Involvement of cysteinyl leukotrienes in airway smooth muscle cell DNA synthesis after repeated allergen exposure in sensitized Brown Norway rats

1 Airway smooth muscle thickening is a characteristic feature of airway wal l remodelling in chronic asthma. We have investigated the role of the leuko trienes in airway smooth muscle (ASM) and epithelial cell DNA synthesis and ASM thickening following repeated allergen exposure in Brown Norway rats s ensitized to ovalbumin. 2 There was a 3 fold increase in ASM cell DNA synthesis, as measured by per centage bromodeoxyuridine (BrdU) incorporation, in repeatedly ovalbumin-exp osed (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). 3 Treatment with a 5-lipoxygenase enzyme inhibitor (SB 210661, 10 mg kg(-1) , p.o.) and a specific cysteinyl leukotriene (CysLT(1)) receptor antagonist , pranlukast (SB 205312, 30 mg kg(-1), p.o.), both attenuated ASM cell DNA synthesis. Treatment with a specific leukotriene Bq (BLT) receptor antagoni st (SB 201146, 15 mg kg(-1), p.o.) had no effect. 4 There was also a significant, 2 fold increase in the number of epithelial cells incorporating BrdU per unit length of basement membrane after repeat ed allergen exposure. This response was not inhibited by treatment with SE 210661, pranlukast or SE 201146. 5 A significant increase in ASM thickness was identified following repeated allergen exposure and this response was attenuated significantly by SE 210 661, pranlukast and SE 201146. 6 Rats exposed to chronic allergen exhibited bronchial hyperresponsiveness to acetylcholine and had significant eosinophil recruitment into the lungs. Treatment with SE 210661, pranlukast or SE 201146 significantly attenuated eosinophil recruitment into the lungs, whilst having no significant effect on airway hyperresponsiveness. 7 These data indicate that the cysteinyl leukotrienes are important mediato rs in allergen-induced ASM cell DNA synthesis in rats, while both LTB4 and cysteinyl leukotrienes contribute to ASM thickening and eosinophil recruitm ent following repeated allergen exposure.