06 ± 0.13 vs. –0.02 ± 0.12 mmol/L) was higher in hsPDA (p < 0.001). Conclusion We demonstrated that serum K+ and iCa2+ level might play a role in ductal constriction.

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Section: Discussionmentioning

confidence: 99%

Do Calcium and Potassium Levels Influence Ductal Patency in Preterm Infants?

et al. 2019

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“…Increased ROS, mainly H 2 O 2 in the mitochondria induces RhoB and Rho-associated protein kinase-1 (ROCK-1) expression, which promotes phosphorylation of myosin phosphatase inhibiting MLCP. Activation of the Rho-kinase pathway induces calcium sensitization, which sustains ductal constriction through positive feedback mechanism ( 51 ). Rho-kinase system balances MLCK and MLCP ( Figure 1 ).…”

Section: Functional Closurementioning

confidence: 99%

“…Extracellular matrix consists of hyaluronan, fibronectin, chondroitin sulfate and elastin, which are mediated by retinoic acid, TGFβ, PGE 2 , IL-15, and oxygen ( 51 ).…”

Section: Anatomic Closure and Remodelingmentioning

confidence: 99%

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Molecular and Mechanical Mechanisms Regulating Ductus Arteriosus Closure in Preterm Infants

Ovalı

2020

Front. Pediatr.

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Failure of ductus arteriosus closure after preterm birth is associated with significant morbidities. Ductal closure requires and is regulated by a complex interplay of molecular and mechanical mechanisms with underlying genetic factors. In utero patency of the ductus is maintained by low oxygen tension, high levels of prostaglandins, nitric oxide and carbon monoxide. After birth, ductal closure occurs first by functional closure, followed by anatomical remodeling. High oxygen tension and decreased prostaglandin levels mediated by numerous factors including potassium channels, endothelin-1, isoprostanes lead to the contraction of the ductus. Bradykinin and corticosteroids also induce ductal constriction by attenuating the sensitivity of the ductus to PGE2. Smooth muscle cells of the ductus can sense oxygen through a mitochondrial network by the role of Rho-kinase pathway which ends up with increased intracellular calcium levels and contraction of myosin light chains. Anatomical closure of the ductus is also complex with various mechanisms such as migration and proliferation of smooth muscle cells, extracellular matrix production, endothelial cell proliferation which mediate cushion formation with the interaction of blood cells. Regulation of vessel walls is affected by retinoic acid, TGF-β1, notch signaling, hyaluronan, fibronectin, chondroitin sulfate, elastin, and vascular endothelial cell growth factor (VEGF). Formation of the platelet plug facilitates luminal remodeling by the obstruction of the constricted ductal lumen. Vasa vasorum are more pronounced in the term ductus but are less active in the preterm ductus. More than 100 genes are effective in the prostaglandin pathway or in vascular smooth muscle development and structure may affect the patency of ductus. Hemodynamic changes after birth including fluid load and flow characteristics as well as shear forces within the ductus also stimulate closure. Current pharmacological treatment for the closure of a patent ductus is based on the blockage of the prostaglandin pathway mainly through COX or POX inhibition, albeit with some limitations and side effects. Further research for new agents aiming ductal closure should focus on a clear understanding of vascular biology of the ductus.

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“…A surfactant more efficient from a biophysical point of view may be able to increase lung compliance and recruit alveoli more quickly, thus allowing to reduce supplemental oxygen. The oxygen exposure is important for the PDA closure [72] and the reduction in circulating reactive oxygen species may crosstalk with the inflammation pathway and contribute to reduce the synthesis of prostaglandins, which are also crucial for ductal patency [72]. Finally, a more efficient surfactant may quickly lower pulmonary vascular resistance through the alveolar recruitment and the increment in alveolar oxygen tension: this will facilitate the inversion of blood flow through the ductus arteriosus [73].…”

Section: Summary Of Evidencementioning

confidence: 99%

Porcine versus bovine surfactant therapy for RDS in preterm neonates: pragmatic meta-analysis and review of physiopathological plausibility of the effects on extra-pulmonary outcomes

Foligno

Luca

2020

Respir Res

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Background: While porcine seems to be superior to bovine surfactants in terms of respiratory outcomes, it is unclear if a surfactant can improve extra-pulmonary outcomes in preterm neonates with respiratory distress syndrome and if there is any physiopathological/biological mechanism linking surfactant therapy to these outcomes. We aim to fill these knowledge gaps. Methods: Systematic and pragmatic review coupled with meta-analysis of randomized controlled trials of bovine or porcine surfactants administered to treat RDS in preterm neonates; common extra-pulmonary neonatal intensive care outcomes were considered. As additional analysis, animal or human translational studies about mechanisms linking surfactant replacement to extra-pulmonary neonatal outcomes were also systematically reviewed. Results: Porcine surfactant is associated with lower incidence of patent ductus arteriosus (OR:0.655; 95%CI:0.460-0.931); p = 0.018; 12 trials; 1472 patients); prenatal steroids (coeff.:-0.009, 95%CI:-0.03-0.009, p = 0.323) and gestational age (coeff.:0.079, 95%CI:-0.18-0.34, p = 0.554) did not influence this effect size. No significant differences were found between porcine and bovine surfactants on neonatal intensive care unit length of stay (mean difference (days):-2.977; 95%CI:-6.659-0.705; p = 0.113; 8 trials; 855 patients), intra-ventricular hemorrhage of any grade (OR:0.860; 95%CI:0.648-1.139); p = 0.293; 15 trials; 1703 patients), severe intra-ventricular hemorrhage (OR:0.852; 95%CI:0.624-1.163); p = 0.313; 15 trials; 1672 patients), necrotizing entero-colitis (OR:1.190; 95%CI:0.785-1.803); p = 0.412; 9 trials; 1097 patients) and retinopathy of prematurity (OR:0.801; 95%CI:0.480-1.337); p = 0.396; 10 trials; 962 patients). Conclusions: Physiopathological mechanisms explaining the effect of surfactant have been found for patent ductus arteriosus only, while they are lacking for all other endpoints. Porcine surfactant is associated with lower incidence of PDA than bovine surfactants. As there are no differences in terms of other extra-pulmonary outcomes and no physiopathological plausibility, these endpoints should not be used in future trials. Registration: PROSPERO n.CRD42018100906.

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Molecular Mechanisms for Regulating Postnatal Ductus Arteriosus Closure

Cited by 40 publications

References 89 publications

Do Calcium and Potassium Levels Influence Ductal Patency in Preterm Infants?

Do Calcium and Potassium Levels Influence Ductal Patency in Preterm Infants?

Molecular and Mechanical Mechanisms Regulating Ductus Arteriosus Closure in Preterm Infants

Porcine versus bovine surfactant therapy for RDS in preterm neonates: pragmatic meta-analysis and review of physiopathological plausibility of the effects on extra-pulmonary outcomes

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