A Role for the Receptor for Advanced Glycation End Products in Idiopathic Pulmonary Fibrosis

Judson M. Englert^*, Lana E. Hanford^*, Naftali Kaminski, Jacob M. Tobolewski^*, Roderick J. Tan^*, Cheryl L. Fattman, Lasse Ramsgaard^*, Thomas J. Richards, Inna Loutaev, Peter P. Nawroth^¶, Michael Kasper^||, Angelika Bierhaus^¶ and Tim D. Oury^*

From the Department of Pathology,^*University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; the Dorothy P. and Richard P. Simmons Center for Interstitial Lung Diseases,Pulmonary Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania; the Department of Environmental and Occupational Health,University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania; Pulmonary and Critical Care Medicine,University of Washington, Seattle, Washington; the Department of Medicine I and Clinical Chemistry,^¶University of Heidelberg, Heidelberg, Germany; and the Institute of Anatomy,^||University of Technology Dresden, Dresden, Germany

Idiopathic pulmonary fibrosis (IPF) is a severely debilitatingdisease associated with a dismal prognosis. There are currentlyno effective therapies for IPF, thus the identification of noveltherapeutic targets is greatly needed. The receptor for advancedglycation end products (RAGE) is a member of the immunoglobulinsuperfamily of cell surface receptors whose activation has beenlinked to various pathologies. In healthy adult animals, RAGEis expressed at the highest levels in the lung compared to othertissues. To investigate the hypothesis that RAGE is involvedin IPF pathogenesis, we have examined its expression in twomouse models of pulmonary fibrosis and in human tissue fromIPF patients. In each instance we observed a depletion of membraneRAGE and its soluble (decoy) isoform, sRAGE, in fibrotic lungs.In contrast to other diseases in which RAGE signaling promotespathology, immunohistochemical and hydroxyproline quantificationstudies on aged RAGE-null mice indicate that these mice spontaneouslydevelop pulmonary fibrosis-like alterations. Furthermore, whensubjected to a model of pulmonary fibrosis, RAGE-null mice developedmore severe fibrosis, as measured by hydroxyproline assay andhistological scoring, than wild-type controls. Combined withdata from other studies on mouse models of pulmonary fibrosisand human IPF tissues indicate that loss of RAGE contributesto IPF pathogenesis.