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Advances in paediatric pulmonary vascular disease associated with bronchopulmonary dysplasia Expert Rev. Respir. Med. 9(1), 35–43 (2015)

Thomas Rossor1 and Anne Greenough*1,2 1 Division of Asthma, Allergy and Lung Biology, MRC and Asthma UK Centre in Allergic Mechanisms of Asthma, King’s College London, London, England, UK 2 NIHR Biomedical Research Centre at Guy’s and St Thomas’ NHS Foundation Trust and King’s College London, London, England, UK *Author for correspondence: Tel.: +44 020 3299 3037 Fax: +44 020 3299 8284 [email protected]

Pulmonary hypertension (PH) is a common finding in infants with bronchopulmonary dysplasia (BPD). The aim of this review is to describe recent advances in the diagnosis and treatment of PH and discuss whether they will benefit infants and children with BPD related PH. Echocardiography remains the mainstay of diagnosis but has limitations, further developments in diagnostic techniques and identification of biomarkers are required. There are many potential therapies for PH associated with BPD. Inhaled nitric oxide has been shown to improve short term outcomes only. Sidenafil in resource limited settings was shown in three randomized trials to significantly reduce mortality. The efficacy of other therapies including prostacyclin, PDE3 inhibitors and endothelin receptor blockers has only been reported in case reports or case series. Randomized controlled trials with long term follow up are required to appropriately assess the efficacy of therapies aimed at improving the outcome of children with PH. KEYWORDS: bronchopulmonary dysplasia • pulmonary hypertension • pulmonary vascular disease

Bronchopulmonary dysplasia (BPD) is a common adverse outcome of very premature birth, in one study affecting 42% of 9575 infants born between 22 and 28 weeks of gestation [1]. Although BPD most usually occurs in prematurely born infants, it can occur in term born infants who had severe lung disease [2]. It is diagnosed if infants remain oxygen dependent beyond 28 days after birth. The severity of the disease is then determined by the respiratory support requirement at a later age: 36 weeks past menstrual age in prematurely born infants of less than 32 weeks of gestation and at a postnatal age of between 28 and 56 days in those born at more than 32 weeks of gestation [3]. Infants are diagnosed as having mild BPD if at the later age they no longer require oxygen therapy, moderate BPD if they require up to 30% supplementary oxygen and severe if they require more than 30% supplementary oxygen and/or positive pressure support [3]. Infants with BPD suffer chronic respiratory morbidity. They may require supplementary oxygen for many months although few remain oxygen dependent beyond 2 years of age [4]. Hospital readmission is common, particularly informahealthcare.com

10.1586/17476348.2015.986470

for respiratory problems; in one series 73% of infants with BPD had at least one readmission [5]. Troublesome respiratory symptoms requiring treatment are common even at school age [6] and may persist into adulthood, particularly in females who had BPD [7]. In the first 2 years after birth, BPD children have a high airways resistance, evidence of gas trapping and ventilation inhomogeneity. In the majority, lung growth and remodeling result in progressive improvement in pulmonary function, but airflow limitation persists [8]. A systematic review demonstrated airway obstruction and impaired gas transfer in adults who had BPD; greater impairment of lung function was unmasked by exercise testing [9]. BPD has a multifactorial etiology. BPD was initially described in infants who had severe lung disease and were exposed to volutrauma and oxygen toxicity, so called old BPD. It can, however, occur in very prematurely born infants who had minimal or even no initial respiratory distress so called new BPD, which has been suggested to be a maldevelopment sequence resulting from interruption/ interference of normal development signalling


