Persistent over‐expression of RAGE in adult mouse lung causes airspace enlargement coincident with emphysema

Abstract

Receptors for advanced glycation end-products (RAGE) are multiligand cell-surface receptors detected abundantly in pulmonary tissue. RAGE signaling assists in the differentiation of alveolar type (AT) I cells during development and can enhance epithelial adhesion to the basement membrane. RAGE is elevated in COPD which is characterized by enlarged airspaces and inflammation and previous work revealed increased RAGE in both cells and lungs exposed to tobacco smoke. However, the precise contribution of RAGE to emphysema is yet unknown. We generated transgenic mice that conditionally over-express RAGE in ATII cells. RAGE was induced from weaning (20 days of age) until sacrifice date at age 50, 80, and 110 days (representing 30, 60, and 90 days of induced RAGE). H&E staining and mean linear intercepts (Lm) revealed incremental dilation of alveolar spaces as RAGE over-expression persisted. Immunohistochemistry using antibodies for ATI (T1alpha) and ATII (proSP-C) cells revealed a decrease in ATI contribution to respiratory surface area and a marked decrease in ATII cell quantity in the RAGE transgenic mice. Staining for FoxJ1 revealed a detectible decrease in ciliated proximal lung epithelium when compared to controls. These data support the concept that RAGE may function in the progression of diseases such as emphysema. Supported by the Flight Attendant's Medical Research Institute (FAMRI, PRR) and a BYU MEG (PRR)