Salmon M, Walsh D A, Huang T J, Barnes P J, Leonard T B, Hay D W, Chung K F
Thoracic Medicine, Imperial College School of Medicine at the National Heart and Lung Institute, London, UK.
Br J Pharmacol. 1999 Jul;127(5):1151-8. doi: 10.1038/sj.bjp.0702669.
Airway smooth muscle thickening is a characteristic feature of airway wall remodelling in chronic asthma. We have investigated the role of the leukotrienes in airway smooth muscle (ASM) and epithelial cell DNA synthesis and ASM thickening following repeated allergen exposure in Brown Norway rats sensitized to ovalbumin. There was a 3 fold increase in ASM cell DNA synthesis, as measured by percentage bromodeoxyuridine (BrdU) incorporation, in repeatedly ovalbumin-exposed (4.1%, 3.6-4.6; mean, 95% c.i.) compared to chronically saline-exposed rats (1.3%, 0.6-2.1; P<0.001). Treatment with a 5-lipoxygenase enzyme inhibitor (SB 210661, 10 mg kg(-1), p.o.) and a specific cysteinyl leukotriene (CysLT1) receptor antagonist, pranlukast (SB 205312, 30 mg kg(-1), p.o.), both attenuated ASM cell DNA synthesis. Treatment with a specific leukotriene B4 (BLT) receptor antagonist (SB 201146, 15 mg kg(-1), p.o.) had no effect. There was also a significant, 2 fold increase in the number of epithelial cells incorporating BrdU per unit length of basement membrane after repeated allergen exposure. This response was not inhibited by treatment with SB 210661, pranlukast or SB 201146. A significant increase in ASM thickness was identified following repeated allergen exposure and this response was attenuated significantly by SB 210661, pranlukast and SB 201146. Rats exposed to chronic allergen exhibited bronchial hyperresponsiveness to acetylcholine and had significant eosinophil recruitment into the lungs. Treatment with SB 210661, pranlukast or SB 201146 significantly attenuated eosinophil recruitment into the lungs, whilst having no significant effect on airway hyperresponsiveness. These data indicate that the cysteinyl leukotrienes are important mediators in allergen-induced ASM cell DNA synthesis in rats, while both LTB4 and cysteinyl leukotrienes contribute to ASM thickening and eosinophil recruitment following repeated allergen exposure.
气道平滑肌增厚是慢性哮喘气道壁重塑的一个特征性表现。我们研究了白三烯在气道平滑肌（ASM）和上皮细胞DNA合成以及卵清蛋白致敏的棕色挪威大鼠反复接触变应原后ASM增厚过程中的作用。通过溴脱氧尿苷（BrdU）掺入百分比测量，与长期暴露于生理盐水的大鼠（1.3%，0.6 - 2.1；P<0.001）相比，反复接触卵清蛋白的大鼠（4.1%，3.6 - 4.6；平均值，95%置信区间）的ASM细胞DNA合成增加了3倍。用5 - 脂氧合酶抑制剂（SB 210661，10 mg kg(-1)，口服）和特异性半胱氨酰白三烯（CysLT1）受体拮抗剂普仑司特（SB 205312，30 mg kg(-1)，口服）治疗均减弱了ASM细胞DNA合成。用特异性白三烯B4（BLT）受体拮抗剂（SB 201146，15 mg kg(-1)，口服）治疗则无效果。反复接触变应原后，每单位长度基底膜掺入BrdU的上皮细胞数量也显著增加了2倍。用SB 210661、普仑司特或SB 201146治疗并未抑制这种反应。反复接触变应原后发现ASM厚度显著增加，而这种反应被SB 210661、普仑司特和SB 201146显著减弱。暴露于慢性变应原的大鼠对乙酰胆碱表现出支气管高反应性，并且有大量嗜酸性粒细胞募集到肺中。用SB 210661、普仑司特或SB 201146治疗显著减弱了嗜酸性粒细胞向肺中的募集，而对气道高反应性没有显著影响。这些数据表明，半胱氨酰白三烯是变应原诱导大鼠ASM细胞DNA合成的重要介质，而白三烯B4和半胱氨酰白三烯在反复接触变应原后均促成了ASM增厚和嗜酸性粒细胞募集。