2015 Informa UK Ltd

ISSN 1747-6348

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for terminal maturation [10]. Histological evidence suggests that premature birth and perinatal lung injury result in impaired alveolarisation and dysmorphic vascular growth [11]. The critical association of vascular and alveolar development has been demonstrated in numerous studies, for example administration of three anti-angiogenic factors (thalidomide, fumagillin and a VEGF blocker) resulted in reduced vascular density and impaired alveolarisation in young rats [12]. Reduced lung vascular growth can persist even into adulthood and may contribute to pulmonary vascular disease. The increased pulmonary vascular resistance (PVR) associated with BPD results from the reduction in vascular density, but also the increased smooth muscle proliferation into small arteries and incorporation of myofibroblasts into the vessel walls [13]. The latter changes increase PVR as the cross sectional area and compliance of the thickened vessels are reduced. Pulmonary hypertension (PH) is the severe manifestation of the pulmonary vascular disease resulting in a high mortality. In one series, only 52% of BPD infants were alive at 2 years after a diagnosis of PH [14]. In a series of 42 infants with BPD and PH diagnosed at greater than 2 months of age by echocardiography or cardiac catheterization, half of the infants had severe PH (systemic or supra-systemic right ventricular pressure), 10% had mild PH and the remainder had moderate PH. Their mortality too was high, only 64% of the infants were alive 6 months after the PH was diagnosed [14]. Cardiovascular anomalies, including aorto-pulmonary collaterals, pulmonary vein stenosis, ASD and PDA are common in infants with PH and worsen the prognosis unless promptly treated [15]. The aims of this review, therefore, are to describe recent advances in the diagnosis and treatment of PH and in particular discuss whether they will benefit infants and children with BPD related PHPH. Diagnosis

It had been suggested that the incidence of PHPH in infants with BPD may be as high as 22% [16] or 25% [17], but in a large single site study in which all extremely low birth weight (ELBW) infants underwent prospective echocardiographic screening only 6% had evidence of PAH at 4 weeks and an additional 12% developed PAH by the time of discharge [16]. Differences in the reported incidences may reflect the limitations of diagnostic techniques in this population (see below). Cardiac catherisation

The gold standard for the diagnosis of PHPH is cardiac catheterization, which can also be used to assess the response to oxygen and other pulmonary vasodilators. PHPH is diagnosed if the mean pulmonary artery pressure is equal to or greater than 25 mmHg at rest. Catheterization, however, is invasive and has risks, hence it is reserved for BPD infants with severe respiratory disease and PH diagnosed on echocardiography. Infants with PH and persistent late pulmonary edema despite aggressive diuretic therapy or worsening pulmonary edema in response to PH treatment such as inhaled nitric oxide (iNO) 36

or sildenafil require cardiac catheterization to rule out left heart function dysfunction or congenital abnormalities such as pulmonary venous obstruction. In addition to abnormalities of left ventricular systolic function, left ventricular diastolic dysfunction has also been reported [18]. Left ventricular diastolic dysfunction is characterized by increased stiffness and abnormal relaxation of the ventricle which leads to abnormal early diastolic filling [19]. It can be diagnosed by Doppler tissue imaging, but these techniques have not been well defined in infants or are part of routine echocardiography [18]. Left ventricular diastolic dysfunction responds to after load reducing agents [18]. Echocardiography

Echocardiography is used to diagnose PH in BPD infants [20], but limitations of that technique (see below) make accurate estimation of the incidence of BPD related pulmonary vascular disease problematic. PHPH is diagnosed when the estimated systolic pulmonary artery pressure is greater than or equal to 40 mmHg [21]. The pulmonary artery pressure is estimated by measurement of the velocity of the regurgitant jet from the tricuspid valve (pressure gradient = 4  jet velocity), but an adequate tricuspid regurgitant jet may be present in only 31–61% of BPD infants with suspected PHPH [16,17]. The absence of a regurgitant jet does not preclude the presence of PHPH. Assessment of the ratio of time to peak velocity over the right ventricular ejection time (TOV: RVET) has demonstrated that mildly elevated pulmonary pressures may be seen in asymptomatic young children who had BPD [22]. The right ventricular index of myocardial performance, defined as the sum of the isovolumetric contraction time and isovolumetric relaxation time divided by the ejection time, has been shown in adults to correlate well with invasively measured PVR [23]. This index is not dependent on a tricuspid regurgitant jet and has been suggested to be a useful marker of right ventricular function in children [24] and differ between infants with and without BPD [25]. There are, however, no data in the neonatal or infant population to correlate with results from right heart catheterization. Other echocardiographic findings such as septal flattening, right atrial enlargement and right ventricle hypertrophy and dilatation are suggestive of PH but have a high inter-observer variability [20]. In a retrospective comparison with subsequent right heart catheterization in 25 infants less than 2 years of age, echocardiography findings had a sensitivity of 88%, but a specificity of only 33% in detecting PH. In addition, the severity of PH was correctly diagnosed by echocardiography in only 47% of the infants. In infants without a tricuspid regurgitant jet qualitative assessment was used; septal flattening had a sensitivity of 88% and specificity of 33% and other qualitative assessments were even less predictive [26]. Cardiac computerized tomography

