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American Journal of Respiratory Cell and Molecular Biology. Vol. 28, pp. 410-419, 2003
© 2003 American Thoracic Society
DOI: 10.1165/rcmb.2002-0032OC

Leukotrienes Mediate Murine Bronchopulmonary Hyperreactivity, Inflammation, and Part of Mucosal Metaplasia and Tissue Injury Induced by Recombinant Murine Interleukin-13

B. Boris Vargaftig and Monique Singer

Unité de Pharmacologie Cellulaire, Unité Associée Institut Pasteur-INSERM U485, Paris, France

Address correspondence to: Monique Singer, Unité de Pharmacologie Cellulaire, Unité Associée Institut Pasteur-INSERM U485, Institut Pasteur 25, rue du Dr Roux, 75015 Paris, France. E-mail: msinger{at}pasteur.fr

Interleukin (IL)-13 induces bronchopulmonary hyperreactivity (BHR), eosinophilic inflammation, and mucus accumulation in the murine airways. To investigate the potential role of leukotrienes (LT) in mediating these effects, we studied the ability of IL-13 to induce the expression of 5-lipoxygenase (5-LO), we compared the effects of IL-13 and of various leukotrienes on different biological parameters and the interference by the 5-LO inhibitor zileuton (orally, 50 mg/kg, 3 times a day for 3 days), and by some antagonists. The cysteinyl (Cys)-LTs LTC4, LTD4, LTE4, and LTB4, (1 µg/d for 3 d, instilled intratracheally) induced BHR, cell recruitment, fibroblast growth, and mucus production and release into the airways. After the intratracheal instillation of recombinant murine (rm) IL-13, Cys-LT increased in the bronchoalveolar lavage fluid (BALF) at 15 min, followed by lower amounts at 3–6 h. Zileuton inhibited LT production in the BALF, eosinophil and neutrophil sequestration in the lungs, and their passage into the BALF. Zileuton and the Cys-LT-receptor antagonist (ra) LY171883 or MK-571, or the LTB4-ra PH-163 (at 3–10, 5–15, and 10 mg/kg, respectively, administered intratracheally), inhibited BHR by recombinant murine IL-13. Airways mucus after recombinant murine IL-13–challenge was reduced by zileuton and by LY171883, MK-571, and PH-163. LT also induced the vascular endothelium remodelling and collagen deposition. Overall, our results demonstrate the major involvement of LT in the effects of IL-13 on the lung.

Abbreviations: smooth muscle {alpha}-actin, {alpha}-SMA • bronchoalveolar lavage fluid, BALF • bronchopulmonary hyperreactivity, BHR • bromodeoxyuridine, BrdU • cysteinyl leukotrienes (LTC4, LTD4, LTE4), Cys-LT • dimethyl sulfoxide, DMSO • eosinoperoxidase, EPO • immunocytochemistry, ICC • leukotrienes, LT • methacholine, Mch • myeloperoxidase, MPO • receptor antagonist, ra • recombinant murine, rm




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