Expression of SLC26A9 in Airways and Its Potential Role in Asthma

SLC26A9 is an epithelial anion transporter with a poorly defined function in airways. It is assumed to contribute to airway chloride secretion and airway surface hydration. However, immunohistochemistry showing precise localization of SLC26A9 in airways is missing. Some studies report localization near tight junctions, which is difficult to reconcile with a chloride secretory function of SLC26A9. We therefore performed immunocytochemistry of SLC26A9 in sections of human and porcine lungs. Obvious apical localization of SLC26A9 was detected in human and porcine superficial airway epithelia, whereas submucosal glands did not express SLC26A9. The anion transporter was located exclusively in ciliated epithelial cells. Highly differentiated BCi-NS1 human airway epithelial cells grown on permeable supports also expressed SLC26A9 in the apical membrane of ciliated epithelial cells. BCi-NS1 cells expressed the major Cl⁻ transporting proteins CFTR, TMEM16A and SLC26A9 in about equal proportions and produced short-circuit currents activated by increases in intracellular cAMP or Ca²⁺. Both CFTR and SLC26A9 contribute to basal chloride currents in non-stimulated BCi-NS1 airway epithelia, with CFTR being the dominating Cl⁻ conductance. In wtCFTR-expressing CFBE human airway epithelial cells, SLC26A9 was partially located in the plasma membrane, whereas CFBE cells expressing F508del-CFTR showed exclusive cytosolic localization of SLC26A9. Membrane localization of SLC26A9 and basal chloride currents were augmented by interleukin 13 in wild-type CFTR-expressing cells, but not in cells expressing the most common disease-causing mutant F508del-CFTR. The data suggest an upregulation of SLC26A9-dependent chloride secretion in asthma, but not in the presence of F508del-CFTR.     

Airway Delivery of Hydrogel-Encapsulated Niclosamide for the Treatment of Inflammatory Airway Disease

Repurposing of the anthelminthic drug niclosamide was proposed as an effective treatment for inflammatory airway diseases such as asthma, cystic fibrosis, and chronic obstructive pulmonary disease. Niclosamide may also be effective for the treatment of viral respiratory infections, such as SARS-CoV-2, respiratory syncytial virus, and influenza. While systemic application of niclosamide may lead to unwanted side effects, local administration via aerosol may circumvent these problems, particularly when the drug is encapsulated into small polyethylene glycol (PEG) hydrospheres. In the present study, we examined whether PEG-encapsulated niclosamide inhibits the production of mucus and affects the pro-inflammatory mediator CLCA1 in mouse airways in vivo, while effects on mucociliary clearance were assessed in excised mouse tracheas. The potential of encapsulated niclosamide to inhibit TMEM16A whole-cell Cl⁻ currents and intracellular Ca²⁺ signalling was assessed in airway epithelial cells in vitro. We achieved encapsulation of niclosamide in PEG-microspheres and PEG-nanospheres (Niclo-spheres). When applied to asthmatic mice via intratracheal instillation, Niclo-spheres strongly attenuated overproduction of mucus, inhibited secretion of the major proinflammatory mediator CLCA1, and improved mucociliary clearance in tracheas ex vivo. These effects were comparable for niclosamide encapsulated in PEG-nanospheres and PEG-microspheres. Niclo-spheres inhibited the Ca²⁺ activated Cl⁻ channel TMEM16A and attenuated mucus production in CFBE and Calu-3 human airway epithelial cells. Both inhibitory effects were explained by a pronounced inhibition of intracellular Ca²⁺ signals. The data indicate that poorly dissolvable compounds such as niclosamide can be encapsulated in PEG-microspheres/nanospheres and deposited locally on the airway epithelium as encapsulated drugs, which may be advantageous over systemic application.     

Interfacial interactions and properties of filled polymers. II: Dispersion of filler particles

The specific interaction characteristics and the inherent agglomeration of variously surface coated rutile pigments have been assessed, respectively, by inverse gas chromatographic and powder rheological methods. Standardized methods were used to disperse the pigments in polyethylene and chlorinated polyethylene. Measurements were made of energy requirements for dispersion and of the quality of dispersion attained. It was found that in the non-polar polyethylene matrix, dispersion processes depended on the strength of pigment agglomerates, but not on the specific interaction potential of the solids. Conversely, in the acidic chlorinated polyethylene, acid/base interactions influenced dispersion but the process was independent of inherent pigment agglomeration.     

Mica as filler for PVC compounds: Effects of particle size and surface treatment

In this study, natural, delaminated and silane-treated micas were screened to give fractions passing 60 to 325 screen mesh sizes. The micas were used as fillers (to 80 wt. percent) in plasticized PVC compounds, their dispersion behavior and their effects on mechanical properties of compounds being noted, and compared with the performance of similarly compounded PVC with CaCO₃ fillers. The fusion and dispersion performance of these solids was contrasted strongly. While fusion time and maximum torque in Brabender mixing responded only weakly to the presence of CaCO₃, in the presence of ?40 wt. percent mica both of these parameters increased sharply. The elastic modulus of filled compounds indicated little reinforcement by CaCO₃, while mica raised the modulus as much as 150 percent, suggesting significant bonding at the filler-matrix interface. This bonding appeared unable to withstand shear strain, elongations at rupture of mica-filled compounds falling catastrophically when compared with CaCO₃-filled controls. The tested micas appear of questionable value as substitutes for inexpensive commodity fillers. As expected, at given loading, finer-particle micas gave increased values of the elastic modulus, but particle size did not strongly affect ultimate mechanical properties. Torque maxima and equilibria in mixing correlated well with particle size. Silane-treated micas produced compounds with properties only mildly different from those using untreated versions. Thus, in PVC (and possibly in other chloride-group containing polymers) interfacial conditions seem only mildly influenced by conventional coupling technology.