The receptor for advanced glycation end-products (RAGE) and its soluble forms are predominantly expressed in lung but its physiological importance in this organ is not yet fully understood. Since RAGE acts as a cell adhesion molecule, we postulated its physiological importance in the respiratory mechanics. Respiratory function in a buffer-perfused isolated lung system and biochemical parameters of the lung were studied in young, adult, and old RAGE knockout (RAGE-KO) mice and wild-type (WT) mice. Lungs from RAGE-KO mice showed a significant increase in the dynamic lung compliance and a decrease in the maximal expiratory air flow independent of age-related changes. We also determined lower mRNA and protein levels of elastin in lung tissue of RAGE-KO mice. RAGE deficiency did not influence the collagen protein level, lung capillary permeability, and inflammatory parameters (TNF-␣, high-mobility group box protein 1) in lung. Overexpressing RAGE as well as soluble RAGE in lung fibroblasts or cocultured lung epithelial cells increased the mRNA expression of elastin. Moreover, immunoprecipitation studies indicated a trans interaction of RAGE in lung epithelial cells. Our findings suggest the physiological importance of RAGE and its soluble forms in supporting the respiratory mechanics in which RAGE trans interactions and the influence on elastin expression might play an important role.receptor for advanced glycation end-products; aging; biomechanics; elastin; mouse THE RECEPTOR FOR ADVANCED glycation end-products (RAGE) is a pattern recognition receptor of the immunoglobulin superfamily (32). RAGE is predominantly expressed in lung, particularly in the type I alveolar epithelial (ATI) cells (12,15,46). This specific localization suggests its important physiological function in the alveolar epithelium. In other cell types and tissues, the expression of RAGE is activated in response to pathophysiological conditions, such as the accumulation of advanced glycation end-products (AGEs) and inflammation (1). RAGE expression is highly associated with lung development and increases during the alveolarization (29,40). High RAGE expression prior to the alveolarization period has adverse effects associated with a severe pulmonary dysplasia (16,41). A reduced alveolar expression of RAGE is related to pathophysiological changes of the lung tissue, such as carcinoma (3), fibrosis (34, 37), and chronic obstructive pulmonary disease (COPD) (34). In addition to the membrane-bound receptor, soluble RAGE (sRAGE) forms exist as the result of either alternative splicing (22) or protein shedding by metalloproteinases (39, 52). sRAGE normally exists in the bronchoalveolar lavage (BAL) at a high level (53), but it is deficient in neutrophilic asthma and COPD (47, 49).The physiological importance of RAGE in lung is not yet fully understood because mice lacking RAGE do not show obvious pulmonary alterations (5, 9). Only intervention studies indicated an adverse effect of RAGE in the development of lung fibrosis (14, 19) and acute lung injury (4...

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Lung aging is associated with morphological and physiological changes in which alterations in transcription factors, including the cyclic adenosine monophosphate response element-binding protein (CREB), could play a role. We studied CREB in lung tissue from mice at different ages and in response to known age-related factors (e.g., cellular senescence and matrix modifications with advanced glycation end-products [AGEs]). Our study shows that protein but not mRNA levels of CREB are reduced in the lungs of old mice. CREB reduction was also observed in senescent human lung fibroblasts (WI-38, LuFi) and human lung epithelial cells (A549) cultured on AGE-modified collagen matrix. Reduction of CREB protein is partially based on pre- and posttranslational modifications as exhibited by an increase in the CREB-regulating microRNA 34b and CREB ubiquitination. Permanent down-regulation of CREB in lung cells impaired cell proliferation and viability and increased the number of cells with senescence-associated β-galactosidase activity. CREB down-regulation was accompanied by the reduced expression of 165 genes in WI-38 fibroblasts and A549 epithelial cells, of which 15 genes showed a reduced expression in lung tissues of old mice. The CREB-dependent reduction in RAB27A coding for the Ras-related protein Rab27A and IGFBP3 coding for the insulin-like growth factor-binding protein 3 has been confirmed for aged lung tissue, senescent fibroblasts, and lung epithelial cells on AGE-modified collagen. Our data demonstrate that the reduced protein expression of CREB might play a significant role in lung aging by modifying the transcription of RAB27A, IGFBP3, and other target genes.

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