RAGE: A beneficial role in pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a severely debilitating disease with a poor prognosis. There are currently no effective therapies for IPF, thus the identification of new therapeutic targets is needed. The receptor for advanced glycation end products (RAGE) is a cell surface receptor whose activation has been linked to many diseases. Although expressed at the highest levels in the lungs of adult animals, the role of RAGE has not been examined in pulmonary disease. This study examined the potential role of RAGE in IPF pathogenesis. Methods: RAGE expression was examined in two mouse models of pulmonary fibrosis and in human IPF lungs. Pulmonary histology and hydroxyproline levels of RAGE null mice was also compared with that of wild-type mice. In addition, cultured human pulmonary fibroblasts were treated with RAGE ligands and α-smooth muscle actin expression was examined. Results: Membrane RAGE and its soluble (decoy) isoform, sRAGE, are significantly depleted in both murine and human fibrotic lungs. In contrast to other diseases in which RAGE signaling promotes pathology, histologic and hydroxyproline studies on aged RAGE null mice indicate that they spontaneously develop pulmonary fibrosis-like alterations. In vitro studies suggest that RAGE signaling may inhibit myofibroblastic phenotypes in pulmonary fibroblasts. Conclusions: Combined with data from mouse models of pulmonary fibrosis and human IPF tissues, these data indicate that loss of RAGE/sRAGE plays an important role in the pathogenesis of IPF.