Abstract
BackgroundGlucocorticoids have been proven to be effective in the therapy of recurrent airway obstruction (RAO) in horses via systemic as well as local (inhalative) administration. Elective analysis of the effects of this drug on bronchoconstriction in viable lung tissue offers an insight into the mechanism of action of the inflammatory cascade occurring during RAO which is still unclear. The mechanism of action of steroids in treatment of RAO is thought to be induced through classical genomic pathways. We aimed at electively studying the effects of the glucocorticoid beclomethasone dipropionate on equine precision-cut lung slices (PCLS).PCLS were used to analyze ex-vivo effects of beclomethasone on inhibiting bronchoconstriction in the horse. The inhibiting effect was measured through instillation of a known mediator of inflammation and bronchoconstriction, leukotriene C4. For this, the accessory lobes of 13 horses subjected to euthanasia for reasons unrelated to the respiratory apparatus were used to obtain viable lung slices.ResultsAfter 30 minutes of PCLS incubation, beclomethasone showed to significantly inhibit the contraction of the bronchioles after instillation with leukotriene C4. The EC50 values of the two contraction curves (LTC4 with and without BDP) differed significantly from each other (p = 0.002). The possibility of a non-genomic rapid mechanism of action seems likely since transcriptional activities require a longer lag period.ConclusionsIn human neuroendocrinology, high levels of glucocorticoids have been proven to function via a non-genomic mechanism of membrane receptors. The concentration of beclomethasone used on the lung slices in our study can be considered as high. This allows speculation about similar rapid non-genomic mechanisms of high-dosage inhaled glucocorticoids in the lower airways of horses. However, further assessment on a molecular basis is needed to confirm this.
Highlights
Glucocorticoids have been proven to be effective in the therapy of recurrent airway obstruction (RAO) in horses via systemic as well as local administration
Beclomethasone dipropionate (BDP) is a widely administered inhaled corticosteroid in equine practice [7,8], in vivo studies have shown that the marked improvement of clinical signs of airway obstruction after administration of low-dose inhaled beclomethasone was not accompanied by a decrease in airway inflammatory cells or a suppression of transcription factors NF-kB and AP-1 DNA-binding activity [9]
After exposure to LTC4, the precision-cut lung slices (PCLS) treated with BDP for 30 minutes showed less contraction than the untreated slices
Summary
Glucocorticoids have been proven to be effective in the therapy of recurrent airway obstruction (RAO) in horses via systemic as well as local (inhalative) administration. Synthetic glucocorticoids are recognized to be effective in the treatment of RAO in horses and have been widely used via various routes of administration in the past 15 years Their beneficial effects are thought to be mainly achieved through their potent anti-inflammatory properties. They inactivate NF-kB, blocking transcription of genes coding for pro-inflammatory cytokines, up-regulate and increase the sensitivity of β2-adrenoceptors and reduce production of pro-inflammatory eicosanoids [1] Their mechanism of action is mainly genomic with lag periods ranging from at least four to several hours or even days the manifest action of drug-induced response takes place [2,3,4]. Beclomethasone dipropionate (BDP) is a widely administered inhaled corticosteroid in equine practice [7,8], in vivo studies have shown that the marked improvement of clinical signs of airway obstruction after administration of low-dose inhaled beclomethasone was not accompanied by a decrease in airway inflammatory cells or a suppression of transcription factors NF-kB and AP-1 DNA-binding activity [9]
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