CysLT₁-R expression following allergen provocation in asthma and allergic rhinitis

Abstract

Cysteinyl leukotrienes (CysLTs) contribute to allergic and inflammatory diseases through CysLT₁-R. We aimed to assess CysLT₁-R mRNA expression in induced sputum of rhinitics with or without asthma before and following allergen challenges. Both groups underwent nasal and “low dose” lung allergen challenges. Asthmatics also underwent “standard” lung challenge. Sputum was obtained before and at different time-points following the challenges for CysLT₁-R, 5-lipoxygenase (5-LO), and eotaxin mRNA assessments. At baseline, there was no difference in mediator levels between groups. An increase in CysLT₁-R mRNA (p=0.04) and a trend towards an increase in 5-LO and eotaxin (p=0.06 for both) at 24 h post-nasal challenge were observed. Following “low dose” lung allergen challenge, there was a trend towards an increase in CysLT₁-R (p=0.07). In conclusion, CysLT₁-R gene expression changes can be detected in sputum following allergen challenges. No difference was observed between groups, suggesting that changes in CysLT₁-R expression occur whether or not the subject has concurrent asthma.

Introduction

Atopy is considered to be a predisposing factor in the development of asthma [1], [2]. Airway inflammation and remodelling may be observed in non-asthmatic subjects with allergic rhinitis, although in a less intense form than in asthmatic patients [3], [4], [5]. Airway inflammation has been associated with the increase in airway responsiveness observed during natural or laboratory exposure to allergens in atopic subjects without asthma [6], [7], [8]. Thus, it seems that asthma and allergic rhinitis result from a similar inflammatory process induced by allergens in the upper as well as in the lower airways of sensitised subjects. The nose and lung should therefore be seen as a continuum rather than as 2 distinct compartments, as proposed by the “united airways” concept. In keeping with this concept, it has been shown that challenging the nose with relevant allergens may induce bronchial inflammation [9].

Cysteinyl leukotrienes (CysLTs) play an important role in asthma. They are known as potent bronchoconstrictors [10] and are implicated in plasma exudation, mucus secretion, and eosinophil recruitment, all of which are well characterised in asthma.

The CysLTs exert their bronchoconstrictive and pro-inflammatory effects through activation of the CysLT₁-receptor (CysLT₁-R). This receptor is blocked by antagonists of CysLT₁-R (e.g. montelukast). CysLT₁-R antagonists seem to play a role in the relief of allergic rhinitis symptoms [11]. CysLT₁-R antagonists have been shown to reduce allergic rhinitis and asthma symptoms [12], [13], [14]. Following allergen challenge, compared with placebo, CysLT₁-R antagonists attenuate the allergen-induced early and late responses [15], [16], and decrease the eosinophil count and eosinophil progenitors at 24 h post-challenge [17], [18], [19]. Moreover, montelukast has significant inhibitory effects on airway structural cells influx into the airways following allergen challenge [20].

Induced sputum (IS) analysis is a standardized and reproducible method to non-invasively assess lower airway inflammation [21], [22], [23]. Inflammatory cell changes may be documented and supernatants may be used to measure various inflammatory mediators. It can be repeated frequently, making it possible to study the dynamics of airway inflammatory responses. CysLT₁-R expression increases in sputum cells in subjects with occupational asthma following exposure to isocyanates [24]. To our knowledge, the expression of CysLT₁-R has never been evaluated in sputum following allergen challenge.

As allergic rhinitis appears to be a predisposing factor in the development of asthma and as CysLT-receptors seem to be implicated in the first steps of asthma manifestations, it is of interest to look at the possible role of the CysLT₁-R in the transition from allergic rhinitis to asthma.

This exploratory study therefore aimed at assessing the expression of the CysLT₁-R (mRNA) in induced sputum of mild asthmatic subjects compared with non-asthmatic subjects with allergic rhinitis, at baseline and following different allergen provocations. We hypothesized that the expression of the CysLT₁-R in sputum would differ between both groups, at baseline and following the allergen challenges, asthmatic patients possibly demonstrating an increased expression compared to non-asthmatic rhinitic patients.