Effect of inhaled fluticasone on bronchial responsiveness to neurokinin A in asthma

Abstract

Neurokinin (NK) A causes airway narrowing in patients with asthma through direct and indirect mechanisms. The effects of the inhaled glucocorticosteroid fluticasone propionate (FP) on the bronchial responsiveness to NKA and methacholine were studied.Patients (n=11) with mild asthma participated in a randomized, double-blind, placebo-controlled crossover trial. FP (500 mg b.i.d) or matched placebo was administered via Diskhaler TM for 14 days. Bronchial challenges were performed on days 1 and 13 (methacholine) and 0 and 14 (NKA) for each treatment period.At the active treatment period, the mean log2 provocative concentration causing a 20% fall in the forced expiratory volume in one second (PC20) ¡ SEM for NKA was -12.72 ¡ 0.63 at the beginning and -9.77 ¡ 0.49 at the end of the period (pv0.0001), while under placebo, it was -12. 16¡0.82 and -12.19¡0.51 respectively (NS). At the active treatment period, the mean log2 PC20 for methacholine was -5.25¡0.40 at the beginning and -4.22¡0.31 at the end of the period (p=0.012), while under placebo, it was -5.47¡0.47 and -5.24¡0.42 respectively (NS). The reduction in response to NKA was significantly larger than that for methacholine.A 2-week course of an inhaled steroid reduces bronchial responsiveness to neurokinin A, an effect more pronounced than the reduction in bronchial responsiveness to methacholine.

Dual tachykinin NK1/NK2 antagonist DNK333 inhibits neurokinin A-induced bronchoconstriction in asthma patients

“…This correlates with the demonstration by immune histochemistry of the presence of both tachykinin NK 1 and NK 2 receptors at the level of airway smooth muscle [14]. Moreover, an important part of the bronchoconstrictor effect of inhaled neurokinin A is indirect and probably mediated by tachykinin NK 1 receptors located on inflammatory and/or neuronal cells [23,24]. So, based on the available evidence, it is to be expected that a dual tachykinin NK 1 /NK 2 tachykinin receptor antagonist offers a better protection against neurokinin A-induced bronchoconstriction than a tachykinin NK 2 receptor antagonist.…”

The role of substance P in inflammatory disease

“…Experiments in rat pancreatic acinar cells and human IM‐9 lymphoblasts indicate a decrease in NK‐1R mRNA after glucocorticoid treatment and NK‐1R mRNA is reduced in asthmatic lung specimens after incubation with dexamethasone (Ihara and Nakanishi, 1990; Gerard et al, 1991; Adcock et al, 1993a). Recent studies have shown that inhaled steroid reduces bronchial responsiveness to tachykinins in patients with asthma (Van Schoor et al, 2002).…”

Adenosine Receptors and Asthma

“…A number of clinical features distinguish asthmatic subjects from other respiratory diseases and may be considered characteristic of this phenotype (Avital et al 1995). These include an exacerbation of disease following exposure to beta-adrenoceptor antagonists (Bond et al 2007), an impairment in the ability to bronchodilate following deep inspiration (Slats et al 2007), and their bronchoconstrictor sensitivity to a wide range of innocuous stimuli (Cockcroft and Davis 2006; Van Schoor et al 2002). Various mechanisms have been proposed to account for this bronchial hyperresponsiveness (BHR) phenomenon, and these include increased airway smooth muscle function (An et al 2007; Gil and Lauzon 2007), altered airway epithelial cell function (Holgate 2007), and the recruitment and activation of numerous inflammatory cells, including dendritic cells, T lymphocytes and eosinophils (Beier et al 2007; Hammad and Lambrecht 2007; Jacobsen et al 2007; Kallinich et al 2007; Lloyd and Robinson 2007; Rosenberg et al 2007), whose cell-derived products trigger a cascade of events within the lung that lead to airway epithelial cell damage, increased bronchial smooth muscle contractility and airway remodeling.…”