Leukotriene antagonism reduces the generation of endothelin-1 and interferon-gamma and inhibits eosinophilic airway inflammation.
The cysteinyl leukotrienes (cysLTs) and the peptide hormone endothelin (ET)-1 are potent bronchoconstrictor substances, and these mediators are also claimed to be implicated in the development of eosinophilic airway inflammation. In the present study, we have investigated the effect of the cysLT1 receptor antagonist montelukaston the development of an eosinophilic airway inflammation 24 h after intratracheal Sephadex (SDX) provocation in rats. Furthermore, the effect of montelukast treatment on the generation of ET-1 and other pro-inflammatory mediators has been studied. The inflammatory response was significantly reduced in the animals receiving SDX + montelukast compared to animals receiving solely SDX, as evaluated by a decrease in bronchoalveolar lavage fluid total cell count (10.3 +/- 1.2 vs. 18.5 +/- 1.8 x 10(4) ml(-1), P<0.001), number of eosinophils (299.7 +/- 43.8 vs. 577.6 +/- 46.6 x 10(2) ml(-1), P<0.001), and lymphocytes (116.8 +/- 20 vs. 222.0 +/- 34.8 x 10(2) ml(-1), P<0.05), as well as the degree of tissue inflammation (P<0.05). Montelukast also inhibited the increase in the concentration of the pro-inflammatory mediators ET-1 (28.5 +/- 75 vs. 40.9 +/- 7.3 x pg ml(-1), P<0.05) and interferon (IFN)-gamma (4.3 +/- 2.2 vs. 15.6+/-8.7 x pg ml(-1), P<0.05), but not tumor necrosis factor-gamma or interleukin-8. In summary, treatment with the cysLT1 receptor antagonist montelukast reduced the inflammatory response during development of an eosinophilic airway inflammation, possibly by inhibiting the release of pro-inflammatory mediators like ET-1 and IFN-gamma.
Finsnes
F
F
Department of Pulmonary Medicine, Ullevål Hospital, University of Oslo, Norway. finn@finsnes.no
Lyberg
T
T
Christensen
G
G
Skjønsberg
O H
OH
D000085:Acetates / Q000494:pharmacology*; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002452:Cell Count; D003521:Cyclopropanes; D019332:Endothelin-1 / Q000032:analysis*; D004804:Eosinophils / Q000473:pathology; D007371:Interferon-gamma / Q000032:analysis*; D016209:Interleukin-8 / Q000032:analysis; D020024:Leukotriene Antagonists / Q000494:pharmacology*; D008168:Lung / Q000187:drug effects*; D008297:Male; D011804:Quinolines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013440:Sulfides; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
D000085:Acetates; D003521:Cyclopropanes; D019332:Endothelin-1; D016209:Interleukin-8; D020024:Leukotriene Antagonists; D011804:Quinolines; D013440:Sulfides; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; C093875:montelukast