Nowadays, there is increasing interest in assessing the role that the mucosal barrier plays in human health as it is the primary defense against pathogens, providing a critical transition between the external environment and the internal human body [1, 19].
In the case of respiratory diseases such as rhinitis, understanding the regulation of airway epithelial barrier function is opening potential new therapeutic targets [1, 5, 6]. Allergic rhinitis is a very common disorder that is frequently ignored, underdiagnosed, misdiagnosed, and mistreated. Undertreated allergic rhinitis underlies many complications, exacerbates asthma and is a major factor in asthma development, affecting quality of life and productivity at work or school [9, 20].
Management of rhinitis involves diagnosis, followed by avoidance of relevant allergens, with additional pharmacotherapy needed for most sufferers. According to severity, saline sprays non-sedating antihistamines (oral or topical, with minimally bioavailable intranasal corticosteroids for moderate/severe disease), possibly plus additional antihistamines or antileukotrienes can be used. The concept of rhinitis control is emerging, but there is no universally accepted definition. Where pharmacotherapy fails, allergen-specific immunotherapy, which is uniquely able to alter long-term disease outcomes, should be considered .
In this context, there is an increasing interest in the use of non-pharmacological measures to avoid allergens and other triggering factors as an integral part of the management strategy (as recommended by the ARIA guidelines) [5, 7, 8] and also to avoid the secondary effects of chronic pharmacological measures; thereby reducing the use of intranasal glucocorticosteroids and antihistamines [5, 8, 9, 21]. Although they have been established as the first-line therapies in allergic rhinitis, there is also an ongoing debate regarding their potential side effects on the nasal structure and ciliary function .
In this study, we have assessed the effects of the non-pharmacological spray Rhinosectan®, which contains xyloglucan, on a MucilAir™ nasal epithelial cell culture model. We have demonstrated that Rhinosectan® does not interfere with normal nasal functioning, for example, in cilia beating frequency, while providing favorable effects such as reducing mucin secretion, improving mucociliary clearance and facilitating the phagocytic activity of nasal epithelial cells.
We did not detect alterations in the cilia beating frequency after exposure to Rhinosectan®. Cilia beat frequency is one of the basic functional parameters quantifying mucociliary activity and an important defense mechanism of the respiratory tract. For this reason, investigation of the influence of drugs on this parameter is of great importance in evaluating the tolerability and safety of nasally administered agents and preservatives, present in intranasal preparations employed in the management of nasal diseases .
Since impairment of ciliary movement is frequently associated with respiratory diseases such as rhinitis, sinusitis, bronchitis and otitis media , a prerequisite for products used in the management of rhinitis, sinusitis and related allergic or chronic conditions is that agents in the formulation do not interfere with normal nasal functioning .
These results are in contrast with studies showing interference of the ciliary movement in presence of nasal pharmacological agents: undiluted aqueous budesonide has shown to cause rapid but reversible ciliostasis , while undiluted or 50% dilution of fluticasone propionate and azelastine induced an irreversible ciliostatic effect [16, 23]. In our study, xyloglucan and the rest of components in the formulation of Rhinosectan® and saline solution (the mainstay of the therapeutic armamentarium for patients with upper airway infections) did not alter the ciliary movement in the MucilAir™Nasal model at the time points evaluated (15 and 60 min, post-exposure), although further in vitro studies should be performed to evaluate the effect of Rhinosectan® during the dosing interval (6–8 h).
Our results are also in line with a previous study performed with Rhinosectan® in MucilAir™Nasal cells, in which Rhinosectan® exhibited protective barrier properties, maintaining the location of tight junctions proteins and preserving the paracellular flux .
We also observed a significant increase in mucociliary clearance at 60 min post-exposure in comparison with saline solution. This increase was not observed at 15 min post-exposure, maybe due to the time required by xyloglucan to initiate the bioadhesion process on the mucous membranes (with mucin-like structure), owing to its high swelling capacity, which gives it its bio-protective film properties .
Mucociliary clearance removes inhaled and deposited particles, such as dust, allergens, bacteria and air pollutants, being essentially dependent upon the unidirectional beating of epithelial cilia and the rheological (visco-elastic) properties of mucus [16, 24]. Impairment of mucociliary clearance results in the accumulation of respiratory secretions and reduced defenses, leading to infections and inflammation . Mucociliary clearance thus functions as a biomarker of nasal mucosal function .
In the case of rhinosinusitis, mucociliary clearance has been shown to be impaired due to both decreased ciliary beat frequency and altered mucus rheology . Therefore, according to the results of this study, in the absence of ciliostasis, the improvement in mucociliary clearance together with the observed decrease in mucin concentration, suggests that Rhinosectan® has optimal properties for use in the management of these disorders. In the case, for example, of hypertonic saline solutions, improvement of mucociliary clearance has also been observed, although a certain degree of ciliostasis may occur as a result of hypertonicity .
We also observed a significant increase in the phagocytic capacity after Rhinosectan® exposure, at both 15 and 60 min post-treatment, suggesting a positive effect of the spray enhancing the ability of the epithelial cells to display their phagocytic function by efficiently trapping and removing inhaled particles and allergens.
Another important result of this study is the reduction in mucin secretion with the application of Rhinosectan® spray, particularly when undiluted. Excessive mucus or impaired clearance contributes to the pathogenesis of all the common airway diseases [27,28,29,30]. When mucin production is increased, so that mucins accumulate intracellularly, and secretion of a large number of granules is then triggered (mucus hypersecretion), airway luminal occlusion can occur [31,32,33]. Additionally, persistent accumulation can lead to infection and inflammation by providing an environment for microbial growth.
Thus, the effect of Rhinosectan® on mucin secretion might indicate a positive role in the regulation of the secretion, which is crucial for essential nasal functions although further studies are needed on this issue and taking into account that oligomeric mucins alone do not constitute mucus, and other mucin and non-mucin components must be important contributors to mucus organization and hence airways defense . This is also in agreement with the results of the recent randomized, double-blind clinical trial performed in patients with rhinosinusitis, in which the application of Rhinosectan® significantly improved main symptoms and reduced the severity of rhinosinusitis in comparison with a physiological saline nasal spray .
Therefore, these results suggest that application of Rhinosectan® contributes to the optimal rheological (visco-elastic) properties of mucus by enhancing mucociliary clearance, taking into account that the balance between mucin production and clearance depends on optimal mucin quantities, the hydration state and periciliary fluid depth . It is also important to note that stimulation of mucin secretion occurs with exposure to irritants and pro-inflammatory compounds and may lead to mucus obstruction of small airways and increased nasal resistance. It has been observed that products commonly used to relieve symptoms of chest congestion (containing products such as camphor, menthol and eucalyptus oil) can adversely affect mucociliary function, increasing mucin secretion and decreasing mucus clearance .
Although more aspects deserve further research, as further in vivo studies and clinical trials in patients with rhinitis during longer periods of time (for example during pollen seasons), the results of this study in the in vitro model of MucilAir™Nasal suggest that the application of Rhinosectan® does not impair ciliary movement, enhances mucociliary clearance and facilitates phagocytosis, while reducing mucin secretion, which are optimal properties for the management of rhinitis and associated conditions.