Tulobuterol patch alleviates allergic asthmic inflammation by blockade of Syk

Background: Tulobuterol patch, one of strongest bronchodilators, was recently shown to improve bronchial hyperresponsiveness and significantly decrease the sputum eosinophil counts by combining with nonspecific anti-inflammatory drugs on patients with asthma. However, there is limited study on the anti-inflammatory activities of tulobuterol patch and its potential machenism.
Results: The tulobuterol patch significantly ameliorated inflammatory cell infiltration in the lung tissue, reduced the number of total leukocytes and its differential count, markedly reduced the production of IL-1β, TNF-α, IL-6, CCL-11 and IL-4 in bronchial alveolar lavage fluid, as well as a reduction in IL-4/IFN-γ ratio. Tulobuterol patch exhibited the best effect on allergic inflammation compared with formoterol and salbutamol. Furthermore, tulobuterol patch treatment significantly suppressed the expression and activation of Syk and its downdream signaling NF-κB and p-NF-κB.Tulobuterol
Conclusions: The present studies revealed that tulobuterol patch effectively ameliorated airway inflammatory responses in allergic asthma, and its mechanisms, at least partially, via down-regulating Syk/NF-κB pathway.
Methods: An ovalbumin induced allergic asthma mouse model were used, and the effects of tulobuterol patch on allergic airway inflammation were evaluated. Also, its anti-airway inflammatory potential was compared with two other β2-agonists, salbutamol and formoterol. Its possible anti-inflammatory mechanisms were identified by using western blotting and immunohistochemistry.
INTRODUCTION

Allergic asthma is a heterogeneous inflammatory lung disease affecting millions of people worldwide and with a steadily increasing incidence [1]. Asthma treatments are predominantly the combination of nonspecific anti-inflammatory drugs (inhaled corticosteroids, ICS) and bronchodilators (β2-agonists), which work in most patients [2]. However, the use of ICS has been associated with growth impairment in children and other systemic adverse effects, such as an increased risk of pneumonia, hyperglycemia, hypertension, osteopenia to patients with large dosages and/or long-term treatment [3, 4]. This leads to poor adherence to ICS and increases the risk of asthma exacerbations. These pitfalls call for some alternative or auxiliary anti-asthma drugs with no or lower toxicity [4], especially for children.
Tulobuterol is a short-acting selective β2-agonist. The tulobuterol patch containing molecular and crystallized forms of tulobuterol provides a favorable pharmacokinetic profile and avoids adverse drug reactions, which make it a useful long-acting β2-agonist with good adherence [5–7]. Recently, some β2-agonists are shown to attenuate the proinflammatory activities of a range of immune and inflammatory cells in vitro, such as neutrophils, monocytes, mast cells, eosinophils, basophils, and lymphocytes, all of which contribute to the pathogenesis of various acute and chronic respiratory diseases [8]. Recent clinical studies also showed that tulobuterol patch as an add-on medication decreased the sputum eosinophil count more significantly compared with ICS or leukotriene receptor antagonist treated alone on patients with asthma [5, 6]. However, the anti-inflammatory activities of tulobuterol patch and its potential machenism is of considerable potential value in the pharmacotherapy of allergic asthma with limited study.
In allergic asthma, airway inflammation is characterized as a T helper (Th) 2 lymphoyte immune response to allergens, by hyper-production of allergen-specific IgE, which binds to high-affinity IgE receptor (FcϵRI) of mast cells and eosinophils, followed by degranulation and release of multiple cytokines [9]. The spleen tyrosine kinase (Syk) plays a critical role in FcεRI-dependent inflammation in inflammatory cells, and triggers a complex series of signaling pathways, including the activation of the nuclear factor-κB (NF-κB), producing a vast array of inflammatory mediators [10, 11]. Considering that syk is involved in the proximal part of signalling pathways initiated by allergen-mediated activation of immunoreceptors on inflammatory cells [12], it may represent an attractive target for new therapeutics.
Therefore, in this study, we investigated the potential value of tulobuterol patch in the pharmacotherapy of allergic airway inflammation by using an ovalbumins (OVA)-induced allergic airway inflammation mouse model, and identified its possible anti-inflammatory mechanism by down-regulating of syk and NF-κB.