Molecular physiopathogenetic mechanisms and development of new potential therapeutic strategies in persistent pulmonary hypertension of the newborn

Distefano and Sciacca Italian Journal of Pediatrics Molecular physiopathogenetic mechanisms and development of new potential therapeutic strategies in persistent pulmonary hypertension of the newborn Giuseppe Distefano 0 Pietro Sciacca 0 0 Department of Pediatrics, Pediatric Cardiology Service, University of Catania , Via S.Sofia 78, Catania 95123 , Italy 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. Persistent neonatal pulmonary hypertension; Pulmonary vascular remodeling; Pulmonary vessels underdevelopment; Lung hypoplasia; Pulmonary vasodilative therapy; Stem cells based therapy - Introduction Persistent pulmonary hypertension of the newborn (PPHN), first described as persistence of fetal circulation by Gersony and Sinclair in 1969 [1], 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% [5]. 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 [9]. In physiological conditions the periarteriolar muscular layer develops mainly during the last months of gestation and thus is not well represented in preterms [10]. 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 [10]. 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 [11]. 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 othe (...truncated)