| Budget Amount *help |
¥3,100,000 (Direct Cost: ¥3,100,000)
Fiscal Year 2001: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 2000: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Research Abstract |
Airway remodeling, such as goblet cell hyperplasia, thickening of the reticular layer beneath the epithelial basement membrane, and increased mass of airway smooth muscle, is important histological feature of chronic asthma. We established an animal model of airway remodeling, especially smooth muscle remodeling. Ovalbumin (OVA) was injected intraperitoneally to BALB/c mice. After sensitization, OVA were inhaled. 3 times/weeks for 6 weeks. Lung tissues were histologically evaluated after hematoxylin-eosin and Massontrichrome stains 24 h after last challenge. Goblet cell hyperplasia and subepithelial eosinophil infiltration were observed after 3 antigen challenges. After 12 challenges, the amount of collagen beneath the basement membrane and the mass of smooth muscle were increased. These results suggest that repeated allergen inhalations induce airway remodeling including the increase of smooth muscle mass in mouse.
Cysteinyl leukotrienes have potent effects on leukocyte trafficking, ai
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rway mucus secretion, and collagen. We investigated the effect of a cysteinyl leukotriene_1 (CysLT_1) receptor antagonist, pranlukast, on smooth muscle thickening, airway hyperresponsiveness, and inflammatory cell accumulation after repeated antigen exposure in sensitized BALB/c mice. Smooth muscle thickness in repeatedly OVA-exposed mice was significantly increased compared with chronically saline-exposed animals. Mice exposed to antigen chronically exhibited airway hyperresponsiveness and had significant eosinophil accumulation in BAL fluid. Pranlukast treatment significantly suppressed smooth muscle thickening and airway hyperresponsiveness but not affect cell profile in BAL fluid. These results suggest that endogenous CysLT_1, may play an important role in ASM thickening and airway hyperresponsiveness following repeated antigen exposure in vivo.
Goblet cell metaplasia is an important morphologic feature in the airways of patients with chronic airway diseases, however, the precise mechanisms that cause this feature are unknown. We investigated the role of endogenous PAF in airway goblet cell metaplasia induced by cigarette smoke in vivo. Guinea pigs were exposed repeatedly to cigarette smoke for 14 consecutive days. The number of goblet cells in each trachea was determined with PAS/AB staining. Differential cell counts and PAF levels in BAL fluid were also evaluated. Cigarette smoke exposure increased the number of goblet cells significantly. Eosinophils, neutrophils, and PAF levels in BAL fluid were also significantly increased after cigarette smoke. Treatment with a specific PAF receptor antagonist, E-6123, significantly attenuated the increases in the numbers of airway goblet cells, eosinophils, and neutrophils observed after cigarette smoke exposure. These results suggest that endogenous PAF may play a key role in goblet cell metaplasia induced by cigarette smoke and that potential roles exist for inhibitors of PAF receptor in treatment of hypersecretory airway diseases. Less
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