Persistent Pulmonary Hypertension of the Newborn: Pathophysiological Mechanisms and Novel Therapeutic Approaches

Sofia Martinho, Rui Adão, Adelino F Leite-Moreira, Carmen Brás-Silva, Sofia Martinho, Rui Adão, Adelino F Leite-Moreira, Carmen Brás-Silva

Abstract

Persistent pulmonary hypertension of the newborn (PPHN) is one of the main causes of neonatal morbidity and mortality. It is characterized by sustained elevation of pulmonary vascular resistance (PVR), preventing an increase in pulmonary blood flow after birth. The affected neonates fail to establish blood oxygenation, precipitating severe respiratory distress, hypoxemia, and eventually death. Inhaled nitric oxide (iNO), the only approved pulmonary vasodilator for PPHN, constitutes, alongside supportive therapy, the basis of its treatment. However, nearly 40% of infants are iNO resistant. The cornerstones of increased PVR in PPHN are pulmonary vasoconstriction and vascular remodeling. A better understanding of PPHN pathophysiology may enlighten targeted and more effective therapies. Sildenafil, prostaglandins, milrinone, and bosentan, acting as vasodilators, besides glucocorticoids, playing a role on reducing inflammation, have all shown potential beneficial effects on newborns with PPHN. Furthermore, experimental evidence in PPHN animal models supports prospective use of emergent therapies, such as soluble guanylyl cyclase (sGC) activators/stimulators, l-citrulline, Rho-kinase inhibitors, peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists, recombinant superoxide dismutase (rhSOD), tetrahydrobiopterin (BH4) analogs, ω-3 long-chain polyunsaturated fatty acids (LC-PUFAs), 5-HT2A receptor antagonists, and recombinant human vascular endothelial growth factor (rhVEGF). This review focuses on current knowledge on alternative and novel pathways involved in PPHN pathogenesis, as well as recent progress regarding experimental and clinical evidence on potential therapeutic approaches for PPHN.

Keywords: persistent pulmonary hypertension of the newborn; pulmonary vascular remodeling; pulmonary vascular resistance; pulmonary vasoconstriction; pulmonary vasodilators.

Copyright © 2020 Martinho, Adão, Leite-Moreira and Brás-Silva.

