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Postnatal Estradiol Up-regulates Lung Nitric Oxide Synthases and Improves Lung Function in Bronchopulmonary Dysplasia

¹ Department of Pediatrics, University of Texas Health Science Center at San Antonio, San Antonio, Texas; ² Southwest Foundation for Biomedical Research, San Antonio, Texas; ³ Department of Internal Medicine, Washington University in St. Louis School of Medicine, St. Louis, Missouri; ⁴ Division of Pulmonary and Vascular Biology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas; ⁵ Department of Medicine, National Jewish Medical and Research Center, Denver, Colorado; ⁶ Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, Utah; ⁷ Department of Pediatrics, University of California San Francisco School of Medicine, San Francisco, California; ⁸ Life Sciences Division, SRI International, Menlo Park, California; ⁹ Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, New York; ¹⁰ Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennesse

Correspondence and requests for reprints should be addressed to Philip W. Shaul, M.D., Department of Pediatrics, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd., Dallas, TX 75390-9063. E-mail: philip.shaul{at}utsouthwestern.edu

Rationale: 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.

Measurements and Main 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.

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Postnatal therapies to prevent bronchopulmonary dysplasia (BPD) in preterm infants are limited. What This Study Adds to the Field These experiments in a primate model indicate that postnatal estradiol treatment has favorable cardiovascular impact, enhances pulmonary function, and lowers requirements for ventilatory support in BPD. These effects occur in association with an up-regulation of lung nitric oxide synthases. Estradiol may be an efficacious postnatal therapy to improve lung function and outcome in preterm infants.