Molecular physiopathogenetic mechanisms and development of new potential therapeutic strategies in persistent pulmonary hypertension of the newborn
© Distefano and Sciacca; licensee BioMed Central. 2015
Received: 8 April 2014
Accepted: 13 January 2015
Published: 8 February 2015
Persistent pulmonary hypertension of the newborn (PPHN) is a cyanogenic plurifactorial disorder characterized by failed postnatal drop of pulmonary vascular resistance and maintenance of right-to-left shunt across ductus arteriosus and foramen ovale typical of intrauterine life. The pathogenesis of PPHN is very complex and can result from functional (vasoconstriction) or structural (arteriolar remodeling, reduced pulmonary vessels density) anomalies of pulmonary circulation. Etiopathogenetic factors heterogeneity can strongly condition therapeutical results and prognosis of PPHN that is particularly severe in organic forms that are usually refractory to selective pulmonary vasodilator therapy with inhaled nitric oxide. This paper reports the more recent acquisitions on molecular physiopathogenetic mechanisms underlying functional and structural forms of PPHN and illustrates the bases for adoption of new potential treatment strategies for organic PPHN. These strategies aim to reverse pulmonary vascular remodeling in PPHN with arteriolar smooth muscle hypertrophy and stimulate pulmonary vascular and alveolar growth in PPHN associated with lung hypoplasia.In order to restore lung growth in this severe form of PPHN, attention is focused on the results of studies of mesenchymal stem cells and their therapeutical paracrine effects on bronchopulmonry dysplasia, a chronic neonatal lung disease characterized by arrested vascular and alveolar growth and development of pulmonary hypertension.
KeywordsPersistent neonatal pulmonary hypertension Pulmonary vascular remodeling Pulmonary vessels underdevelopment Lung hypoplasia Pulmonary vasodilative therapy Stem cells based therapy
Persistent pulmonary hypertension of the newborn (PPHN), first described as “persistence of fetal circulation” by Gersony and Sinclair in 1969 , is a cyanogenic disorder characterized by the lack of postnatal drop of pulmonary vascular resistance and by the persistence of the typical intrauterine right-to-left shunting of blood through foramen ovale and ductus arteriosus. The incidence of PPHN is between 0.43 and 6.6 newborns per 1000 live births and is most common in term and near term newborns [2-4]. Despite the major advances in treatment of newborns with cardiorespiratory diseases, PPHN is still one of the main causes of neonatal death, mortality being around 10-20% . The severe outcome of PPHN is probably linked to the broad spectrum of etiopathogenetic factors some of which can negatively influence therapeutical results. Recent researches on the development of PPHN have shown the important role of perinatal fetal environment (e.g. smoke and drug exposure, stress or pain, maternal obesity and diabetes, caesarean section etc.) plus the epigenetic changes that pre and postnatal stimuli can determine in the expression of genes involved in perinatal pulmonary circulation regulation [6-8].
The purpose of this article is to review the physiopatogenetic aspects of PPHN and underline the molecular mechanisms that can constitute the basis of new potential therapeutical strategies for severe forms of PPHN that are resistant to current treatment.
Regulation of perinatal pulmonary circulation
During intrauterine life, pulmonary vascular resistance is elevated and systemic resistance low, fetal channels (ductus arteriosus and foramen ovale) are patent with right-to-left shunt and both ventricles work in parallel instead of in series.
Elevated fetal pulmonary vascular resistance is partly caused by pulmonary collapse and vessels tortuosity but above all by pulmonary arterioles vasoconstriction. Normally these arterioles present a muscular medial tunic up to the preacinar zones then disappearing in intraacinar branches . In physiological conditions the periarteriolar muscular layer develops mainly during the last months of gestation and thus is not well represented in preterms . A thicker muscle layer results in a narrower lumen and reduced arterioles compliance, and this may play a role in increased vascular pulmonary resistance, regardless of vasoconstriction . Relative hypoxia in the blood perfusing the fetal lung plays an important role in pulmonary arteriolar vasoconstriction. Pulmonary arteriolar muscle fibers are very sensitive to oxygen tension and pH variations and they contract in conditions of hypoxia and acidosis and relax when Pa02 and pH increase . Pulmonary arteriolar tone can also be influenced by several humoral factors present in the perinatal circulation. Some of these (thromboxane, endothelin etc.) possess a vasoconstricting action, whereas others (prostacyclin, nitric oxide, etc.) determine vasodilatation [12,13].
At birth systemic resistance rises rapidly. On the contrary, when breathing starts pulmonary resistance falls after lung and pulmonary vascular bed expansion and, in particular, following arteriolar dilatation caused by the rapid increase of arterial oxygen tension. Oxygen can act directly on myocytes, but its action is mainly mediated by humoral factors (specially prostacyclin and nitric oxide) secreted by the pulmonary arteriolar endothelium, a tissue that performs a key function in perinatal pulmonary circulation regulation [10,12,14,15]. Secretion of these vasodilating agents can also be induced by mechanical stimuli such as ventilation and shear stress caused by vascular bed distension and abrupt increment of pulmonary blood flow .