Figures

Figure 1
Figure 1
Signaling pathways involved in the pathogenesis of persistent pulmonary hypertension of the newborn (PPHN) and its interactions. 5-HT, serotonin; 5-HT2A, 5-HT receptor 2A; AA, arachidonic acid; AC, adenylyl cyclase; AMP, adenosine monophosphate; cAMP, cyclic adenosine monophosphate; cGMP, cyclic guanylyl monophosphate; COX, cyclooxygenase; eETB, endothelial relaxant endothelin receptor B; eNOS, nitric oxide synthase; EP, PGE1-receptor; ET-1, endothelin-1; ETA, endothelin receptor A; GMP, guanylyl monophosphate; IGF-1, insulin growth factor 1; IGF-1R, IGF-1 receptor; IL-1β, IL-6, IL-8, interleukins-1β, 6, and 8; IP, PGI2-receptor; mETB, smooth muscle contractile endothelin receptor B; NgBR, Nogo-B receptor; NO, nitric oxide; PDE3, phosphodiesterase-3; PDE5, phosphodiesterase-5; PGE1, prostaglandin E1; PGI2, prostacyclin; PGSs, prostaglandin synthases; PPAR- γ, peroxisome proliferator-activated receptor-γ; ROCK, Rho-kinase; ROS, reactive oxygen species; sGC, soluble guanylyl cyclase; SNAT1, sodium-coupled neutral amino acid transporter; TNF-α: tumor necrosis factor α; TP, TXA2-receptor; TXA2, thromboxane A2; VEGF, vascular endothelial growth factor; VEGFR, VEGF receptor. This figure was created with BioRender.com.
Figure 2
Figure 2
Pathogenic mechanisms of persistent pulmonary hypertension of the newborn (PPHN) and its current and potential target therapies: NO-cGMP pathway. cGMP, cyclic guanylyl monophosphate; eNOS, nitric oxide synthase; GMP, guanylyl monophosphate; iNO, inhaled nitric oxide; NgBR, Nogo-B receptor; NO, nitric oxide; PDE5, phosphodiesterase-5; ROS, reactive oxygen species; sGC, soluble guanylyl cyclase; SNAT1, sodium-coupled neutral amino acid transporter; VEGF, vascular endothelial growth factor; VEGFR, VEGF receptor. Target therapies are marked with a syringe icon and are colored based on the type of evidence supporting its use on PPHN—purple, evidence on its was obtained by adequately powered RCTs/meta-analysis; pink, evidence limited to observational studies or small and underpowered RCTs and/or inconsistent results in human newborns; blue, beneficial effects only demonstrated in experimental models of PPHN. This figure was created with BioRender.com.
Figure 3
Figure 3
Pathogenic mechanisms of persistent pulmonary hypertension of the newborn (PPHN) and its current and potential target therapies: Arachidonic acid-prostacyclin-cAMP pathway. AA, arachidonic acid; AC, adenylyl cyclase; AMP, adenosine monophosphate; cAMP, cyclic adenosine monophosphate; COX, cyclooxygenase; EP, PGE1-receptor; IL-1β, IL-6, IL-8, interleukins-1β, 6 and 8; IP, PGI2-receptor; PDE3, phosphodiesterase-3; PGE1, prostaglandin E1; PGES, PGE1 synthase; PGI2, prostacyclin; PGIS, PGI2 synthase; RV, right ventricle; TBXAS, TXA2 synthase; TNF-α: tumor necrosis factor α; TP, TXA2-receptor; TXA2, thromboxane A2. Target therapies are marked with a syringe icon and are colored based on the type of evidence supporting its use on PPHN- Purple: Evidence on its was obtained by adequately powered RCTs/meta-analysis; Pink: Evidence limited to observational studies or small and underpowered RCTs and/or inconsistent results in human newborns; Blue: Beneficial effects only demonstrated in experimental models of PPHN. This figure was created with BioRender.com.
Figure 4
Figure 4
Pathogenic mechanisms of persistent pulmonary hypertension of the newborn (PPHN) and its current and potential target therapies: endothelin-1-ETA/ETB receptors. eETB, endothelial relaxant endothelin receptor B; eNOS, nitric oxide synthase; ET-1, endothelin-1; ETA, endothelin receptor A; IL-1β, IL-6, IL-8, interleukins-1β, 6 and 8; mETB, smooth muscle contractile endothelin receptor B; PPAR-γ, peroxisome proliferator-activated receptor-γ; ROCK, Rho-kinase; ROS, reactive oxygen species; TNF-α, tumor necrosis factor α. Target therapies are marked with a syringe icon and are colored based on the type of evidence supporting its use on PPHN—purple, evidence on its was obtained by adequately powered RCTs/meta-analysis; pink, evidence limited to observational studies or small and underpowered RCTs and/or inconsistent results in human newborns; blue, beneficial effects only demonstrated in experimental models of PPHN. This figure was created with BioRender.com.
Figure 5
Figure 5
Pathogenic mechanisms of persistent pulmonary hypertension of the newborn (PPHN) and its current and potential target therapies: RhoA/ROCK signaling, PPAR-γ, and 5-HT signaling pathways. 5,HT, serotonin; 5-HT2A, 5-HT receptor 2A; eETB, endothelial relaxant endothelin receptor B; eNOS, nitric oxide synthase; ET-1, endothelin-1; ETA, endothelin receptor A; IL-1β, IL-6, IL-8, interleukins-1β, 6, and 8; mETB, smooth muscle contractile endothelin receptor B; MLC, myosin light chain; MLCP: myosin light chain phosphatase; PDE5, phosphodiesterase-5; PPAR- γ, peroxisome proliferator-activated receptor γ; Rac1, Ras-related C3 botulinum toxin substrate 1; RhoA, Ras homolog family member A; ROCK, Rho-kinase; TNF-α: tumor necrosis factor α; TPH1, tryptophan hydrolase 1. Target therapies are marked with a syringe icon and are colored based on the type of evidence supporting its use on PPHN—purple, evidence on its was obtained by adequately powered RCTs/meta-analysis; pink, evidence limited to observational studies or small and underpowered RCTs and/or inconsistent results in human newborns; blue, beneficial effects only demonstrated in experimental models of PPHN. This figure was created with BioRender.com.
Figure 6
Figure 6
Pathogenic mechanisms of persistent pulmonary hypertension of the newborn (PPHN) and its current and potential target therapies: perinatal inflammation and hyperoxia and reactive oxygen species (ROS). ω-3 LC-PUFAs, ω-3 long-chain polyunsaturated fatty acids; 5-HT, serotonin; 5-HT2A, 5-HT receptor 2A; BH4, tetrahydrobiopterin; cGMP, cyclic guanylyl monophosphate; CHIP, C terminus of Hsc70-interacting protein; eNOS, nitric oxide synthase; ET-1, endothelin-1; ETA, endothelin receptor A; GMP, guanylyl monophosphate; IL-1β, IL-6, IL-8, interleukins-1β, 6, and 8; mETB, smooth muscle contractile endothelin receptor B; NgBR, Nogo-B receptor; NO, nitric oxide; OLA1, Obg-like ATPase 1; PDE5, phosphodiesterase-5; rhSOD, recombinant superoxide-dismutase; ROS, reactive oxygen species; sGC, soluble guanylyl cyclase; SOD2, superoxide-dismutase 2; TNF-α: tumor necrosis factor α; TP, TXA2-receptor; TXA2, thromboxane A2. Target therapies are marked with a syringe icon and are colored based on the type of evidence supporting its use on PPHN—purple, evidence on its was obtained by adequately powered RCTs/meta-analysis; pink, evidence limited to observational studies or small and underpowered RCTs and/or inconsistent results in human newborns; blue, beneficial effects only demonstrated in experimental models of PPHN. This figure was created with BioRender.com.

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