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

Michael Salmon, David A. Walsh, Tung Jung Huang, Peter J. Barnes, Thomas B. Leonard, Douglas W.P. Hay, K. Fan Chung

Research output: Contribution to journalJournal Article peer-review

83 Scopus citations

Abstract

1. 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. 2. 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). 3. 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. 4. 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. 5. 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. 6. 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. 7. 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.

Original languageEnglish
Pages (from-to)1151-1158
Number of pages8
JournalBritish Journal of Pharmacology
Volume127
Issue number5
DOIs
StatePublished - 1999
Externally publishedYes

Keywords

  • Airway remodelling
  • Airway smooth muscle
  • Allergic reactions
  • Cysteinyl leukotrienes
  • DNA synthesis
  • Eosinophils

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