Hormone adjustment may lead to new ways to prevent and treat lung damage in premature infants

Findings reported in The American Journal of Pathology indicate that adrenomedullin helps resolve lung damage and pulmonary hypertension caused by oxygen exposure during the newborn period in mice


Philadelphia, February 21, 2020

Prematurely born babies often need oxygen therapy to prevent brain damage or death. Unfortunately, excessive oxygen can damage immature lungs and cause severe life-long problems including bronchopulmonary dysplasia (BPD) and pulmonary hypertension (PH). A new study in The American Journal of Pathology, published by Elsevier, provides insights into the important role that the hormone adrenomedullin plays in the development, recovery, and prevention of BPD and PH.

“Our study provides evidence that adrenomedullin may influence the progression and resolution of experimental BPD and PH by affecting lung vascular health,” explained Binoy Shivanna, MD, DM, PhD, of the Section of Neonatology, Department of Pediatrics, Baylor College of Medicine, and Texas Children’s Hospital, Houston, TX, USA. “Importantly, there is no cure for BPD; however, our findings suggest that adrenomedullin can be developed as a therapy to reduce the burden of BPD-associated PH in premature babies.

Though adrenomedullin helps repair damaged lungs, blood vessels, and the heart in older humans, mice, and rats, its role in resolving experimental BPD–associated PH is unclear. To understand this role, investigators studied lung structure and function in newborn mice genetically bred to have lower-than-normal adrenomedullin levels and compared them with those with normal levels. They exposed one-day-old mice to normal or increased oxygen concentrations for 14 days. Lung structure, including the number of blood vessels and markers of cell damage, was examined at different times up to day 28, and the heart was examined for PH by imaging on days 28 and 70.

The study found that newborn mice deficient in adrenomedullin exposed to high levels of oxygen were more likely to develop lung damage. They had greater cell death, fewer lung sacs (alveoli), fewer lung blood vessels, and more severe symptoms of BPD and PH from which they were slower to recover compared with mice with normal levels of adrenomedullin. This suggests that adrenomedullin is necessary for normal lung development.

The adrenomedullin-deficient mice also showed lower levels of the enzyme endothelial nitric oxide synthase (eNOS), indicating that adrenomedullin may mediate its effect via eNOS.

The investigators also looked at the effect of adrenomedullin in human lung endothelial cells in culture. “We found blocking adrenomedullin or its receptors decreased the expression of eNOS and the ability of these cells to form blood vessels. On the other hand, treatment with adrenomedullin increased the ability of the cells to form blood vessels, and this ability of adrenomedullin was lost when the eNOS function was blocked by genetic manipulation,” said Dr. Shivanna.

Dr. Shivanna believes that adrenomedullin could be a novel therapeutic target to treat BPD-associated PH in infants. “This hormone is normally produced in the body and, therefore, this hormonal treatment can be safe without major effects. Our study also suggests that adrenomedullin can improve the quality of life of BPD-associated PH patients by its long-lasting beneficial effects on the lungs and heart.”

BPD, a lung disease caused by a reduced rate of lung growth, frequently occurs in babies born before their due date. In the United States, BPD affects 10,000 neonates each year and is the second most expensive childhood disease. Oxygen therapy increases the risk of BPD. Babies with BPD may go on to develop lung infections, asthma, and physical or mental disabilities. Nearly one third of babies with BPD develop PH, which can elevate both short- and long-term morbidity.

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Notes for editors
The article is “Adrenomedullin Is Necessary to Resolve Hyperoxia-Induced Experimental Bronchopulmonary Dysplasia and Pulmonary Hypertension in Mice,” by Renuka T. Menon, Amrit Kumar Shrestha, Corey L. Reynolds, Roberto Barrios, Kathleen M. Caron, and Binoy Shivanna (https://doi.org/10.1016/j.ajpath.2019.11.011). It will appear in The American Journal of Pathology, volume 190, Issue 3 (March 2020) published by Elsevier.

This work was supported by the National Institutes of Health (HD073323 and HL139594 to B.S., U54 HG006348 to the Mouse Phenotyping Core at Baylor College of Medicine (BCM), DK56338, and CA125123 to the Integrated Microscopy Core at BCM, and P30DK056338 to the Digestive Disease Center Core at BCM), CPRIT (RP150578 and RP170719 to the Integrated Microscopy Core at BCM), the American Heart Association (BGIA-20190008 to B.S.), the American Lung Association (RG-349917 to B.S.), and the Texas Children’s Hospital (Pediatric Pilot Award to B.S.).

Full text of the study is available to credentialed journalists upon request; contact Eileen Leahy at +1 732 238 3628 or ajpmedia@elsevier.com. Journalists wishing to interview the authors should contact Homa Shalchi, Communications Specialist, Baylor College of Medicine, at +1 713 798 4710 or shalchi@bcm.edu.

About The American Journal of Pathology
The American Journal of Pathology
, official journal of the American Society for Investigative Pathology, published by Elsevier, seeks high-quality original research reports, reviews, and commentaries related to the molecular and cellular basis of disease. The editors will consider basic, translational, and clinical investigations that directly address mechanisms of pathogenesis or provide a foundation for future mechanistic inquiries. Examples of such foundational investigations include data mining, identification of biomarkers, molecular pathology, and discovery research. High priority is given to studies of human disease and relevant experimental models using molecular, cellular, and organismal approaches. ajp.amjpathol.org

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Elsevier
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The American Journal of Pathology
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