In adults, cardiac computerized tomography (CT) has been studied as a potential tool to diagnose PH. ECG gated acquisition allows consistent measurement of the distensibility of the right pulmonary artery, cross sectional area of the Expert Rev. Respir. Med. 9(1), (2015)

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Advances in paediatric pulmonary vascular disease associated with BPD

pulmonary arteries and right ventricular wall dynamics [27], but these assessments have not been validated in infants. Nevertheless, CT examination enables detection of cardiovascular anomalies such as aorto-pulmonary collaterals, pulmonary vein stenosis, atrial septal defects and patent ductus arteriosus that may contribute to PH and remain undetected by echocardiography. In a retrospective study of 29 infants with PH diagnosed by echocardiography, cardiovascular anomalies were found in 65% of infants on CT examination [15]. Ionising radiation may limit the use of CT in the evaluation of PH in the BPD population. Cardiac MRI

In adults, cardiac MRI results and right heart catheterization data have been compared for the evaluation of mean pulmonary artery pressure and PVR [28,29]. Phase contrast MRI allows accurate assessment of cardiac and pulmonary vascular flow dynamics. MRI estimation of pulmonary artery pressure from the tricuspid regurgitant jet with a modified Bernoulli equation had a better correlation with catheter derived right heart pressures than echocardiographic derived estimates [30]. The ratio of septal and free wall curvature of the left ventricle has been demonstrated to have 87% sensitivity and 100% specificity in detecting elevated right ventricular pressure; in addition the estimated right ventricular pressure was shown to correlate moderately with right heart catheterization data [31]. It is now possible to perform single breath-hold studies in adults; the technology to perform such studies in spontaneously breathing infants is in development. The use of respiratory gated MRI sequences may yield high definition images in the neonates and infants [32], hence whether this technique improves the assessment of BPD related PH merits investigation. Biomarkers

Biomarkers have been assessed as non-invasive diagnostic tests for PAH. These include Brain-type natriuretic peptide, which is an endogenous peptide secreted by the cardiac ventricles in response to increased wall stress and hence could be a marker of right heart strain. Brain-type natriuretic peptide levels have been shown to correlate with echocardiographic findings of PH [33] and reference values have been reported [34]. Other possible biomarkers have been assessed in adults and include endothelin-1, troponin-T and exhaled NO [35]. Management

Echocardiographic and cardiac catherisation data show that the elevated PVR associated with BPD has a structural component which does not respond to oxygen or other vasodilators and a reactive component which is responsive to such therapies. Infants with BPD have an exaggerated vasoconstrictive response to hypoxia [36], hence it is important to maintain oxygen saturations at a level that avoids hypoxia induced pulmonary vasoconstriction and increased PH. Target saturations of 91–95% in BPD infants with PH are commonly used [37], greater than 92% has been recommended [38]. informahealthcare.com

