Superoxide dismutase restores eNOS expression and function in resistance pulmonary arteries from neonatal lambs with persistent pulmonary hypertension

• Published in: American journal of physiology. Lung cellular and molecular physiology 2008-12, Vol.295 (6), p.L979-L987
• Main Authors: Farrow, Kathryn N, Lakshminrusimha, Satyan, Reda, William J, Wedgwood, Stephen, Czech, Lyubov, Gugino, Sylvia F, Davis, Jonathan M, Russell, James A, Steinhorn, Robin H
• Format: Article
• Language: English
• Subjects: Animals; Animals, Newborn; Babies; Biopterins - analogs & derivatives; Biopterins - biosynthesis; Gene Expression Regulation, Enzymologic - drug effects; GTP Cyclohydrolase - biosynthesis; Humans; Hypertension; Infant, Newborn; Lung - enzymology; Nitric oxide; Nitric Oxide - metabolism; Nitric Oxide Synthase Type III - biosynthesis; Oxidative Stress - drug effects; Oxygen; Persistent Fetal Circulation Syndrome - drug therapy; Persistent Fetal Circulation Syndrome - enzymology; Pulmonary Artery - enzymology; Reactive Oxygen Species - metabolism; Recombinant Proteins - pharmacology; Respiration, Artificial; Sheep; Superoxide Dismutase - pharmacology; Veins & arteries
• ISSN: 1040-0605; 1522-1504
• DOI: 10.1152/ajplung.90238.2008

1 Department of Pediatrics, Northwestern University, Chicago, Illinois; Departments of 2 Pediatrics and 3 Physiology and Biophysics, University of Buffalo, Buffalo, New York; and 4 Department of Pediatrics, Tufts University School of Medicine, Boston, Massachusetts Submitted 22 March 2008 ; accepted in final form 10 September 2008 Endothelial nitric oxide (NO) synthase (eNOS) expression and activity are decreased in fetal lambs with persistent pulmonary hypertension (PPHN). We sought to determine the impact of mechanical ventilation with O 2 with or without inhaled NO (iNO) or recombinant human SOD (rhSOD) on eNOS in the ductal ligation model of PPHN. PPHN lambs and age-matched controls were ventilated with 100% O 2 for 24 h alone or combined with 20 ppm iNO continuously or a single dose of rhSOD (5 mg/kg) given intratracheally at delivery. In 1-day spontaneously breathing lambs, eNOS expression in resistance pulmonary arteries increased relative to fetal levels. eNOS expression increased in control lambs ventilated with 100% O 2 , but not in PPHN lambs. Addition of iNO or rhSOD increased eNOS expression and decreased generation of reactive oxygen species (ROS) in PPHN lambs relative to those ventilated with 100% O 2 alone. However, only rhSOD restored eNOS function, increased tetrahydrobiopterin (BH 4 ), a critical cofactor for eNOS function, and restored GTP cyclohydrolase I expression in isolated vessels and lungs from PPHN lambs. These data suggest that ventilation of PPHN lambs with 100% O 2 increases ROS production, blunts postnatal increases in eNOS expression, and decreases available BH 4 in PPHN lambs. Although the addition of iNO or rhSOD diminished ROS production and increased eNOS expression, only rhSOD improved eNOS function and levels of available BH 4 . Thus therapies designed to decrease oxidative stress and restore eNOS coupling, such as rhSOD, may prove useful in the treatment of PPHN in newborn infants. reactive oxygen species; biopterin Address for reprint requests and other correspondence: K. N. Farrow, Dept. of Pediatrics, Northwestern Univ. Feinberg School of Medicine, 303 E. Chicago Ave., Ward 12-196, Chicago, IL 60611 (e-mail: k-farrow{at}northwestern.edu )