Histochemical Analyses of Altered Fetal Lung Development Following Single versus Multiple Courses of Antenatal Steroids

Zarah J. Pua ¹, Barbara S. Stonestreet ¹, Anne Cullen ¹, Aliakbar Shahsafaei ¹, Grazyna B. Sadowska ¹ and Mary E. Sunday ^1*

¹ Departments of Medicine and Pathology, Children’s Hospital and Harvard Medical School, Boston, Massachusetts (ZJP,AC); Department of Pediatrics, Women’s & Infants’ Hospital and Brown University, Providence, Rhode Island (BSS,GBS); Department of Pathology, Brigham & Women’s Hospital, Boston, Massachusetts (AS); and Departments of Pathology, Children’s Hospital, Brigham & Women’s Hospital, and Harvard Medical School, Boston, Massachusetts (MES)

^* To whom correspondence should be addressed. E-mail: mary.sunday{at}duke.edu.

Submitted on April 20, 2005
Accepted on 4 May 2005

	Abstract

A single course of antenatal steroids is widely used during preterm labor to promote fetal lung maturation. However, little is known regarding efficacy and safety of multiple courses of antenatal steroids. In animal models and clinical trials, treatment with glucocorticoids can inhibit growth. The present study of single versus multiple-course steroids in pregnant ewes analyzes the effects of steroids versus placebo on fetal lung histopathology. Single course groups received dexamethasone (Dex, 6-mg) or normal saline every 12-hr for 48-hr @104-106 days (d) of gestation (term = 150d). Multiple course groups received the first course at 76-78d; this was repeated weekly for 5 weeks. At 108d, lungs were analyzed using immunohistochemistry for alpha-smooth muscle actin, a myofibroblast marker, and proliferating cell nuclear antigen. Cell injury/death was evaluated using TUNEL analysis. Although fetal growth was restricted by either single or multiple courses of Dex, alveolar development was accelerated as measured by mean linear intercepts. Alveolar walls were thinner, developing septa were longer, and septal myofibroblasts were increased for both Dex groups compared with controls. Cell proliferation increased following multiple steroid courses, especially in the distal parenchyma, with a corresponding decrease in apoptosis. These observations suggest that Dex promotes alveolarization, whether given in single or multiple courses.

Key Words: glucocorticoids, sheep, immunohistochemistry, morphometry, smooth muscle actin, proliferating cell nuclear antigen, apoptosis

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