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Inhaled NO

iNO causes pulmonary vasodilation, vascular remodeling, bronchodilation and reduced inflammation, there are however relatively few data regarding its use in infants with established BPD. iNO at a dosage of 20 ppm improved oxygenation in 11 of 16 infants with severe BPD who were ventilator dependent at one to 7 months of age [39]. The long term outcomes of the infants, however, were variable, four of 11 infants who responded to iNO were ultimately weaned off the ventilator and four others died; the infants who failed to respond to iNO either remained ventilator dependent or died [40]. iNO has been shown to reduce pulmonary artery pressure and the pulmonary to systemic vascular resistance ratio in BPD infants with PH undergoing cardiac catheterization [36]. PDE-5 inhibitors

Sildenafil is a phosphodiesterase (PDE-5) inhibitor that reduces degradation of cyclic GMP and hence influences contractility of vascular smooth muscle. Given orally, maximum serum concentrations are reached within 0.5–1.5 h. Its half-life is 4 h, but delays in maturation after birth may prolong this and hence a 6 h regime has been recommended [40]. An advantage of sildenafil over iNO is that it can be given orally and hence administered over long time periods, but enteral administration can be compromised by inconsistent gastrointestinal absorption experienced by critically ill children. It can also be administered parenterally with positive effect [41]. It is frequently used in the management of PH of various aetiologies in the pediatric population, but there is limited evidence for its use in BPD associated PH. There are a number of case reports [42–44]. In an infant born at 26 weeks of gestation with a presumptive diagnosis of BPD and associated pulmonary hypertensive crisis at 23 weeks of age, in the absence of iNO, sildenafil administration resulted in a rapid improvement in her oxygenation index from 43 to 14, she made a full recovery [42]. In an infant born at 23 weeks of gestation, sildenafil at 5 months of age resulted in normalization of right ventricular morphology and pulmonary artery pressures. Reduction of the dose at 8 months of age resulted in a marked increase in pulmonary artery pressures. Treatment was therefore continued for 12 months of age with complete resolution of the PH; the pulmonary artery pressures remained normal at follow-up 18 months after discontinuation of therapy [43]. Use of sildenafil with iNO has been reported in two retrospective studies including 34 patients with improvements in the pulmonary artery pressures [45,46], but this was not accompanied by an improvement in gas exchange and, in one of the series, four infants died during treatment [45]. The US FDA issued a warning against the use of sildenafil in children from 1 to 17 years of age following the increased mortality associated with a high dose of oral sildenafil in the STARTS-2 study [47], the relevance of those data to BPD related PH remains unknown [40]. Sidenafil has been assessed in three RCTs which enrolled a total of 77 infants with persistent PH of the newborn (PPHN) in resource limited settings, where iNO and high frequency ventilation were not 37

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available [48]. There were improvements in oxygenation and a significant reduction in mortality in the sildenafil group (typical risk ratio: 0.20, 95 CI: 0.07–0.57) [48]. A large RCT comparing iNO and sidenafil is required to assess their relative efficacy and safety.

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Prostacyclin

Prostacyclin (PGI2) is produced by the vascular endothelium and when bound to the PGI2 receptor activates adenylyl cyclase, increasing cyclic AMP levels resulting in smooth muscle relaxation. Prostacyclin analogues have been successfully used for many years in the treatment of PH in adults and children [49]. Evidence for use in BPD associated PH is limited. In a case report, intravenous iloprost, oral sildenafil and digoxin were used successfully in a 4 month old prematurely born infant [50]. In another case report, long term home ventilation in combination with chronic intravenous epoprostenol resulted in reduction in the pulmonary artery pressures and improved quality of life in a 2 year old with severe PAH associated with BPD [51]. Prostacyclin has a short half-life necessitating continuous infusion, thus limiting its applicability for long-term or out of hospital use. Synthetic analogues, such as iloprost, have a longer half-life and can be given by inhalation [52] or subcutaneously [53]. Inhaled PGI2 has been used to improve oxygenation in infants with severe PPHN with an inadequate response to iNO [54]. There are however concerns including airway irritation from the alkaline solution needed to maintain the drug stability and inconsistent drug delivery due to loss in the circuit [55].

