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Am. J. Respir. Crit. Care Med., Volume 165, Number 1, January 2002, 108-116

A Role for Cysteinyl Leukotrienes in Airway Remodeling in a Mouse Asthma Model

WILLIAM R. HENDERSON JR., LI-OU TANG, SHI-JYE CHU, SHIH-MING TSAO, GERTRUDE K. S. CHIANG, FALAAH JONES, MECHTHILD JONAS, CHONG PAE, HUAIJING WANG, and EMIL Y. CHI

Departments of Medicine and Pathology, University of Washington, Seattle, Washington; Department of Neurology, Qingdao Medical College, Qingdao University, Qingdao, Shandong, China; Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan; Department of Medicine, Chung San Medical and Dental College, Taichung, Taipei, Taiwan; and Department of Anatomy, Shandong Medical University, Jinan, Shandong, China

Airway inflammation and remodeling in chronic asthma are characterized by airway eosinophilia, hyperplasia of goblet cells and smooth muscle, and subepithelial fibrosis. We examined the role of leukotrienes in a mouse model of allergen-induced chronic lung inflammation and fibrosis. BALB/c mice, after intraperitoneal ovalbumin (OVA) sensitization on Days 0 and 14, received intranasal OVA periodically Days 14-75. The OVA-treated mice developed an extensive eosinophil and mononuclear cell inflammatory response, goblet cell hyperplasia, and mucus occlusion of the airways. A striking feature of this inflammatory response was the widespread deposition of collagen beneath the airway epithelial cell layer and also in the lung interstitium in the sites of leukocytic infiltration that was not observed in the saline-treated controls. The cysteinyl leukotriene1 (CysLT1) receptor antagonist montelukast significantly reduced the airway eosinophil infiltration, mucus plugging, smooth muscle hyperplasia, and subepithelial fibrosis in the OVA-sensitized/challenged mice. The presence of Charcot-Leyden-like crystals in airway macrophages and the increased interleukin (IL)-4 and IL-13 mRNA expression in lung tissue and protein in BAL fluid seen in OVA-treated mice were also inhibited by CysLT1 receptor blockade. These data suggest an important role for cysteinyl leukotrienes in the pathogenesis of chronic allergic airway inflammation with fibrosis.




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