No abstract

Pulmonary arterial hypertension (PAH) is a deadly disease with no cure. Alternate conversion of angiotensin II (AngII) to angiotensin-(1-7) (Ang-(1-7)) by angiotensin-converting enzyme 2 (ACE2) resulting in Mas receptor (Mas1) activation improves rodent models of PAH. Effects of recombinant human (rh) ACE2 in human PAH are unknown. Our objective was to determine the effects of rhACE2 in PAH.We defined the molecular effects of Mas1 activation using porcine pulmonary arteries, measured AngII/Ang-(1-7) levels in human PAH and conducted a phase IIa, open-label pilot study of a single infusion of rhACE2 (GSK2586881, 0.2 or 0.4 mg·kg intravenously).Superoxide dismutase 2 (SOD2) and inflammatory gene expression were identified as markers of Mas1 activation. After confirming reduced plasma ACE2 activity in human PAH, five patients were enrolled in the trial. GSK2586881 was well tolerated with significant improvement in cardiac output and pulmonary vascular resistance. GSK2586881 infusion was associated with reduced plasma markers of inflammation within 2-4 h and increased SOD2 plasma protein at 2 weeks.PAH is characterised by reduced ACE2 activity. Augmentation of ACE2 in a pilot study was well tolerated, associated with improved pulmonary haemodynamics and reduced markers of oxidant and inflammatory mediators. Targeting this pathway may be beneficial in human PAH.

Objective To assess the utility of clinical predictors of persistent respiratory morbidity in extremely low gestational age newborns (ELGAN). Study Design We enrolled ELGAN (<29 weeks’ gestation) at ≤7 postnatal days and collected antenatal and neonatal clinical data through 36 weeks’ post-menstrual age. We surveyed caregivers at 3, 6, 9 and 12 months corrected age to identify post-discharge respiratory morbidity, defined as hospitalization, home support (oxygen, tracheotomy, ventilation), medications, or symptoms (cough/wheeze). Infants were classified as post-prematurity respiratory disease (PRD, the primary study outcome), if respiratory morbidity persisted over ≥2 questionnaires. Infants were classified with severe respiratory morbidity if there were multiple hospitalizations, exposure to systemic steroids or pulmonary vasodilators, home oxygen after 3 months or mechanical ventilation, or symptoms despite inhaled corticosteroids. Mixed effects models generated with data available at one day (perinatal) and 36 weeks’ postmenstrual age were assessed for predictive accuracy. Results Of 724 infants (918±234g, 26.7±1.4 weeks’ gestational age) classified for the primary outcome, 68.6% had PRD; 245/704 (34.8%) were classified as severe. Male sex, intrauterine growth restriction, maternal smoking, race/ethnicity, intubation at birth, and public insurance were retained in perinatal and 36-week models for both PRD and respiratory morbidity severity. The perinatal model accurately predicted PRD (c-statistic 0.858). Neither the 36-week model nor the addition of bronchopulmonary dysplasia (BPD) to the perinatal model improved accuracy (0.856, 0.860); c-statistic for BPD-alone was 0.907. Conclusion Both BPD and perinatal clinical data accurately identify ELGAN at risk for persistent and severe respiratory morbidity at one year. Trial registration ClinicalTrials.gov: NCT01435187

To examine the effect of chronic hypoxia on nitric oxide (NO) production and the amount of the endothelial isoform of nitric oxide synthase (eNOS) in lungs of newborn piglets, studies were performed using 1- to 3-day-old piglets raised in room air (control) or 10% O2 (chronic hypoxia) for 10–12 days. Exhaled NO output and plasma nitrites and nitrates (collectively termed[Formula: see text]) were measured in anesthetized animals. [Formula: see text]concentrations were measured in the perfusate of isolated lungs. eNOS amounts were assessed in whole lung homogenates. In the intact piglets, exhaled NO outputs and plasma [Formula: see text]were lower in the chronically hypoxic (exhaled NO output = 0.2 ± 0.1 nmol/min; plasma [Formula: see text] = 10.3 ± 3.7 nmol/ml) than in control animals (exhaled NO output = 0.8 ± 0.2 nmol/min; plasma [Formula: see text] = 22.3 ± 4.3 nmol/ml). In perfused lungs, the perfusate accumulation of [Formula: see text] was lower in chronic hypoxia (1.0 ± 0.3 nmol/min) than in control (2.6 ± 0.6 nmol/min) piglets. The amount of whole lung homogenate eNOS from the chronic hypoxia piglets was 40 ± 8% less than that from the control piglets. The reduced NO production observed in anesthetized animals or perfused lungs of chronically hypoxic newborn piglets is consistent with the finding of reduced lung eNOS protein amounts. Decreased NO production might contribute to the development of chronic hypoxia-induced pulmonary hypertension in newborns.