LJ-2698, an Adenosine A3 Receptor Antagonist, Alleviates Elastase-Induced Pulmonary Emphysema in Mice
Hye-Jin Boo1,†, So Jung Park1,†, Myungkyung Noh1, Hye-Young Min2, Lak Shin Jeong1 and Ho-Young Lee1,2,*
1College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826,
2Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, and College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
*E-mail: hylee135@snu.ac.kr
Tel: +82-2-880-9277, Fax: +82-2-6280-5327
The first two authors contributed equally to this work.
Received: September 30, 2019; Revised: December 15, 2019; Accepted: December 24, 2019; Published online: February 17, 2020.
© The Korean Society of Applied Pharmacology. All rights reserved.

Abstract
Emphysema, a major component of chronic obstructive pulmonary disease (COPD), is a leading cause of human death worldwide. The progressive deterioration of lung function that occurs in the disease is caused by chronic inflammation of the airway and destruction of the lung parenchyma. Despite the main impact of inflammation on the pathogenesis of emphysema, current therapeutic regimens mainly offer symptomatic relief and preservation of lung function with little therapeutic impact. In the present study, we aimed to discover novel therapeutics that suppress the pathogenesis of emphysema. Here, we show that LJ-2698, a novel and highly selective antagonist of the adenosine A3 receptor, a G protein-coupled receptor involved in various inflammatory diseases, significantly reversed the elastase-induced destructive changes in murine lungs. We found that LJ-2698 significantly prevented elastase-induced airspace enlargement, resulting in restoration of pulmonary function without causing any obvious changes in body weight in mice. LJ-2698 was found to inhibit matrix metalloproteinase activity and pulmonary cell apoptosis in the murine lung. LJ-2698 treatment induced increases in anti-inflammatory cytokines in macrophages at doses that displayed no significant cytotoxicity in normal cell lines derived from various organs. Treatment with LJ-2698 significantly increased the number of anti-inflammatory M2 macrophages in the lungs. These results implicate the adenosine A3 receptor in the pathogenesis of emphysema. Our findings also demonstrate the potential of LJ-2698 as a novel therapeutic/preventive agent in suppressing disease development with limited toxicity.
Keywords: Adenosine A3 receptor, LJ-2698, Emphysema


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