infants with BPD and PH, ET receptor antagonists were successfully used either alone or in conjunction with sildenafil, with follow-up of three to 4 years [64]. A 5 year experience of bosentan in 101 children with PH (either idiopathic or associated with congenital heart disease) highlighted that there appeared to be slowing of disease progression without adverse effects [65]. The safety profile in BPD infants, however, has not been established; possible side effects include raised liver transaminases, hence liver function should be monitored regularly during treatment. Selective ETA receptor blockade with agents such as ambrisentan or sitaxsentan also causes vasodilation [60], evaluation of the efficacy of such agents in BPD infants with PH is required. Long term outcome Mortality

In one study [14] over a third of infants with BPD and severe PH died within 6 months of the diagnosis. Assessment of PH over the next year demonstrated improvements over the next year in 24 of 26 of the survivors, although right ventricular pressures only fully normalized in five infants. BPD infants who have PH require a longer duration of supplementary oxygen post discharge [66,67]. In a retrospective cohort of BPD infants requiring prolonged ventilation, those with evidence of PH were four times more likely to die than those without echocardiographic evidence of PH [58]. Infants with BPD are at increased risk of PH crises while under anaesthesia or sedation and this contributes to their increased mortality. A retrospective review demonstrated that children with PH had a sixfold increased risk of perioperative/periprocedural cardiac risk [68].

PDE-3 inhibitors

cAMP signalling is also controlled by cAMP hydrolysing PDE isoforms such as PDE3 and PDE4. Milrinone is an inhibitor of PDE3 and is used in pediatric patients to improve myocardial contractility. There are reports of its use to decrease rebound PH after stopping iNO [56] and increasing pulmonary vasodilation in infants with PPHN refractory to iNO [57,58]. There are no RCTs assessing milrinone in infants with PPHN [59]. Endothelin receptor blockers

Endothelin (ET) is a potent vasoconstrictor produced by endothelial cells in response to hypoxia, causing smooth muscle cell proliferation and remodeling [60]. Prophylactic treatment with an ET receptor antagonist in rats subjected to hyperoxia induced lung injury resulted in improved survival, preserved alveolar architecture and prevented pulmonary artery hypertension and right ventricular hypertrophy [61]. ET-1 acts via two G proteins-coupled receptors: ETA promotes smooth muscle cells proliferation and vasoconstriction and ETB promotes proliferation and vasoconstriction, but also mediates vasodilation by release of NO and PGI2 from endothelial cells [62]. Bosentan, a non-selective antagonist of ETA and ETB receptors has been successfully used in the treatment of PH in adults and there is emerging evidence of its efficacy in children [63]. In six 38

Outcome in childhood

There are few studies assessing cardiovascular function at school age of prematurely born infants who had had BPD. In 60 children born at less than 33 weeks of gestation, 28 of whom had BPD, compared to term-born controls baseline oxygen saturation, heart rate, blood pressure and echocardiographic markers of left and right ventricular function were similar at 8–12 years of age [69]. While breathing 12% oxygen the fall in oxygen saturation levels was significantly greater in the BPD children compared to the prematurely born and term born controls. In response to hypoxia (12 and 15% oxygen), all three groups showed increases in the velocity of tricuspid regurgitation, end-diastolic velocity of pulmonary regurgitation and right ventricular relaxation time and decreases in pulmonary artery acceleration time and the ratio of right ventricular acceleration time to ejection time. There were, however, no significant differences between the three groups [69]. In contrast at 11–14 years of age, 13% of 191 very prematurely born infants, but none of 107 term born controls had a peak TR velocity of greater than 2.5 m/sec (p < 0.01) [70]. In addition, the prematurely born children had significantly higher TR peak velocity, mean right atrium-right ventricle ratio and inferior vena cava diameter [70]. The differences in the results of the two studies [69,70] may be explained by the prematurely Expert Rev. Respir. Med. 9(1), (2015)

Advances in paediatric pulmonary vascular disease associated with BPD

born children included in the latter study prior to 29 weeks of gestation.