Physiopathology of PPHN
Pathogenesis of PPHN
Pathogenetically there are two forms of PPHN: one functional where elevated vascular pulmonary resistance is only due to pulmonary arteriolar vasoconstriction, and the other organic where vasoconstriction is of secondary importance and increased resistance is mainly caused by substantial structural changes in the pulmonary circulation. These changes are generally represented by pulmonary arterioles lumen narrowing caused by muscular tunic hypertrophy and extension of smooth muscle to the intraacinar branches (normally without muscle fibers), or by poor pulmonary vessels development that reduces the size of the pulmonary vascular bed and thus increases blood flow resistance. Organic forms of PPHN include rare, and almost always fatal, cases of alveolar capillary dysplasia caused by diffuse misalignment of the arteriolar capillary venous axis that compromises respiratory exchange . Both functional and organic forms of PPHN can be primary or secondary and have diverse causes .
Postnatal persistence of fetal pulmonary vasoconstriction
Hypertrophy of pulmonary arteriolar muscular tunic
Underdevelopment of pulmonary vascular bed
In this form of PPHN the failed postnatal drop of pulmonary resistance is due to diminished number of pulmonary vessels that, decreasing the cross-sectional area of pulmonary vascular bed, causes a restrictive type enhancement of resistance to pulmonary blood flow. This severe hemodynamic situation is typical of pulmonary hypoplasia, a condition often associated with congenital diaphragmatic hernia (CDH) . Indeed, it has been clearly documented that normal pulmonary vessel development is crucial for pulmonary alveoli growth and is regulated by various biochemical factors, in particular vascular endothelial growth factor (VEGF), a potent vascular cell mitogen and modulator of angiogenesis [52,53]. Studies on lamb fetuses demonstrated that inhibition of VEGF receptors impairs vascular growth and provokes pulmonary hypertension . Impairment of alveolarization and vascular growth associated with reduced VEGF expression has been reported also in animals with chronic intrauterine pulmonary hypertension induced by ductus ligation . The hypoplastic CDH lung, in addition to reduced vessels density, presents increased vascular reactivity to vasoconstricting stimuli associated with reduced nitric oxide synthase (NOS) expression and elevated endothelin production [23,56,57,6].
Current medical treatment of PPHN
PPHN treatment is influenced by the multiplicity of etiopathogenic factors, the severity of pulmonary hypertension and by heart and lung function alterations. It includes a general therapy aimed at stabilizing the newborns’ clinical conditions, and a more important specific treatment with pulmonary vasodilators aimed at eliminating the right-to-left shunt causing severe hypoxemia [2,3,7,12,58]. If such treatment fails, extracorporeal membrane oxygenation (ECMO) is required . General therapy,that has been well codified for several years [12,7], and ECMO will not be addressed in this paper.
Pulmonary vasodilator therapy
Pulmonary vasodilators are essential in the treatment of PPHN to achieve the reversal of the right-to-left shunt causing hypoxemia and cyanosis.
The advent of nitric oxide (NO) therapy represented a turning-point in the treatment of PPHN. Many clinical and experimental studies have shown that inhaled nitric oxide (iNO), unlike other vasodilators (tolazoline, magnesium sulfate etc.) acting also on the systemic circle [60,3], carries out a selective vasodilating action on pulmonary arterial circulation and eliminates pulmonary hypertension related hypoxemia [61-63]. iNO spreads through the alveolar epithelium to smooth muscle of the underlying vessels and dilates the pulmonary arterioles, while the part that reaches the vessel lumen, through which it could enter the peripheral circulation and cause systemic hypotension, is rapidly inactivated by combination with hemoglobin and formation of methaemoglobin . In PPHN, iNO rapidly improves the oxygenation status and reduces the need for ECMO [64,65,63,2]. In a recent randomized comparative study Gonzalez et al. , showed that the best results with iNO were obtained when therapy was administered early on. Nevertheless clinical experience has demonstrated that iNO therapy is effective only in 50–60% of PPHN patients [67,2]. In all likelihood, this depends on the pathogenesis with optimal response to treatment in functional PPHN, that is induced only by pulmonary arteriolar vasoconstriction, and partial or absent response in organic PPHN where structural alterations of pulmonary arterioles sustain stable pulmonary vascular resistance.
PPHN refractory to INO can also be linked to disruptions in the complex down stream signaling pathways activated by the same NO and negatively interfering with its action on vascular myocytes. These changes are sometimes induced by epigenetic alterations and include various anomalies, such as reduced response of guanylate cyclase to NO, reduced expression or activity of guanylate cyclase, increased clearance of cGMP by phosphodiesterase . In cases of resistant PPHN to INO therapy, an alternative treatment could be the use of PDE inhibitors that preventing cGMP degradation and raising its intramyocytic concentration, promote pulmonary arterioles vasodilation [63,2]. One of these substances, the powerful PDE5 inhibitor sildenafil, has attracted most attention. PDE5 is the most expressed isoform in the lung during the perinatal period and its activity is increased in PPHN animal models . Oral or intravenous administration of sildenafil is able to lower pulmonary vascular resistance with poor impact on systemic resistance in experimental and clinical studies [69-71]. Some studies revealed its efficacy also in cases of PPHN associated with congenital diaphragmatic hernia where it can improve pulmonary vascular function and promote pulmonary growth . Furthermore it has been reported that this drug enhances vasodilative response to endogenous nitric oxide and thus prevents pulmonary hypertension rebound after the suspension of nitric oxide therapy . Adenosine, an eNOS agonist, could increase the formation of N0 and because of its extremely short half-life, it may have fewer systemic side effects. However, the experience using this substance in PPHN is still very limited . Additional pulmonary vasodilatory effect in cases of PPHN not responding well to INO therapy has been reported using inhaled prostacyclin (PGI2) and intravenous infusion of milrinone. These substances trigger off complementary effects on pulmonary vascular myocytes to those obtained by NO as they raise cAMP intracellular concentrations. PGI2 directly stimulates adenil cyclase, while milrinone acts indirectly by inhibiting PDE3, a cAMP hydrolyzing enzyme. However, to date controlled studies confirming their efficacy are lacking [63,3]. A recent randomized, double-blind, placebo-controlled, prospective study in 47 newborns infants with PPHN showed that Bosentan, an endothelin-1 antagonist, is an efficacious pulmonary vasodilator .
