TY - JOUR T1 - Pharmacological Blockade of the DP2 Receptor Inhibits Cigarette Smoke-Induced Inflammation, Mucus Cell Metaplasia, and Epithelial Hyperplasia in the Mouse Lung JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 764 LP - 775 DO - 10.1124/jpet.109.161919 VL - 332 IS - 3 AU - Karin J. Stebbins AU - Alex R. Broadhead AU - Christopher S. Baccei AU - Jill M. Scott AU - Yen P. Truong AU - Heather Coate AU - Nicholas S. Stock AU - Angelina M. Santini AU - Patrick Fagan AU - Patricia Prodanovich AU - Gretchen Bain AU - Brian A. Stearns AU - Christopher D. King AU - John H. Hutchinson AU - Peppi Prasit AU - Jilly F. Evans AU - Daniel S. Lorrain Y1 - 2010/03/01 UR - http://jpet.aspetjournals.org/content/332/3/764.abstract N2 - Prostaglandin D2 (PGD2) is one of a family of biologically active lipids derived from arachidonic acid via the action of COX-1 and COX-2. PGD2 is released from mast cells and binds primarily to two G protein-coupled receptors, namely DP1 and DP2, the latter also known as chemoattractant receptor-homologous molecule expressed on Th2 cells. DP2 is predominantly expressed on eosinophils, Th2 cells, and basophils, but it is also expressed to a lesser extent on monocytes, mast cells, and epithelial cells. Interaction of PGD2 and its active metabolites with DP2 results in cellular chemotaxis, degranulation, up-regulation of adhesion molecules, and cytokine production. Chronic obstructive pulmonary disease (COPD) is a chronic progressive inflammatory disease characterized by elevated lung neutrophils, macrophages, and CD8+ T lymphocytes and mucus hypersecretion. Cigarette smoke contributes to the etiology of COPD and was used here as a provoking agent in a murine model of COPD. In an acute model, {2′-[(cyclopropanecarbonyl-ethyl-amino)-methyl]-6-methoxy-4′-trifluoro-methyl-biphenyl-3-yl}-acetic acid, sodium salt (AM156) and (5-{2-[(benzoyloxycarbonyl-ethyl-amino)-methyl]-4-trifluoromethyl-phenyl}-pyridin-3-yl)-acetic acid, sodium salt) (AM206), potent DP2 receptor antagonists, dose-dependently inhibited influx of neutrophils and lymphocytes to smoke-exposed airways. In a subchronic model, AM156 and AM206 inhibited neutrophil and lymphocyte trafficking to the airways. Furthermore, AM156 and AM206 treatment inhibited mucus cell metaplasia and prevented the thickening of the airway epithelial layer induced by cigarette smoke. These data suggest that DP2 receptor antagonism may represent a novel therapy for COPD or other conditions characterized by neutrophil influx, mucus hypersecretion, and airway remodeling.Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics ER -