[70]

were all born

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Outcome in adulthood

At 20–39 years, prematurely born infants with a mean gestational age of 30 weeks, compared to term born controls had increased ventricular mass with significant reductions in systolic and diastolic functional parameters as assessed by cardiovascular magnetic resonance [71]. Higher blood pressure, a known complication of premature birth, may have accounted for a proportion of the increased left ventricular mass. For any given level of blood pressure, however, prematurity was associated with additional significant increases in left ventricular mass and that increase in left ventricular mass was graded according to the degree of prematurity independently of other perinatal factors. The presence of increased left ventricular mass in those with hypertension or prehypertension is known to have an independent prognostic significance [72,73]. It would be interesting to determine if PH in those who had BPD is associated with right ventricular changes in adulthood, but there are technical challenges in the creation of the an accurate 3-dimensional model of the geometrically complex right ventricle. Expert commentary

PH (PH) associated with BPD increases mortality and morbidity and, as such, requires more intense attention. Due to the limitations of echocardiography the true incidence of PH in this population is not accurately known. Prospective studies are required to inform recommendations for screening and the most high risk population in which this should be undertaken. To make such recommendations clinically relevant, there needs to be further developments in the diagnostic techniques. Currently, treatment for PH in BPD patients is not based on large RCTs with long term follow-up and these need to be undertaken. Studies in animal models and adults and potentially interesting results from case reports/series should generate appropriately designed, hypothesis driven clinical trials. The long term outcome of BPD associated PH needs to be better investigated and documented. Accurate biomarkers have not been identified, yet would facilitate preventative studies. Five-year view

It is only in the past 5 years that the scale of pulmonary vascular disease in infants with BPD has started to become apparent. The apparent high incidence of PH in BPD infants [16] and associated mortality argue for all BPD infants to undergo screening. For the results of such screening to be meaningful, there needs to be improvements in diagnosis. Large prospective studies need to be undertaken to determine the true incidence of PH, the associated mortality and morbidity and biomarkers determined identifying high risk infants. There needs to be a much greater evidence base regarding the therapeutic agents used to treat BPD infants with PH. There are, however, challenges to drug trials in neonates and children with pulmonary hypertensive vascular disease as informahealthcare.com

