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Int J Clin Exp Pathol 2011;4(3):241-254

Original Article
Paradoxical function for the receptor for advanced glycation end products in mouse
models of pulmonary fibrosis

Judson M. Englert, Corrine R. Kliment, Lasse Ramsgaard, Pavle S. Milutinovic, Lauren Crum, Jacob M. Tobolewski, Tim D. Oury

Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.

Received March 9, 2011; accepted March 20, 2011; Epub March 21, 2011; published March 31, 2011

Abstract: Idiopathic pulmonary fibrosis (IPF) is a progressive disease with poor survival. The identification of therapeutic targets is essential to
improving outcomes. Previous studies found that expression of the receptor for advanced glycation end products (RAGE) in the lung is
significantly decreased in human IPF lungs and in two animal models of pulmonary fibrosis. In addition, RAGE-null mice spontaneously
develop pulmonary fibrosis with age and more severe fibrosis when challenged with asbestos. In contrast to the findings that the lack of RAGE
enhanced pulmonary fibrosis, He et al. found that RAGE null mice were protected from bleomycin-induced fibrosis and suggested the effect
was due to a lack of HMGB1 induced RAGE signaling. The current study further tests this hypothesis by blocking RAGE signaling via
administration of soluble RAGE, a decoy receptor, to determine if this will also protect against pulmonary fibrosis. Wild-type, RAGE+/-, and
RAGE-/- mice were treated with bleomycin and assessed for fibrosis. Wild-type mice were also treated with exogenous soluble RAGE or
vehicle control. In addition, in vitro studies with primary alveolar epithelial cells from wild-type and RAGE null mice were used to investigate the
effect of RAGE on cell viability and migration in response to injury. A lack of RAGE was found to be protective against bleomycin injury in both in
vivo and in vitro studies. However, soluble RAGE administration was unable to ameliorate fibrosis. This study confirms paradoxical responses
to two different models of pulmonary fibrosis and suggests a further role for RAGE in cellular migration. (IJCEP1103004).

Keywords: Bleomycin, RAGE knockout, soluble RAGE, asbestos

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