Receptors for advanced glycation end-products (RAGE) are pattern recognition receptors of the immunoglobulin superfamily highly expressed in the lung. Likely functions include the modulation of pulmonary inflammation during disease. However, the contributions of RAGE in the developing lung in cases where secondhand smoke (SHS) exposure occurs are unknown. In order to test the hypothesis that RAGE misexpression adversely affects lung morphogenesis, we exposed gestating dams to a controlled dose of SHS during the last four critical days of in utero lung morphogenesis. We discovered that both maternal and fetal lungs respond to SHS by up-regulating RAGE. Exposed fetuses were markedly smaller compared to controls and lungs were compromised in terms of apoptotic status, collagen abundance necessary in the derivation of respiratory compartments, and the expression of MMP-9, a protease known to target extracellular matrix. Interestingly, RAGE knock out animals similarly exposed to SHS were protected, in part, from the same SHS-mediated pulmonary abnormalities. We next generated a conditional transgenic mouse that provided an opportunity to genetically augment distal lung RAGE expression in the absence of SHS exposure. Our RAGE transgenic mice (RAGE TG) were severely hypoplastic and ultrastructural analysis demonstrated weakened basement membranes in RAGE TG animals compared to controls. Specific observations in RAGE TG mice included diminished type IV collagen required for basement membrane derivation, augmented MMP-9 expression, and inhibition of pulmonary vasculature visualized by Pecam-1 staining, a marker of vascular endothelial cells. The further observation that FoxM1, a critical transcriptional regulator of endothelial cell differentiation, was inhibited in RAGE TG mice suggested a novel potential mechanism of impaired vascularization mediated by RAGE. These data provide evidence that RAGE expression must be tightly regulated during lung organogenesis. Furthermore, additional research into the nuances of RAGE signaling during development may shed needed light on the pathobiochemistry of adult lung diseases that potentially have in utero origins.



College and Department

Life Sciences; Physiology and Developmental Biology



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RAGE, transgenic, apoptosis, lung