Despite progress in PPHN therapy, this syndrome has still a severe prognosis. Clearly, the major problems involve newborns presenting structural changes in pulmonary circulation, such as muscle hypertrophy and pulmonary vascular bed hypoplasia that reduce the efficacy of vasodilator therapy also when it acts selectively on pulmonary vessels. Advances in molecular pathogenetic studies seem to offer new potential therapeutic solutions for these severe cases of PPHN.
New potential therapeutical strategies
Increasing knowledge of complex molecular mechanisms involved in the muscularization process of pulmonary arterioles and the development of pulmonary vascular bed, forms the basis for new therapeutic strategies aimed at promoting periarteriolar muscle involution in PPHN associated with pulmonary vascular remodeling, and at stimulating angiogenic processes in PPHN associated with underdevelopment of pulmonary vasculature.
Regarding PPHN with reduced pulmonary vascular bed it is known that the syndrome is typical of the pathological conditions associated with pulmonary hypoplasia, in particular congenital diaphragmatic hernia (CDH) . Reduced pulmonary vessel density has also been observed in clinical and experimental forms of PPHN secondary to chronic intrauterine fetal pulmonary hypertension [55,7].
Following embryonic vasculogenesis where primordial vascular structures are formed, pulmonary circulatory network development is induced by angiogenesis a biological process regulated by a series of transcription and growth factors, in particular VEGF that is paramount in pulmonary vessel growth . In the human fetal lung, VEGF is expressed in epithelial cells and myocytes while its receptors are located in endothelial cells closely apposed to the developing epithelium . VEGF’s angiogenic effect on pulmonary endothelium is mediated by NO produced by the activation of endothelial nitric oxide synthase (eNOS) . Reduced VEGF expression with impaired nitric oxide signals has been reported in experimental PPHN models associated with chronic fetal pulmonary hypertension after in utero ductal ligation, and with nitrofen-induced diaphragmatic hernia. Both these conditions present vascular remodeling and reduced pulmonary vessel density [54,83]. NO administered to rats with nitrofen-induced CDH to stimulate angiogenesis enhanced lung growth . The results of this research suggest that cases of PPHN associated with reduced pulmonary vessels development could benefit from prolonged treatment with iNO or with NO donors. Benefits would be two-fold as such therapy could determine the regression of periarteriolar muscular hypertrophy, and also stimulate pulmonary angiogenesis. On the other hand, reduced eNOS expression with low blood levels of NO has been reported in human newborns with diaphragmatic hernia  and in experimental animal models with PPHN associated with chronic hypoxia and pulmonary hypertension [84,85]. Recently Teng et al. performed in vitro studies on pulmonary artery endothelial cells (PAEC) isolated from lambs with intrauterine ductal ligation-induced PPHN and showed that angiogenesis can be strongly stimulated by sepiapterin, a substance capable of increasing intracellular levels of tetrahydrobiopterin (BH4) that are low in these cells. BH4 is a cofactor of critical importance to maintain active eNOS catalytic function for NO production, and in PAEC of these PPHN lambs can be inactivated by its oxidation in dihydrobiopterin (BH2), due to increased peroxynitrite formation in these cells . Moreover, in their previous study using the same PPHN lamb model, Teng et al.  showed that impaired angiogenesis in PAEC improved after addition of antioxidants on tissue culture media. The results of such researches suggest that the use of sepiapterin to increase PAEC BH4 intracellular levels might be a potentially useful therapy for improving eNOS function and restoring angiogenesis in PPHN cases with reduced density of pulmonary vessels. Furthermore, the effectiveness of this treatment could be potentiated by combining sepiapterin supplementation and antioxidant therapy.
Future perspectives in PPHN with lung hypoplasia
In this field, very interesting therapeutical perspectives are emerging from experimental studies on bronchopulmonary dysplasia (BPD), a chronic neonatal lung disease characterized by arrested vascular and alveolar growth and development of pulmonary hypertension. They indicate the potential use of mesenchymal stem cells (MSCs) or endothelial progenitors cells (EPCs) for restoring vascular and alveolar growth [88,89]. MSCs are multipotent cells capable of self-renewal and differentiating into various cell types, including parenchymal and vascular pulmonary cells, and can be obtained from bone marrow (BM), umbilical cord blood (UCB) and adipose tissue . EPCs are BM or UCB-derived vascular precursor cells which can be circulating and also resident within vessels wall. Recently several studies In various animal models of BPD have demonstrated that intravenous or intratracheal delivery of bone marrow-derived MSCs (BMSCs) was capable of regenerating lung vascular and alveolar growth and reversing associated pulmonary hypertension . The same effects in BPD models have been obtained with human UCB-derived EPCs . However, a very important acquisition emerging from stem cells studies is that, rather than cells replacement, the beneficial therapeutic effect of BM and UCB-derived MSCs or EPCs can be mediated through a paracrine mechanism . This possibility is suggested by low intrapulmonary engraftment rates of these transplanted cells and supported by in vitro and in vivo studies showing that cell-free conditioned media, derived from cultures of these cells, prevent and/or restore arrested alveolar and vascular growth in neonatal rodents models of lung injury induced by chronic hyperoxia . MSCs-derived conditioned media are rich in soluble factors such as VEGF, stanniocalcin-1 (a potent antioxidant) and specially exosomes, microvesicles containing microRNAs molecules and other bioactive molecules involved, respectively, in gene expression regulation, intercellular communication signals and the control of inflammatory response. These factors can protect the lung from injuries inducing alveolar and vascular damage and stimulate proliferation and differentiation of resident epithelial and endothelial progenitors cells and restore pulmonary growth [92,93]. Recently, the therapeutical importance of exosomes has been demonstrated by Lee et al.  in the rodent model of chronic hypoxia-induced pulmonary hypertension. In this model the intravenous delivery of both animal or human MSC-derived exosomes inhibited vascular remodeling and development of pulmonary hypertension; on the contrary, no therapeutical effect was obtained by removing exosomes from MSCs-conditioned media.
