Signaling Pathways Involved in the Development of Bronchopulmonary Dysplasia and Pulmonary Hypertension

Abstract

The alveolar and vascular developmental arrest in the premature infants poses a major problem in the management of these infants. Although, with the current management, the survival rate has improved in these infants, but bronchopulmonary dysplasia (BPD) is a serious complication associated with a high mortality rate. During the neonatal developmental period, these infants are vulnerable to stress. Hypoxia, hyperoxia, and ventilation injury lead to oxidative and inflammatory stress, which induce further damage in the lung alveoli and vasculature. Development of pulmonary hypertension (PH) in infants with BPD worsens the prognosis. Despite considerable progress in the management of premature infants, therapy to prevent BPD is not yet available. Animal experiments have shown deregulation of multiple signaling factors such as transforming growth factorβ (TGFβ), connective tissue growth factor (CTGF), fibroblast growth factor 10 (FGF10), vascular endothelial growth factor (VEGF), caveolin-1, wingless & Int-1 (WNT)/β-catenin, and elastin in the pathogenesis of BPD. This article reviews the signaling pathways entailed in the pathogenesis of BPD associated with PH and the possible management.

Intrauterine Hypoxia and Epigenetic Programming in Lung Development and Disease

“…There is preclinical and clinical evidence that the new form of BPD is caused by early developmental arrest and impaired lung development rather than acute lung injury. This highlights the need for a better understanding of the molecular pathways that guide normal lung development and discover of the mechanisms and applications of lung regeneration [19][20][21][22].…”

A multidisciplinary chronic lung disease team in a neonatal intensive care unit is associated with increased survival to discharge of infants with tracheostomy

“…Secondary pulmonary hypertension is a known complication of severe BPD/CLD and contributes to early mortality [ 19 ]. The role of prematurity, inflammation, and oxidative stress in the pathophysiology of pulmonary hypertension in BPD has been shown to result into deregulation of various signaling pathways leading to impaired alveolarization and disrupted angiogenesis [ 20 ]. The reported incidence of BPD-associated pulmonary hypertension varies between 20 and 40% [ 21 , 22 ].…”

Neonatal and Postneonatal Pulmonary Hypertension

“…Among preterm infants, PH can present during an early period (usually first week) associated with respiratory distress syndrome (RDS) or later associated with bronchopulmonary dysplasia (BPD) [4]. The use of inhaled nitric oxide (iNO) in preterm infants is controversial [9,10].…”

“…The presence of PH along with BPD is associated with increased mortality in these patients and is directly related to severity of PH. Increased pulmonary vascular tone and reactivity, vascular remodeling, abnormal vasculogenesis and angiogenesis contribute to PH in BPD [ 4 ]. The risk factors for PH in preterm infants includes low birth weight, SGA status, severity of BPD, oligohydraminios, maternal smoking and maternal preeclampsia.…”

“…In some infants, the transition can happen in a normal pattern but postnatal increase in PVR can result in post-neonatal PH. Such increase can be seen in preterm infants with bronchopulmonary dysplasia (BPD) [ 4 ]. This special issue of Children includes articles on pathogenesis and management of neonatal and postneonatal PH.…”