Specific mediator inhibition by the NO donors SNP and NCX 2057 in the peripheral lung: implications for allergen-induced bronchoconstriction

Anna-Karin Larsson,Sven-Erik Dahlén,Magnus Bäck,Jon O Lundberg

doi:10.1186/1465-9921-10-46

Anna-Karin Larsson, Sven-Erik Dahlén + Show 2 more

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https://doi.org/10.1186/1465-9921-10-46

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Journal: Respiratory research	Publication Date: Jun 4, 2009
Citations: 52	License type: cc-by

Affiliation: Karolinska Institutet, Lund University

Abstract

BackgroundThe aim of this study was to examine potential therapeutic effect of the two NO donors NCX 2057 (3-(4-hydroxy-3-methoxyphenyl)-2-propenoic acid) 4-(nitrooxy)butyl ester) and SNP (sodium nitroprusside) on the early allergic airway response in the peripheral lung.MethodsThe experiments were performed in guinea pig lung parenchyma (GPLP) derived from ovalbumin (OVA) sensitized guinea pigs. The effects of NCX 2057 and SNP were evaluated by contractile responses and mediator release during OVA challenge. The generation of nitrite and nitrate was assessed by chemiluminescence. Statistical analysis was evaluated by ANOVA.ResultsCumulatively increasing concentrations of OVA (1–10,000 ng/ml) induced concentration-dependent contractions of the GPLP that were reduced by NCX 2057 (100 μM, p < 0.001) and SNP (100 μM, p < 0.05). Antigen-induced eicosanoid release was decreased by NCX 2057 (100 μM, p < 0.001) but not by SNP (100 μM), whereas the release of histamine was reduced by SNP (100 μM, p < 0.001) but not by NCX 2057 (100 μM). In addition, NCX 2057 (0.1–100 μM), but not SNP (0.1–100 μM), relaxed leukotriene D4 (10 nM) precontracted GPLP (p < 0.01). The guanylyl cyclase inhibitor ODQ had no effect on the NCX 2057 mediated relaxation. SNP released significantly less nitrite than NCX 2057.ConclusionAlthough both SNP and NCX 2057 reduced the release of pro-inflammatory mediators, their profiles were distinctly different. Furthermore, NCX 2057 also induced smooth muscle dilation in the GPLP. The findings point to specific anti-inflammatory effects of different NO donors in the peripheral lung tissue.

Highlights

The aim of this study was to examine potential therapeutic effect of the two nitric oxide (NO) donors NCX 2057 (3-(4-hydroxy-3-methoxyphenyl)-2-propenoic acid) 4-(nitrooxy)butyl ester) and sodium nitroprusside (SNP) on the early allergic airway response in the peripheral lung
Basal release in the bath fluid before OVA challenge was below detection limit for histamine, CysLTs and LTB4, whereas measurable levels were obtained for TXB2 (46 ± 11 pg/ml) and PGD2 (56 ± 16 pg/ml)
The release of histamine was significantly inhibited by SNP (100 μM, p < 0.001), whereas NCX 2057 (100 μM) did not significantly affect this release

Summary

Introduction

The aim of this study was to examine potential therapeutic effect of the two NO donors NCX 2057 (3-(4-hydroxy-3-methoxyphenyl)-2-propenoic acid) 4-(nitrooxy)butyl ester) and SNP (sodium nitroprusside) on the early allergic airway response in the peripheral lung. Exogenous NO has the ability to exert bronchodilatory effects in bronchial asthma [3] and NO is used in the treatment of preterm children to improve lung capacity [4]. The release of histamine and eicosanoids (leukotrienes and prostaglandins) from activated inflammatory cells, such as mast cells and macrophages, may contribute significantly to the symptoms of allergic rhinitis and asthma [5,6,7,8]. Mast cells and alveolar macrophages represent a major source of NO [2,9,10,11], which may act both directly on smooth muscle cells and in an autocrine fashion to suppress allergen-induced responses, as release of histamine [12] and leukotriene synthesis [13]. Inhibitors of NO synthases have been shown to enhance antigen-induced bronchoconstriction in sensitized guinea pigs by increased generation of leukotrienes [14]

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