Effect of zidovudine on human fetal lung development

Zidovudine (AZT) is currently used to treat human immunodeficiency virus (HIV)-positive women during pregnancy to prevent the prenatal transmission of HIV type 1 (HIV-1). However, AZT not only inhibits HIV replication but also affects the DNA polymerases of human cells; hence AZT is not recommended during the first trimester of pregnancy. The lung is a unique organ because it continues to grow and develop throughout fetal life. Using a man fetal lung organ culture system, we sought to determine the effect of AZT on morphogenesis and epithelial cytodifferentiation of developing alveoli. Lung tissues from three fetuses, 14-15 weeks gestational age, were grown in culture for 24 hours (day 0). AZT at a concentration of either 0.4, 4.0, 8.0, or 40.0 μmol/L was added on days 1, 5, and 10 of growth. The cultures were interrupted on days 6 and 15 and examined by light and electron microscopy for alveolar saccular development, interstitial thinning, and epithelial cell differentiation. On day 6 of growth the treated cultures demonstrated fewer alveolar saccules and a thicker, more cellular interstitium compared to the controls. After 15 days of growth the cultures treated with 0.4 μmol/L of AZT appeared structurally similar to the controls. The cultures treated with AZT concentrations of 4.0 to 40.0 μmol/L appeared unchanged from day 6, implying arrested maturation of the culture. However, epithelial cell differentiation was unaffected. We conclude that AZT at concentrations of 4.0 μmol/L and greater affects the structural development of the human fetal lung in vitro. It is possible that this effect could occur in vivo throughout gestation if similar fetal AZT serum levels are attained.