Embryonic over‐expression of RAGE in mouse lung causes an imbalance between apoptosis and proliferation leading to severe lung hypoplasia

Abstract

Receptors for advanced glycation end-products (RAGE) are multi-ligand cell surface receptors prominently detected in lung epithelium. Previous experiments demonstrate that over-expression of RAGE in murine alveolar type (AT) II cells during development causes lung hypoplasia and neonatal lethality. In order to characterize lung hypoplasticity, proliferation and apoptosis were evaluated in RAGE over-expressing mice. Histology spanning developmental milestones revealed marked loss of lung tissue beginning in the canalicular stage of lung development and continuing throughout the saccular period (embryonic day (E) 15.5–18.5). In situ cell death detection using TUNEL assay revealed a significant elevation in apoptotic cells in RAGE over-expressing pulmonary tissue at E17.5 compared to age-matched controls. The balance between cell death and proliferation was also characterized by PCNA staining. These findings were further supported by electron micrographic analysis of E18.5 lungs that demonstrated extracellular matrix degradation and ATI and ATII cell death in RAGE over-expressed mice. The data suggest that elevated RAGE expression alters the normal balance between proliferation and apoptosis in the developing lung leading to significant loss in respiratory surface area. Supported by the Flight Attendant's Medical Research Institute (FAMRI, PRR) and a BYU Mentoring Environment Grant (PRR).