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documented in the report of the PH academic research consortium pediatric advisory committee [74]. These include that the pulmonary vascular bed is developing in childhood which may influence the disease and outcome of drug trials. In addition, drug therapy is influenced by developmental changes in renal and metabolic blood flow, as well as in metabolic systems such as cytochrome P450. In addition, clinical endpoints such as exercise capacity, using traditional classifications and testing, cannot be routinely applied to children [74]. New strategies also need to be assessed, which will involve a greater understanding of the pathogenesis of pulmonary vascular development and hence PH in prematurely born infants. An interesting area to explore will be transcription factors such as Hypoxia-inducible factor 1(HIF-1). HIF-1 is a highly conserved transcription factor regulating the expression of hundreds of genes, including VEGF, according to oxygen availability [75]. A heterodimer, it consists of a HIF-1b subunit which is ubiquitously expressed, which combines with the HIF-1a subunit which is highly unstable in normoxic conditions, but stabilises and binds HIF-1b under hypoxic conditions to activate DNA binding activity [75]. HIF-1a is expressed by all cell types in adult lung and is localized in branching epithelium in the developing lung. HIF-1a + b levels are low in mechanically ventilated, prematurely born animals [76]. Degradation of the a subunits is catalysed by prolyl hydroxylase domain proteins (PHDs) and inhibition of PHDs in a baboon model of prematurity resulted in improved lung function and growth [77] and pulmonary vascular development [78]. Hypoxia increased the capacitance of pulmonary artery smooth muscle cells in wildtype mice, but not in those with HIF-1a heterozygous deletion, suggesting that smooth muscle hypertrophy in pulmonary vascular remodeling may be HIF-1 dependent [75]. Conditional deletion of HIFF-1a in a mouse model resulted in attenuation of hypoxia induced PH, but no improvement in right ventricular hypertrophy [79]. In rodent models of BPD, sidenafil improved alveolarisation and decreased modelling of the pulmonary vasculature. In neonatal rats with BPD, sildenafil improved lung growth and alveolarisation and there was increased expression of HIF and its downstream target VEGF [80]. In vitro experiments demonstrated that the sildenafil effect of HIF was most likely to be mediated by cGMP. Whether sildenafil might prevent BPD and associated PH merits investigation. VEGF, an endothelial cell specific mitogen, is critical to vascular development. VEGF levels are low in animal models of BPD [81]. VEGF blockade impairs alveolar development and results in a loss of lung capillaries [82]. Postnatal intratracheal adenovirus mediated VEGF gene therapy in newborn rats with hyperoxia induced BPD improved survival and promoted lung capillary formation and preserved alveolar development. Similarly intra-muscular recombitant human VEGF in neonatal rats with hypoeroxic induced lung injury enhanced vessel growth and alveolarisation [83]. Those results suggest VEGF should be considered as a potential therapy for PH. Genome-wide expression profiling of lung tissue of infants who died of BPD compared to age-matched infants who died of 39

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other causes demonstrated 159 genes differentially expressed in the BPD patients [84]. Three of the five most highly induced genes were mast cell (MC) specific markers, interestingly there was an increased accumulation of connective tissue (MCTC chymase expressing) mast cells in the BPD tissues [84]. RCTs of an inhibitor of mast-cell degranulation, cromolyn sodium showed no benefit [85], but that agent has limited effect on connective tissue type mast-cells, but more targeted intervention may have potential. Disorder extracellular matrix production is a feature of BPD. Excessive stabilization of the extracellular matrix by excessive lysyl oxidase activity might impede the normal matrix remodeling required for pulmonary alveolarisation and contribute to BPD [86]. Investigation of expression and regulation of three members of the lysyl hydroxylase family of the extracellular matric remodeling enzymes (Plod1, Plod2 and Plod3) demonstrated all three enzymes were localized to the septal walls in the developing lung. Plod1 was also expressed in the vessel walls of the developing lung [87]. The expression of all three enzymes was upregulated in the lungs of mouse pups exposed to 85% oxygen. These data suggest another avenue to explore

interventions to prevent abberant lung growth and vascular development. The potential of stem cell therapy should be further investigated. Vascular growth occurs via two mechanisms: angiogenesis, which is the extension of existing vessels; and vasculogenesis, which is the formation of new endothelial sinuses [88]. Vasculogenesis is dependent on circulating endothelial progenitor cells (EPCs) and mesenchymal stromal cells (MSCs). EPC levels in bloods, lung and bone marrow were reduced in a rodent model of hyperoxic lung injury [89] and intratracheal or intravenous administration of MSCs resulted in normalization of vascular structure and alveolarisation [90,91]. Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.

Key issues • Bronchopulmonary dysplasia (BPD) associated pulmonary hypertension (PH) has a high mortality. • The true incidence of BPD associated PH needs to be established. • Further work is required to identify reliable, non-invasive diagnostic techniques and, in particular, those being used in adults merit investigation in BPD patients. • Accurate biomarkers need to be identified. • Current treatment of BPD associated PH is based on limited evidence. • A large randomized trial with long term outcomes comparing sildenafil and iNO should be undertaken. • Other vasodilators need to be appropriately investigated in this population. • The outcome of BPD related PH in childhood needs to be better understood. • Identification of efficacious preventative therapies is key; whether in this respect sidenafil or stem cell therapy will improve outcome merit investigation.

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