Pulmonary hypertension and oxidative stress: Where is the link?

Abstract

Oxidative stress can be associated with hyperoxia and hypoxia and is characterized by an increase in reactive oxygen (ROS) and nitrogen (RNS) species generated by an underlying disease process or by supplemental oxygen that exceeds the neutralization capacity of the organ system. ROS and RNS acting as free radicals can inactive several enzymes and vasodilators in the nitric oxide pathway promoting pulmonary vasoconstriction resulting in persistent pulmonary hypertension of the newborn (PPHN). Studies in animal models of PPHN have shown high ROS/RNS that is further increased by hyperoxic ventilation. In addition, antioxidant therapy increased PaO₂ in these models, but clinical trials are lacking. We recommend targeting preductal SpO₂ between 90 and 97%, PaO₂ between 55 and 80 mmHg and avoiding FiO₂ > 0.6-0.8 if possible during PPHN management. This review highlights the role of oxidative and nitrosative stress markers on PPHN and potential therapeutic interventions that may alleviate the consequences of increased oxidant stress during ventilation with supplemental oxygen.

Keywords: Antioxidant therapy; Free radical; Nitric oxide; Oxidative stress; Peroxynitrite; Persistent pulmonary hypertension; Superoxide anions.

Fig. 1.

Normal and abormal transition at birth and role of oxidative stress in persistent pulmonary hypertension of the newborn (PPHN). The fetus lives in a state of hypoxemia with low arterial (PaO₂) and alveolar oxygen (PAO₂) tension. Normal transition at birth results in room air ventilation and a modest increase in PaO2 and PAO2 leading to pulmonary vasodilation and establishment of lungs as the site of gas exchange. When transition is abnormal, pulmonary vasodilation does not occur resulting in persistence of high pulmonary arterial pressures and right-to-left extrapulmonary shunts leading to systemic hypoxemia despite alveolar hyperoxia. Alveolar hyperoxia leads to oxidative stress and release of reactive oxygen species. See text for details. Copyright Satyan Lakshminrusimha.

Fig. 2.

Alterations in biochemical pathways in pulmonary vascular endothelial and smooth muscle cells in normal and persistent pulmonary hypertension of the newborn (PPHN). Endothelial dysfunction, smooth muscle hyperplasia and hypertrophy and adventitial thickening are common in PPHN. Increased oxidative stress with high levels of superoxide anions (${\text{O}}_2^{•-}$) alters several enzymes in the nitric oxide (NO) pathway increasing the risk of vasoconstriction. ADMA - asymmetric dimethyl arginine; eNOS – endothelial nitric oxide synthase; ET – endothelin; SOD – superoxide dismutase; MnSOD – Manganese, mitochondrial superoxide dismutase; EC-SOD – extracellular superoxide dismutase; sGC – soluble guanylate cyclase; PDE 5 – phosphodiesterase 5; GTP – guanosine triphosphate; cGMP – cyclic guanosine monophosphate; NO – nitric oxide; CaM – calmodulin; Modified from Polin and Fox Fetal and Neonatal Physiology, 6th edition, copyright Satyan Lakshminrusimha (with permission).

Fig. 3.

Definition of oxidative stress and the imbalance between pro-oxidants and antioxidants. Excess reactive oxygen species (ROS) can have acute and chronic effects. Please see text for details. Copyright Satyan Lakshminrusimha.

Fig. 4.

Biochemical reactions involved in oxidative and nitrosative stress. Prx - peroxiredoxins, GPX - glutathione peroxidases (GPX) and CAT - catalases. Please see text for details. Copyright Satyan Lakshminrusimha.

Fig. 5.

Benefits and risks of low and high oxygen saturation by pulse oximeter (SpO₂) targets. Preductal SpO₂ in the mid-90s (90–97% - green zone) results in lower oxidative stress, increased cerebral blood flow and better response to inhaled nitric oxide (iNO). However, in the presence of hypothermia and acidosis, low SpO₂ target may not be adequate to promote optimal pulmonary vasodilation resulting in high right ventricular afterload. High SpO₂ targets (~100%) require higher inspired (FiO₂) and alveolar (PAO2) increasing the risk of oxidative stress. Such targets may transiently improve pulmonary vasodilation especially in the presence of hypothermia or acidosis but there is a higher risk of reactive oxygen species formation leading to inactivation of inhaled nitric oxide (iNO), surfactant inactivation and inflammation. Copyright Satyan Lakshminrusimha.