Effect of the cell surface receptor RAGE to pulmonary biomechanics and vascular adaptation of the lung to hypoxia

• Applicant: Privatdozentin Dr. Babett Bartling
• Subject Area: Biogerontology and Geriatric Medicine ; Pneumology, Thoracic Surgery
• Term: from 2009 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 160117542

The receptor for advanced glycation end-products (RAGE) is a cell surface protein of the immunoglobulin superfamily. In physiological conditions, RAGE is mainly present in lung, particularly in the intact alveolar epithelium and as soluble form (sRAGE) in the lung lavage. In contrast, RAGE is much less present in pathologically altered lung tissue including lung carcinoma. Even though intensive research, the detailed pulmonary function of RAGE is still unclear. Because RAGE enhances the adhesion of alveolar epithelial cells and the intact alveolar epithelium is subjected to chronic biomechanical forces due to breathing, we supposed the importance of RAGE in maintaining the lung biomechanics. Within the first period of our project, we confirmed this supposition mainly by studies using the isolated lung organ of RAGE knock out mice. These studies showed a RAGE-related reduction of the lung compliance and, therefore, better elastic recoiling of the lung, which is important for passive expiration. Further studies indicated the importance of direct (RAGE interactions between neighbouring cells) as well as indirect (RAGE-dependent level of elastin) mechanisms for biomechanical changes. Additionally to RAGE the aging process, which is associated with an increase in AGEs (advanced glycation end-products), influences the biomechanical parameter of the lung. As RAGE also results in a reduced level the enzyme Glyoxalase 1, which restricts the AGE formation, we suppose an additional indirect effect of RAGE on the pulmonary biomechanics via age-associated protein modifications of elastin with AGEs. Therefore, our continue project aimed at the RAGE-dependency of the AGE-modification of elastin and its effect on the pulmonary biomechanics as well as the simultaneous influence of physical activity (running wheel model). As RAGE and sRAGE are protected against proteolytic degradation by N-glycosylation, we also aim at the investigation of the sugar structure of RAGE. In addition, our previous studies indicated a vascular effect of RAGE. This vascular effect was associated with a RAGE-dependent level of endoglin, an endothelial cell-related surface protein of the lung capillaries, and an age-dependent stabile pulmonary artery pressure. Therefore, our continue project also aimed at the investigation of the alveolar vessel density as well as the adaptation of the lung to short-term pulmonary hypoxia by vasoconstriction in a RAGE-dependent manner. In addition, we want to investigate components of the TGF-beta pathway, which probably enhances the generation of elastin and endoglin in a RAGE-dependent manner.

• DFG Programme: Research Grants
• Participating Person: Professor Dr. Andreas Simm