A leukotriene receptor antagonist modulates iNOS in the lung and in a leukotriene-free cell model

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• 作者：Offer ; Sarit ; Shoseyov ; David ; Bibi ; Haim ; Eliraz ; Abraham ; Madar ; Zecharia
• 关键词：BN rats ; Respiratory epithelial cells ; Nitric oxide ; Leukotriene receptor antagonist ; Cytokines
• 刊名：Nitric Oxide
• 出版年：2003
• 出版时间：August, 2003
• 年：2003
• 卷：9
• 期：1
• 页码：10-17
• 全文大小：368 K

文摘

Nitric oxide (NO), an important cell signaling molecule, is considered a marker of inflammatory response and is elevated in asthmatics. This study investigated the effects of montelukast (a leukotriene receptor antagonist) on iNOS expression and activity in a Brown Norway (BN) rat allergic inflammation model and in L2 lung epithelial cells. Allergic inflammation was induced by ovalbumin (OVA) injection in BN rats followed by treatment with either montelukast or dexamethasone (DX). Allergen inhalation was performed, and post-allergen Penh was measured 5min after the challenge. Cysteinyl leukotriene levels were measured in bronchoalveolar lavage (BAL) fluid and lung iNOS expression and activity determined. These parameters were also measured in cytokine stimulated L2 lung epithelial cells. iNOS expression was significantly higher in OVA challenged rats compared to the naive, DX, and montelukast treated groups, as confirmed by immunohistochemistry and Western blot analysis. However, no significant differences in NOS activity were found. Cysteinyl leukotriene measured in BAL was significantly higher in all OVA challenged rats compared to naive controls. Incubation of L2 cells with a mixture of interferon gamma (IFNγ), lipopolysaccharide (LPS), and tumor necrosis factor (TNFα) resulted in high levels of nitrite formation resulting from iNOS induction. Treatment of cytokine stimulated cells with DX or montelukast significantly decreased iNOS expression and activity. No detectable cysteinyl leukotrienes were found in the supernatant fluid of L2 cells. This study confirms the ability of montelukast to modulate iNOS function and raises the possibility that changes in iNOS expression and activity may occur via pathways independent of cysteinyl leukotrienes.