PPHN is a plurifactorial syndrome with a complex pathogenesis sustained by functional (vasoconstriction) or structural (periarteriolar muscular hypertrophy, reduced pulmonary vessels density) pulmonary circulation anomalies. Despite considerable therapeutical progress achieved using inhaled nitric oxide (INO), a selective pulmonary vasodilator, PPHN still remains a major cause of mortality in all neonatal centers. Prognosis is particularly severe in organic forms, that are refractory to INO and other alternative pulmonary vasodilators such as sildenafil and prostacyclin. Recent advances, in the understanding of molecular physiopathogenetic mechanisms, have paved the way for new potential therapeutical strategies for these organic forms that, as observed in animal models, could benefit from prolonged use of nitric oxide donors (NO-donors) and of L-citrulline and sepiapterin. These substances are capable of increasing, respectively, the exogenous and endogenous availability of NO. In PPHN with pulmonary vascular remodeling, increased circulatory levels of NO can reverse periarteriolar muscular hypertrophy counteracting the stimulating effect of endothelin-1 (whose concentrations are elevated in these cases) on pulmonary myocites proliferation and growth. While in PPHN with reduced density of pulmonary vessels, high NO levels can stimulate vascular growth mediating angiogenic effect of VEGF on pulmonary endothelial cells.
Nevertheless, regarding more severe PPHN associated with lung hypoplasia (as in congenital diaphragmatic hernia), very fascinating future therapeutical perspectives are emerging from experimental studies on bronchopulmonary dysplasia (BPD). Such indicate the possible use of human umbilical cord blood-derived mesenchymal stem cells (UCB-derived MSCs) and/or of bioactive factors obtained by their cultures to restore vascular and alveolar growth and reverse pulmonary hypertension. Recently, it has been shown that some of these factors (exosomes) are, also, effective in inhibiting vascular remodeling and pulmonary hypertension development in rodents models of hypoxia-induced PPHN. If the beneficial results achieved in experimental models are confirmed by further controlled studies and reproduced in human newborns, it is reasonable to postulate that, in near future, the use of bioactive substances obtained by cultures of human UCB-derived MSCs (easily accessible at birth) could revolutionize the prognosis of severe organic PPHN.
- Gersony WM, Duc GV, Sinclair JC. ”PCF” syndrome (persistence of the fetal circulation). Circulation. 1969;40(SupplIII):87.Google Scholar
- Stayer SA, Liu Y. Pulmonary hypertension of the newborn. Best Pract Res Clin Anesthesiol. 2010;24:375–86.View ArticleGoogle Scholar
- Teng R-J, Wu T-J. Persistent pulmonary hypertension of the newborn. J Formosan Med Assoc. 2013;112:177–84.View ArticlePubMed CentralPubMedGoogle Scholar
- Roofthooft MTR, Elema A, Bergman KA, Berger RMF. Patient characteristics in persistent pulmonary hypertension of the newborn. Pulmon Med. 2011;2011:858154. doi:10.1155/2011/858154.Google Scholar
- Abman SH. Recent advances in the pathogenesis and treatment of persistent pulmonary hypertension of the newborn. Neonatology. 2007;91:283–90.View ArticlePubMedGoogle Scholar
- Delaney C, Cornfield DN. Risk factors for persistent pulmonary hypertension of the newborn. Pulmon Circul. 2012;2:15–20.View ArticleGoogle Scholar
- Storme L, Aubry E, Rakza T, Houeijeh A, Debarge V, Tourneux P, et al. Pathophysiology of persistent pulmonary hypertension of the newborn: impact of the perinatal environment. Arch Cardiovasc Dis. 2013;106:169–77.View ArticlePubMedGoogle Scholar
- Xu X-F, Ma X-L, Shen Z, Wu X-L, Cheng F, Du L-Z. Epigenetic regulation of the endothelial nitric oxide synthase gene in persistent pulmonary hypertension of the newborn rat. J Hypertens. 2010;28:2227–35.View ArticlePubMedGoogle Scholar
- Geggel RL, Reid LM. The structural basis of PPHN. Clin Perinat. 1984;2:525–49.Google Scholar
- Rudolph AM. High pulmonary vascular resistance after birth.I. Pathophysiologic consideration and etiologic classification. Clin Pediatr. 1980;19:585–90.View ArticleGoogle Scholar
- Rudolph AM, Yuan S. Response of the pulmonary vasculature to hypoxia and H+ ion concentration changes. J Clin Invest. 1966;45:399–411.View ArticlePubMed CentralPubMedGoogle Scholar
