The receptor for advanced glycation end-products supports lung tissue biomechanics

Abstract

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...

Receptor for advanced glycation endproducts (RAGE) maintains pulmonary structure and regulates the response to cigarette smoke

“…In their study, lungs of RAGE -/- mice showed a decreased expiratory airflow and increased lung compliance as compared to WT mice. However, they could only define an impact of RAGE on the respiratory function in mice from an age of five months, whereas we could detect an influence even in younger mice [36]. Sambamurthy et al observed comparable enlargement of alveolar dimensions in native RAGE -/- mice [37].…”

“…The RAGE-dependent differences in lung function and structure could be caused by insufficient cell-cell- and cell-matrix contacts. RAGE mediates interactions between two adjacent cells and enhances the adherence of alveolar epithelial cells to the basal membrane [2, 36]. …”

“…Leakage of serum proteins from the blood into the lung indicates an endothelial-epithelial barrier defect in RAGE -/- mice [34, 38–40]. Other studies using increased total protein content in the BALF of mice as a marker for barrier dysfunction could not determine any differences between WT and RAGE -/- mice [36, 41, 42]. …”

Increased AGE-RAGE ratio in idiopathic pulmonary fibrosis

“…According to this observation, Quiesser et al suggested an important function of RAGE in cellular adhesion and spreading to the basal membrane, playing a structural role in the maintenance of the alveolar epithelium [32]. It has also been demonstrated that RAGE stimulates elastin expression and plays a supporting role in respiratory mechanics [48]. Furthermore, RAGE may belong to a family of cell adhesion molecules [49], making links with basal lamina components such as type IV collagen or laminin [28, 50].…”

Role of advanced glycation end products in cellular signaling

“…Al-Robaiy et al elucidate the importance of the high RAGE expression in supporting the respiratory mechanics of the lung. Lungs from RAGE knockout (RAGE −/− ) mice show a significant increase in dynamic lung compliance and a decrease in the maximal expiratory air flow [176]. It is discussed that the biomechanically interaction of cells and their matrix, as well as the mechanically coupling of cells are affected.…”