Postnatal estradiol up-regulates lung nitric oxide synthases and improves lung function in bronchopulmonary dysplasia.
BACKGROUND
Nitric oxide (NO) plays an important role in lung development and perinatal lung function, and pulmonary NO synthases (NOS) are decreased in bronchopulmonary dysplasia (BPD) following preterm birth. Fetal estradiol levels increase during late gestation and estradiol up-regulates NOS, suggesting that after preterm birth estradiol deprivation causes attenuated lung NOS resulting in impaired pulmonary function.


OBJECTIVE
To test the effects of postnatal estradiol administration in a primate model of BPD over 14 days after delivery at 125 days of gestation (term = 185 d).


METHODS
Cardiopulmonary function was assessed by echocardiography and whole body plethysmography. Lung morphometric and histopathologic analyses were performed, and NOS enzymatic activity and abundance were measured.


RESULTS
Estradiol caused an increase in blood pressure and ductus arteriosus closure. Expiratory resistance and lung compliance were also improved, and this occurred before spontaneous ductal closure. Furthermore, both oxygenation and ventilation indices were improved with estradiol, and the changes in lung function and ventilatory support requirements persisted throughout the study period. Whereas estradiol had negligible effect on indicators of lung inflammation and on lung structure assessed after the initial 14 days of ventilatory support, it caused an increase in lung neuronal and endothelial NOS enzymatic activity.


CONCLUSIONS
In a primate model of BPD, postnatal estradiol treatment had favorable cardiovascular impact, enhanced pulmonary function, and lowered requirements for ventilatory support in association with an up-regulation of lung NOS. Estradiol may be an efficacious postnatal therapy to improve lung function and outcome in preterm infants.
McCurnin
Donald C
DC
Department of Pediatrics, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.
Pierce
Richard A
RA
Willis
Brigham C
BC
Chang
Ling Yi
LY
Yoder
Bradley A
BA
Yuhanna
Ivan S
IS
Ballard
Philip L
PL
Clyman
Ronald I
RI
Waleh
Nahid
N
Maniscalco
William
W
Crapo
James D
JD
Grubb
Peter H
PH
Shaul
Philip W
PW
D000818:Animals; D000831:Animals, Newborn; D001794:Blood Pressure / Q000187:drug effects; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D001997:Bronchopulmonary Dysplasia / Q000628:therapy*; D004195:Disease Models, Animal; D004373:Ductus Arteriosus / Q000187:drug effects; D004549:Elastin / Q000235:genetics / Q000378:metabolism; D004958:Estradiol / Q000097:blood / Q000494:pharmacology*; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008170:Lung Compliance; D008297:Male; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D010100:Oxygen / Q000097:blood; D010215:Papio; D011663:Pulmonary Surfactants / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011897:Random Allocation; D011959:Receptors, Estradiol / Q000378:metabolism; D012121:Respiration, Artificial; D015854:Up-Regulation
D004967:Estrogens; D011663:Pulmonary Surfactants; D012333:RNA, Messenger; D011959:Receptors, Estradiol; D004958:Estradiol; D004549:Elastin; D019001:Nitric Oxide Synthase; D010100:Oxygen