- Distefano G, Romeo MG, Parisi MG, Magro G. Physiopathologic and therapeutic aspects of the persistence of fetal circulation. Review of literature and personal histologic observations. Med Surg Ped. 1992;14:387–98.Google Scholar
- Gao Y, Raj JU. Regulation of the pulmonary circulation in the fetus and newborn. Physiol Rev. 2010;90:1291–335.View ArticlePubMedGoogle Scholar
- Ziegler JW, Ivy DD, Kinsella JP, Abman SH. The role of nitric oxide, endothelin, and prostaglandins in the transition of the pulmonary circulation. Clin Perinatol. 1995;22:387–403.PubMedGoogle Scholar
- Steinhorn RH, Millard SL, MorinIII PC. Persistent pulmonary hypertension of the newborn. Role of nitric oxide and endothelin in pathophysiology and treatment. Clin Perinat. 1995;22:405–28.Google Scholar
- Solomonson LP, Flam BR, Pendleton LC, Goodwin BL, Eichler D. The caveolar nitric oxide synthase/arginine regeneration system for NO production in endothelial cells. J Exp Biol. 2003;206:2083–7.View ArticlePubMedGoogle Scholar
- Deruelle P, Grover TR, Storme L, Abman SH. Effect of BAY 41–2272, a soluble guanylate cyclase activator on pulmonary vascular reactivity in the ovine fetus. Am J Physiol Lung Cell Mol Physiol. 2005;288:L727–733.View ArticlePubMedGoogle Scholar
- Jallard S, Larrue B, Deruelle P. Effects of phosphodiesterase 5 inhibitor on pulmonary vascular reactivity in the fetal lamb. Ann Thorac Surg. 2006;81:935–42.View ArticleGoogle Scholar
- Naeye RL. Arterial changes during the perinatal period. Arch Pathol. 1961;71:121–8.PubMedGoogle Scholar
- Naeye RL, Letts HV. The effects of prolonged neonatal hypoxemia on the pulmonary vascular bed and heart. Pediatrics. 1962;30:902–9.PubMedGoogle Scholar
- Haworth SG, Reid L. Persistent fetal circulation. Newly recognized structural features. J Pediatr. 1976;88:614–20.View ArticlePubMedGoogle Scholar
- Haworth SG. Pulmonary vascular remodeling in neonatal pulmonary hypertension. Chest. 1988;93(3 Suppl):133S–8S.PubMedGoogle Scholar
- Castilla-Fernandez Y, Copons-Fernàndez C, Jordan-Lucas R, Linde-Sillo A, Valenzuela-Palafoil I, Ferreres Pinas JC, et al. Alveolar capillary dysplasia with misalignment of pulmonary veins: concordance between pathological and molecular diagnosis. J Perinatol. 2013;33:401–3.View ArticlePubMedGoogle Scholar
- Rocha G, Baptista MJ, Guimaraes H. Persistent pulmonary hypertension of non cardiac cause in a neonatal intensive care unit. Pulmon Med. 2012;2012:818971.Google Scholar
- Haworth SG. Pulmonary endothelium in the perinatal period. Pharmacol Rep. 2006;58:153–64.PubMedGoogle Scholar
- Pearson DL, Dawling S, Walsh WF, Haines JL, Christman BW, Bazyk A. Neonatal pulmonary hypertension. Urea-cycle intermediate, nitric oxide production, and carbamoyl-phosphate synthetase function. N Engl J Med. 2001;344:1832–8.View ArticlePubMedGoogle Scholar
- Hernàndez-Diaz S, Van Marter LI, Werler MM, Loik C, Mitchell AA. Risk factors for persistent pulmonary hypertension of the newborn. Pediatrics. 2007;120:e272–282.View ArticlePubMedGoogle Scholar
- Byers HM, Dagle JM, Klein JM, Ryckman KK, McDonald EL, Murray JC. Variations in CRHR1 are associated with persistent pulmonary hypertension of the newborn. Pediatr Res. 2012;71:162–7.View ArticlePubMed CentralPubMedGoogle Scholar
- Chandrasekar I, Eis A, Konduri GG. Betamethasone attenuates oxidant stress in endothelial cells from fetal lambs with persistent pulmonary hypertension. Pediatr Res. 2008;63:67–72.View ArticlePubMedGoogle Scholar
- da Costa DE, Nair AK, Pai MG, Al Khusaiby SM. Steroids in full term infants with respiratory failure and pulmonary hypertension due to meconium aspiration syndrome. Eur J Pediatr. 2001;160:150–3.View ArticlePubMedGoogle Scholar
- Stenmark KR, James SR, Voelkel BF. Leukotriene C4 and D4 in neonates with hypoxemia and pulmonary hypertension. N Engl J Med. 1983;309:77–80.View ArticlePubMedGoogle Scholar
- Hammerman C, Komar K, Abu-Khudair H. Hypoxic versus septic pulmonary hypertension: selective role of thromboxane mediation. Am J Dis Child. 1988;142:319–25.View ArticlePubMedGoogle Scholar
- Sanderud J, Norstein J, Saugstad OD. Reactive oxygen metabolites produce pulmonary vasoconstriction in young pigs. Pediatr Res. 1991;29:543–7.View ArticlePubMedGoogle Scholar
- Pinheiro JMB, Pitt BR, Gillis CN. Roles of platelet-activating factor and thromboxane in group B streptococcus-induced pulmonary hypertension in piglets. Pediatr Res. 1989;26:420–4.View ArticlePubMedGoogle Scholar
