the-perinatal-asphyxiated-lamb-model-a-model-for-newborn-resuscitation

The Perinatal Asphyxiated Lamb Model: A Model for Newborn Resuscitation

Birth asphyxia accounts for nearly one million deaths worldwide each year, and is one of the primary causes of early neonatal morbidity and mortality. ...

University of California Davis

Phosphodiesterase-5 (PDE5) is the primary phosphodiesterase in the pulmonary vasculature. It degrades cyclic guanosine monophosphate (cGMP) and inhibits cGMP-mediated vasorelaxation. We previously reported that hydrocortisone treatment decreased hyperoxia-induced PDE5 activity and markers of oxidative stress in lambs with persistent pulmonary hypertension of the newborn (PPHN) ventilated with 100% O2. The objective of our study was to determine the molecular mechanism by which hydrocortisone downregulates PDE5 and oxidative stress in fetal pulmonary artery smooth muscle cells (FPASMCs) from PPHN lambs. PPHN FPASMC were incubated for 24 hours in either 21% or 95% O2. Some cells were treated with 100 nM hydrocortisone and/or ±1 μM helenalin, an inhibitor of nuclear factor κ B (NFκB), a redox-sensitive transcription factor. Exposure to hyperoxia led to increased PDE5 activity, oxidative stress, and NFκB activity. Pretreatment of PPHN FPASMC with hydrocortisone normalized PDE5 activity, decreased cytosolic oxidative stress, increased expression of extracellular superoxide dismutase and NFκB inhibitory protein, and decreased NFκB activity. Similarly, treatment with NFκB inhibitor, helenalin, decreased PDE5 activity. These data suggest that hyperoxia activates NFκB, which in turn induces PDE5 activity in PPHN FPASMC, whereas treatment with hydrocortisone attenuates these changes by blocking reactive oxygen species-induced NFκB activity. 

Hydrocortisone normalizes phosphodiesterase-5 activity in pulmonary artery smooth muscle cells from lambs with persistent pulmonary hypertension of the newborn.

Mitochondrial reactive oxygen species (ROS) levels and nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) activity are increased in a lamb model of persistent pulmonary hypertension of the newborn (PPHN). These events can trigger hypoxia inducible factor (HIF) signaling in response to hypoxia, which has been shown to contribute to pulmonary vascular remodeling in rodent models of pulmonary hypertension. However, the role of HIF signaling in chronic intrauterine pulmonary hypertension is not well understood.

Hypoxia inducible factor signaling and experimental persistent pulmonary hypertension of the newborn.

This study was designed to determine whether cyclic stretch induces a persistent pulmonary hypertension of the newborn (PPHN) phenotype of increased NADPH oxidase (Nox) 4 signaling in control pulmonary artery smooth muscle cells (PASMC), and to identify the signal transduction molecules involved. To achieve this, PPHN was induced in lambs by antenatal ligation of the ductus arteriosus at 128 days gestation. After 9 days, lungs and PASMC were isolated from control (twin) and PPHN lambs. Control PASMC were exposed to cyclic stretch at 1 Hz and 15% elongation for 24 h. Stretch-induced Nox4 expression was attenuated by inhibition of mitochondrial complex III and NF-κB, and stretch-induced protein thiol oxidation was attenuated by Nox4 small interfering RNA and complex III inhibition. NF-κB activity was increased by stretch in a complex III-dependent fashion, and stretch-induced cyclin D1 expression was attenuated by complex III inhibition and Nox4 small interfering RNA. This is the first study to show that cyclic stretch increases Nox4 expression via mitochondrial complex III-induced activation of NF-κB in fetal PASMC, resulting in ROS signaling and increased cyclin D1 expression. Targeting these signaling molecules may attenuate pulmonary vascular remodeling associated with PPHN. 

Cyclic stretch stimulates mitochondrial reactive oxygen species and Nox4 signaling in pulmonary artery smooth muscle cells.

Neonates suffering from pulmonary hypertension of the newborn (PPHN) continue to represent an important proportion of patients requiring intensive neonatal care, and have an increased risk of morbidity and mortality. The human fetus has evolved to maintain a high pulmonary vascular resistance (PVR) in utero to allow the majority of the fetal circulation to bypass the lungs, which do not participate in gas exchange, towards the low resistance placenta. At birth, oxygen plays a major role in decreasing PVR to enhance pulmonary blood flow and establish the lungs as the organ of gas exchange. The failure of PVR to fall following birth results in PPHN, and oxygen remains the mainstay therapeutic intervention in the management of PPHN. Knowledge gaps on what constitutes the optimal oxygenation target leads to a wide variation in practices, and often leads to excessive oxygen use. Owing to the risk of oxygen toxicity, avoiding hyperoxemia is as important as avoiding hypoxemia in the management of PPHN. Current evidence supports maintaining arterial oxygen tension in the range of 50-80 mm Hg, and oxygen saturation between 90-97% in term infants with hypoxemic respiratory failure. Clinical studies evaluating the optimal oxygenation in the treatment of PPHN will be enthusiastically awaited.

The Fetus Can Teach Us: Oxygen and the Pulmonary Vasculature.

To determine the characteristics of term infants with persistent pulmonary hypertension of the newborn (PPHN) associated with moderate or severe hypoxic ischemic encephalopathy (HIE).

Pulmonary Hypertension Associated with Hypoxic-Ischemic Encephalopathy-Antecedent Characteristics and Comorbidities.

Using Paralytic as Part of Premedication for Elective Intubation of Premature Neonates May Result in Transient Impairment of Ventilation.

Congenital diaphragmatic hernia (CDH) is associated with lung hypoplasia, cardiac dysfunction and pulmonary hypertension. Inhaled nitric oxide (iNO) and milrinone are commonly used pulmonary vasodilators in CDH. We studied the hemodynamic effects of iNO and milrinone in infants with CDH.

Article	Year
Hydrocortisone normalizes phosphodiesterase-5 activity in pulmonary artery smooth muscle cells from lambs with persistent pulmonary hypertension of the newborn. Pulmonary circulation\| PubMed ID: 25006423	2014
Hypoxia inducible factor signaling and experimental persistent pulmonary hypertension of the newborn. Frontiers in pharmacology\| PubMed ID: 25814954	2015
Cyclic stretch stimulates mitochondrial reactive oxygen species and Nox4 signaling in pulmonary artery smooth muscle cells. American journal of physiology. Lung cellular and molecular physiology\| PubMed ID: 26024892	2015
The Fetus Can Teach Us: Oxygen and the Pulmonary Vasculature. Children (Basel, Switzerland)\| PubMed ID: 28771211	2017
Pulmonary Hypertension Associated with Hypoxic-Ischemic Encephalopathy-Antecedent Characteristics and Comorbidities. The Journal of pediatrics\| PubMed ID: 29502880	2018
Using Paralytic as Part of Premedication for Elective Intubation of Premature Neonates May Result in Transient Impairment of Ventilation. American journal of perinatology\| PubMed ID: 29510421	2018
Response to pulmonary vasodilators in infants with congenital diaphragmatic hernia. Pediatric surgery international\| PubMed ID: 29808281	2018
Case 2: Beware of Lumps and Bumps after Cooling! NeoReviews\| PubMed ID: 29861664	2017

Satyan Lakshminrusimha

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