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Loss of RAGE in Pulmonary Fibrosis

Molecular Relations to Functional Changes in Pulmonary Cell Types

Departments of ¹ Biochemistry and ² Medicine II, University of Giessen Lung Center, Justus-Liebig-University, Giessen, Germany

Correspondence and requests for reprints should be addressed to Klaus T. Preissner, PhD, Department of Biochemistry, University of Giessen Lung Center, Justus-Liebig-University, Friedrichstr. 24, 35392 Giessen, Germany. E-mail: klaus.t.preissner{at}biochemie.med.uni-giessen.de

The receptor for advanced glycation end products (RAGE) is a transmembrane receptor of the Ig superfamily. While vascular RAGE expression is associated with kidney and liver fibrosis, high expression levels of RAGE are found under physiological conditions in the lung. In this study, RAGE expression in idiopathic pulmonary fibrosis was assessed, and the relationship of the receptor to functional changes of epithelial cells and pulmonary fibroblasts in the pathogenesis of the disease was investigated. Significant down-regulation of RAGE was observed in lung homogenate and alveolar epithelial type II cells from patients with idiopathic pulmonary fibrosis, as well as in bleomycin-treated mice, demonstrated by RT-PCR, Western blotting, and immunohistochemistry. In vitro, RAGE down-regulation was provoked by stimulation of primary human lung fibroblasts and A549 epithelial cells with the proinflammatory cytokines, transforming growth factor-β1 or TNF-. Blockade of RAGE resulted in impaired cell adhesion, and small interfering RNA–induced knockdown of RAGE increased cell proliferation and migration of A549 cells and human primary fibroblast in vitro. These results indicate that RAGE serves a protective role in the lung, and that loss of the receptor is related to functional changes of pulmonary cell types, with the consequences of fibrotic disease.

Key Words: receptor for advanced glycation end products • pulmonary fibrosis • idiopathic pulmonary fibrosis • adhesion molecule • alveolar epithelial cells

CLINICAL RELEVANCE Our study provides evidence that the expression and regulation of receptor for advanced glycation end products (RAGE) in the pulmonary system differs from that in the vascular system. Here, a possible functional mechanism of RAGE in pulmonary fibrosis is described for the first time.