- Curtis J, Kim G, Wehr NB, Levine RL. Group B streptococcus, phospholipids, and pulmonary hypertension. J Perinatol. 2011;31 Suppl 1:S24–8.View ArticlePubMed CentralPubMedGoogle Scholar
- Velvis H, Krusell J, Roman C. Leukotrienes C4, D4 in fetal lamb tracheal fluid. J Dev Physiol. 1990;14:37–41.PubMedGoogle Scholar
- Isozaki-Fukuda Y, Kojima T, Hirata Y. Plasma immunoreactive endothelin-1 concentration in human fetal blood: its relation to asphyxia. Pediatr Res. 1991;30:244–7.View ArticlePubMedGoogle Scholar
- Fostermann U. oxidative stress in vascular disease: causes, defense mechanisms and potential therapies. Nat Clin Pract Cardiovasc Med. 2008;5:338–49.View ArticleGoogle Scholar
- Gong Y, Fediuk J, Lizotte PP, Dakshinamurti S. Hypoxic neonatal pulmonary arterial myocites are sensitized to ROS-generated 8-isoprostane. Free Radical Biol Med. 2010;48:882–94.View ArticleGoogle Scholar
- Allen KM, Haworth SG. Impaired adaptation of pulmonary circulation to extrauterine life in newborn pigs exposed to hypoxia: an ultrastructural study. J Pathol. 1986;150:205–12.View ArticlePubMedGoogle Scholar
- Kuo C, Chen J. Effect of meconium aspiration on plasma endothelin-1 level and pulmonary hemodynamics in a piglet model. Biol Neonate. 1999;76:228–34.View ArticlePubMedGoogle Scholar
- Simpson CM, Smolich JJ, Shekerdemian LS, Penny DJ. Urotensin-II contributes to pulmonary vasoconstriction in a perinatal model of persistent pulmonary hypertension of the newborn secondary to meconium aspiration syndrome. Pediatr Res. 2010;67:150–7.View ArticlePubMedGoogle Scholar
- Murphy JD, Rabinovitch M, Goldstein JD, Reid LM. The structural basis of persistent pulmonary hypertension of the newborn infant. J Pediatr. 1981;98:962–7.View ArticlePubMedGoogle Scholar
- Levin DL, Heymann MA, Kitterman JA, Gregory GA, Phibbs RH, Rudolph AM. Persistent pulmonary hypertension of the newborn infant. J Pediatr. 1976;89:626–30.View ArticlePubMedGoogle Scholar
- Turner GR, Levin DL. Prostaglandin synthesis inhibition in persistent pulmonary hypertension of the newborn. Clin Perinatol. 1984;11:581–9.PubMedGoogle Scholar
- Gersony WM, Morishima HO, Daniel SS, Kohl S, Cohen H, Brown W, et al. The hemodynamic effects of intrauterine hypoxia: an experimental model in newborn lamb. J Pediatr. 1976;89:631–5.View ArticlePubMedGoogle Scholar
- Abman SH, Shanley PF, Accurso FJ. Failure of postnatal adaptation of the pulmonary circulation after chronic intrauterine pulmonary hypertension in fetal lambs. J Clin Invest. 1989;83:1849–58.View ArticlePubMed CentralPubMedGoogle Scholar
- Villamor E, Le Cras TD, Horan MP, Albower AC, Tuder RM, Abman SH. Chronic intrauterine pulmonary hypertension impairs endothelial nitric oxide synthase in the ovine fetus. Am J Physiol. 1997;272:L1013–20.PubMedGoogle Scholar
- Belik J, Keeley FW, Baldwin F, Rabinovitch M. Pulmonary hypertension and vascular remodeling in fetal sheep. Am J Physiol. 1994;266:H2303–9.PubMedGoogle Scholar
- Delaney C, Gien J, Grover TR, Roe G, Abman SH. Pulmonary vascular effects of serotonin and selective serotonin reuptake inhibitors in the late gestation ovine fetus. Am J Physiol Lung Cell Mol Physiol. 2011;301:L937–44.View ArticlePubMed CentralPubMedGoogle Scholar
- Kieler H, Artama M, Engeland A, Ericcson O, Furu K, Gissler M, et al. Selective serotonin reuptake inhibitors during pregnancy and risk of persistent pulmonary hypertension in the newborn:population based cohort study from the five Nordic countries. BMJ. 2012;344:d8012.View ArticlePubMedGoogle Scholar
- Jakkula M, Le Cras TD, Gebb S. Inhibition of angiogenesis decreases alveolarization in the developing rat lung. Am J Physiol Lung Cell Mol Physiol. 2000;279:L600–7.PubMedGoogle Scholar
- Leung DW, Cacianes G, Kuang WJ, Goedel DV, Ferrara N. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science. 1989;246:1306–9.View ArticlePubMedGoogle Scholar
- Grover TR, Parker TA, Zenge JP, Markham NE, Kinsella JP, Abman SH. Intrauterine hypertension decreases lung VEGF expression and VEGF inhibition causes pulmonary hypertension in the ovine fetus. Am J Physiol Lung Cell Mol Physiol. 2003;284:L508–17.PubMedGoogle Scholar
- Gien J, Seedorf GJ, Balasubramaniam V, Markham N, Abman SH. Intrauterine pulmonary hypertension impairs angiogenesis in vitro. Role of vascular endothelial growth factor-nitric oxide signaling. Am J Respir Crit Care Med. 2007;176:1146–53.View ArticlePubMed CentralPubMedGoogle Scholar
