Maternal Exposure to Enalapril Impairs Alveolarization in Neonatal Developing Rat Lung

Author(s): Diego N. Capelari, Susana I. Sánchez, Hugo H. Ortega, Lucia B. Fuentes

The renin-angiotensin system (RAS) during fetal or neonatal stages has been involved in lung growth and differentiation process. We studied the effects of maternal exposure to enalapril during late gestation (G13-G21) on lungs from their offsprings. Pregnant rats were administered with enalapril (2,85 mg/kg/day) and lungs analyzed at postnatal ages, significant difference between P0 and P30. Enalapril-treatment did not modify ACE activity in mothers, but decreased significantly in P0 treated-pups suggesting direct placental drug transference. sACE expression increased with age in both groups. AT1 receptors expression was high and localized in alveolar, bronchiole and endothelium cells. We detected larger but fewer alveoli with decreased septation at earlier postnatal stage in enalapril-treated pups. Quantification of immunopositive nuclei demonstrated that in treated pups the proliferation impairs in newborn lungs and thus progressively increased during two postnatal weeks, at difference with controls animals, where the highest proliferation levels were at P0 and then decreased significantly. In coincidence, high α-smooth muscle actin staining at the tips of developing secondary septal structures was observed at P15, evidencing an active elastogenesis. In summary, decreased ACE activity produced histomorphological changes and an impaired cellular proliferation at the saccular stage; however an active proliferation and elastogenesis, at later stages, suggest that the developing lung has the capacity to recover once treatment was stopped. Alterations in RAS function could contribute to the abnormalities in lung development tissue indicating that the system is one intrinsic factor necessary to differentiation and alveolarization process. However, other local factors could be involved in this mechanism.

Renin-Angiotensin-System, Angiotensin-Converting Enzyme, Cellular Proliferation, Enalapril, Lung Development

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