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Role of Soluble Receptor for Advanced Glycation End Products on Endotoxin-induced Lung Injury

¹ Division of Pulmonary Medicine, Keio University School of Medicine, Tokyo, Japan; ² Emergency Department, The First Affiliated Hospital, China Medical University, Shenyang, China; ³ Department of Anesthesiology, Keio University School of Medicine, Tokyo, Japan; ⁴ Laboratory of Veterinary Biochemistry, Rakuno Gakuen University, Ebetsu, Japan; and ⁵ Department of Laboratory and Molecular Medicine, Faculty of Medicine, Kagoshima University, Kagoshima, Japan

Correspondence and requests for reprints should be addressed to Sadatomo Tasaka, M.D., Ph.D., Division of Pulmonary Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. E-mail: tasaka{at}cpnet.med.keio.ac.jp

Rationale: The interaction of receptor for advanced glycation end products (RAGE) and its ligands often leads to inflammatory processes or tissue injury, although the effect of the blockade of RAGE signaling on lung injury remains to be investigated.

Objectives: Using a murine model of lung injury induced by intratracheal lipopolysaccharide (LPS), we evaluated RAGE expression in the airspace and the effect of recombinant soluble RAGE (sRAGE) on LPS-induced lung injury.

Methods: First, the expression of sRAGE in bronchoalveolar lavage (BAL) fluid was determined at 24 hours after intratracheal instillation of LPS or phosphate-buffered saline. Next, to evaluate the effect of sRAGE, BAL fluid was collected for cell counting and measurements of lung permeability and cytokine concentrations 24 hours after intratracheal LPS in the mice with or without intraperitoneal administration of sRAGE 1 hour after the instillation. In another series, lungs were sampled for histopathology and detection of apoptotic cells. The activation of nuclear factor (NF)-B was analyzed 4 hours after LPS instillation.

Measurements and Main Results: In response to LPS challenge, a RAGE isoform of 48 kD was detected in the BAL fluid. Treatment with sRAGE significantly attenuated the increases in neutrophil infiltration, lung permeability, production of inflammatory cytokines, NF-B activation, and apoptotic cells in the lung as well as development of pathologic changes after LPS instillation.

Conclusions: RAGE plays an important role in the pathogenesis of LPS-induced lung injury in mice. It was suggested that sRAGE should be tested as a treatment modality in other models of acute lung injury.

Key Words: RAGE • lung injury • apoptosis • chemokine • mouse model

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject The receptor for advanced glycation end products (RAGE) recognizes a variety of ligands, including high-mobility group box 1, but little is known concerning its role in the development of endotoxin-induced lung injury. What This Study Adds to the Field Soluble RAGE is up-regulated during LPS-induced lung injury, which was ameliorated by recombinant soluble RAGE. Soluble RAGE may be secreted as a decoy receptor and contribute to the suppression of excessive inflammatory response during acute lung injury/acute respiratory distress syndrome.

 

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