- Sheata SM, Sharma HS, Mooi WJ, Tibboel D. Pulmonary Hypertension in human newborns with congenital diaphragmatic hernia is associated with decreased vascular expression of nitric oxide synthase. Cell Biochem Biophys. 2006;44:147–55.View ArticleGoogle Scholar
- Keller RL, Tacy TA, Hendricks-Munoz K, Xu J, Moon-Grady AJ, Neuhaus J, et al. Congenital diaphragmatic hernia:endothelin-1, pulmonary hypertension, and disease severity. Am J Respir Crit Care Med. 2010;182:555–61.View ArticlePubMed CentralPubMedGoogle Scholar
- Luna MS, Franco ML, Bernardo B. Therapeutic strategies in pulmonary hypertension of the newborn: where are we now? Curr Med Chem. 2012;19:4640–53.View ArticleGoogle Scholar
- Lazar DA, Cass DL, Olutoye OO, Welty SE, Fernandes CJ, Rycus PT, et al. The use of ECMO for persistent pulmonary hypertension of the newborn: a decade of experience. J Surg Res. 2012;177:263–7.View ArticlePubMedGoogle Scholar
- Kulik TJ, Lock JE. Pulmonary vasodilator therapy in persistent pulmonary hypertension of the newborn. Clin Perinatol. 1984;11:693–701.PubMedGoogle Scholar
- Roberts JD, Shaul PW. Advances in the treatment of persistent pulmonary hypertension of the newborn. Pediatr Clin N AM. 1993;40:983–1004.Google Scholar
- Geggel RL. Inhalational nitric oxide: a selective pulmonary vasodilator for treatment of persistent pulmonary hypertension of the newborn. J Pediatr. 1993;123:76–9.View ArticlePubMedGoogle Scholar
- Konduri GG, Kim UO. Advances in the diagnosis and management of persistent pulmonary hypertension of the newborn. Pediatr Clin N Am. 2009;56:579–600.View ArticleGoogle Scholar
- Christou H, Van Marter LJ, Wessel DL, Allred EN, Kane JW, Thompson JE, et al. Inhaled nitric oxide reduces the need for extracorporeal membrane oxygenation in infants with persistent pulmonary hypertension of the newborn. Crit Care Med. 2000;28:3722–7.View ArticlePubMedGoogle Scholar
- The Neonatal Inhaled Nitric Oxide Study Group. Inhaled nitric oxide in full-term and near full-term infants with hypoxic respiratory failure. N Engl J Med. 1997;336:597–604.View ArticleGoogle Scholar
- Gonzàlez A, Fabres J, D’Apremont I, Urcelay G, Avaca M, Gandolfi C, et al. Randomized controlled trial of early compared with delayed use of inhaled nitric oxide in newborns with a moderate respiratory failure and pulmonary hypertension. J Perinatol. 2010;30:420–4.View ArticlePubMedGoogle Scholar
- Finer NN, Barrington KJ. Nitric oxide for respiratory failure in infants born at or near term. Cochrane Database Syst Rev. 2006;4:CD000399.PubMedGoogle Scholar
- Steinhorm RH, Russel JA, Morin FC. Disruption of cyclic GMP production in pulmonary arteries isolated from fetal lambs with pulmonary hypertension. Am J Physiol Heart Circ Physiol. 1995;268:H1483–9.Google Scholar
- Baquero H, Soliz A, Neira F, Venegas ME, Sola A. Oral sildenafil in infants with persistent pulmonary hypertension of the newborn: a pilot randomized blinded study. Pediatrics. 2006;117:1077–83.View ArticlePubMedGoogle Scholar
- Vargas-Origel A, Gòmez-Rodrìguez G, Aldana-Valenzuela C, Vela-Huerta MM, Amador-Licona N. The use of sildenafil in persistent pulmonary hypertension of the newborn. Am J Perinatol. 2010;27:225–30.View ArticlePubMedGoogle Scholar
- Steinhorm RH, Kinsella JP, Pierce C, Butrous G, Dilleen M, Oakes M, et al. Intravenous sildenafil in the treatment of neonates with persistent pulmonary hypertension. J Pediatr. 2009;155:841–7.View ArticleGoogle Scholar
- Noori S, Friedlich P, Wong P, Garingo A, Seri I. Cardiovascular effects of sildenafil in neonates and infants with congenital diaphragmatic hernia and pulmonary hypertension. Neonatology. 2007;91:92–100.View ArticlePubMedGoogle Scholar
- Mohamed WA, Ismail M. A randomized, double-blind, placebo-controlled, prospective study of bosentan for the treatment of persistent pulmonary hypertension of the newborn. J Perinatol. 2012;32:608–13.View ArticlePubMedGoogle Scholar
- Wedgwood S, Dettman RW, Black SM. ET-1 stimulates pulmonary arterial smooth muscle cell proliferation via induction of reactive oxygen species. Am J Physiol. 2001;281:L1058–67.Google Scholar
- Wedgwood S, Black SM. Role of reactive oxygen species in vascular remodeling associated with pulmonary hypertension. Antioxid Redox Signal. 2003;5:759–69.View ArticlePubMedGoogle Scholar
- Wedgwood S, Black SM. Molecular mechanisms of nitric oxide-induced growth arrest and apoptosis in fetal pulmonary arterial smooth muscle cells. Nitric Oxide. 2003;9:201–10.View ArticlePubMedGoogle Scholar
- Brennan LA, Steinhorm RH, Wedgewood S, Mata-Greenwood E, Roark EA, Russel A, et al. Increased superoxide generation is associated with pulmonary hypertension in fetal lambs: a role for NADPH oxidase. Circ Res. 2003;92:683–91.View ArticlePubMedGoogle Scholar
- Black SM, Johengen MJ, Soifer SJ. Coordinated regulation of genes of the nitric oxide and endothelin pathways during the development of pulmonary hypertension in fetal lambs. Pediatr Res. 1998;44:821–30.View ArticlePubMedGoogle Scholar
- Ananthakrishnan M, Barr FE, Summar ML, Smith HA, Kaplowitz M, Cunningham G, et al. L-Citrulline ameliorates chronic hypoxia-induced pulmonary hypertension in newborn piglets. Am J Physiol Lung Cell Mol Physiol. 2009;297:L506–511.View ArticlePubMedGoogle Scholar
- Smith HAB, Canter JA, Christian KG, Drinkwater DC, Scholl FG, Christman BW, et al. Nitric oxide precursors and congenital heart surgery: a randomized controlled trial of oral citrullin. J Thorac Cardiovasc Surg. 2006;132:58–65.View ArticlePubMedGoogle Scholar
- Shifren JL, Doldi N, Ferrara N, Mesiano S, Jaffe RB: In the human fetus, vascular endothelial growth factor is expressed in epithelial cells and miocytes, but not in vascular endothelium: implications for mode of action. J Clin Endocrinol Metab 79:316–322Google Scholar
- Papapetropoulos A, Garcia-Cardena G, Madri JA, Sessa WC. Nitric oxide production contributed to angiogenic properties of vascular endothelial growth factor in human endothelial cells. J Clin Invest. 1997;100:3131–9.View ArticlePubMed CentralPubMedGoogle Scholar
- Chang R, Andreoli S, Ng YS, Truong T, Sith SR, Wilson J. VEGF expression is downregulated in nitrofen-induced congenital diaphragmatic hernia. J Pediatr Surg. 2004;39:825–8.View ArticlePubMedGoogle Scholar
- Shaul PW, Yuhanna IS, German Z, Chen Z, Steinhorm RH, Morin FC. Pulmonary endothelial NO synthase gene expression is decreased in fetal lambs with pulmonary hypertension. Physiol Lung Cell Mol Physiol. 1997;16:L1005–12.Google Scholar
- Fike CD, Kaplowitz MR, Thomas CJ, Nelin LD. Chronic hypoxia decreases nitric oxide production and endothelial nitric oxide synthase in newborn ping lungs. Am J Physiol Lung Cell Mol Physiol. 1998;274:L517–26.Google Scholar
- Teng RJ, Du J, Xu H, Bakhutashvili I, Eis A, Shi Y, et al. Sepiapterin improves angiogenesis of pulmonary artery endothelial cells with in utero pulmonary hypertension by recoupling endothelial nitric oxide synthase. Am J Physiol Lung Cell Mol Physiol. 2011;301:L334–45.View ArticlePubMed CentralPubMedGoogle Scholar
- Teng RJ, Eis A, Bakhutashvili I, Arul NKonduri GG. Increased superoxide production contributes to the impaired angiogenesis of fetal pulmonary arteries with in utero pulmonary hypertension. Am J Physiol Cell Mol PHysiol. 2009;297:L184–95.View ArticleGoogle Scholar
- Tuder RM, Abman SH, Braun T, Capron F, Stevens T, Thistlethwaite A, et al. Development and pathology of pulmonary hypertension. J Am Coll Cardiol. 2009;54(N 1,suppl S):S3–9.View ArticlePubMedGoogle Scholar
- Alphonse RS, Thèbaud B. Growth factors, stem cells and bronchopulmonary dysplasia. Neonatology. 2011;99:326–37.View ArticlePubMedGoogle Scholar
- Hansmann G, Fernandez-Gonzalez A, Aslam M, Vitali SH, Martin T, Mitsialis SA, et al. Mesenchymal stem cell-mediated reversal of bronchopulmonary dysplasia and associated pulmonary hypertension. Pulm Circ. 2012;2:170–81.View ArticlePubMed CentralPubMedGoogle Scholar
- Alphonse R, Vadivel A, Waszac P, Fung M, Coltan L, Eaton FYoder M, et al. Existence, functional impairment and therapeutic potential of endothelial colony forming cells (ECFCs) in oxygen-induced arrested alveolar growth. Am J Respir Crit Care Med. 2011;183:A1237.Google Scholar
- Fung ME, Thèbaud B: Stem cell-based therapy for neonatal lung disease. It is in the juice. Pediatr Res 2013, doi:10.1038/pr2013.176Google Scholar
- O’Reilly M, Thèbaud B. The promise of stem cells in bronchopulmonary dysplasia. Sem Perinatol. 2013;37:79–84.View ArticleGoogle Scholar
- Lee C, Mitsialis SA, Aslam M, Vitali SH, Vergadi E, Kostantinou G, et al. Exosomes mediate the cytoprotective action of mesenchymal stromal cells on hypoxia-induced pulmonary hypertension. Circulation. 2012;126:2601–11.View ArticlePubMed CentralPubMedGoogle Scholar
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.