Rosemary Sugar

Camostat attenuates airway epithelial sodium channel function in vivo through the inhibition of a channel-activating protease

Inhibition of airway epithelial sodium channel (ENaC) function enhances mucociliary clearance (MCC). ENaC is positively regulated by channel-activating proteases (CAPs), and CAP inhibitors are therefore predicted to be beneficial in diseases associated with impaired MCC. The aims of the present study were to 1) identify low-molecular-weight inhibitors of airway CAPs and 2) to establish whether such CAP inhibitors would translate into a negative regulation of ENaC function in vivo, with a consequent enhancement of MCC. To this end, camostat, a trypsin-like protease inhibitor, provided a potent (IC50 ∼50 nM) and prolonged attenuation of ENaC function in human airway epithelial cell models that was reversible upon the addition of excess trypsin. In primary human bronchial epithelial cells, a potency order of placental bikunin > camostat > 4-guanidinobenzoic acid 4-carboxymethyl-phenyl ester > aprotinin >> soybean trypsin inhibitor = α1-antitrypsin, was largely consistent with that observed for inhibition of prostasin, a molecular candidate for the airway CAP. In vivo, topical airway administration of camostat induced a potent and prolonged attenuation of ENaC activity in the guinea pig trachea (ED50 = 3 μg/kg). When administered by aerosol inhalation in conscious sheep, camostat enhanced MCC out to at least 5 h after inhaled dosing. In summary, camostat attenuates ENaC function and enhances MCC, providing an opportunity for this approach toward the negative regulation of ENaC function to be tested therapeutically.

Capsaicin-induced mucus secretion in rat airways assessed in vivo and non-invasively by magnetic resonance imaging

An up‐regulation of the sensory neural pathways in the lung has been implicated in asthma and chronic obstructive pulmonary disease (COPD) and is thought to contribute to mucus hypersecretion, an essential feature of both diseases. The aim of this study was to assess non‐invasively the acute effects (up to 60 min) of sensory nerve stimulation by capsaicin in the lung, using magnetic resonance imaging (MRI).

Mucociliary clearance is enhanced in rat models of cigarette smoke and lipopolysaccharide-induced lung disease.

In this study, the authors describe a new technique enabling the rapid assessment of mucociliary clearance (MCC) in rats and characterize this aspect of innate host defense in 2 animal models of bronchitis. Following instillation into the airways, fluorescent microspheres were rapidly cleared over 24 hours, with 60% to 80% of clearance occurring within 4 hours. On a background of airway neutrophilia and mucus hypersecretion, induced by either lipopolysaccharide or cigarette smoke, MCC was significantly enhanced. This reserve capacity in the MCC system will need to become overwhelmed in order to model the clinically observed impairment of lung mucus clearance in an animal system.

The guinea-pig tracheal potential difference as an in vivo model for the study of epithelial sodium channel function in the airways

The epithelial sodium channel (ENaC) is a key regulator of airway mucosal hydration and mucus clearance. Negative regulation of airway ENaC function is predicted to be of clinical benefit in the cystic fibrosis lung. The aim of this study was to develop a small animal model to enable the direct assessment of airway ENaC function in vivo.

NVP‐QBE170: an inhaled blocker of the epithelial sodium channel with a reduced potential to induce hyperkalaemia

Inhaled amiloride, a blocker of the epithelial sodium channel (ENaC), enhances mucociliary clearance (MCC) in cystic fibrosis (CF) patients. However, the dose of amiloride is limited by the mechanism‐based side effect of hyperkalaemia resulting from renal ENaC blockade. Inhaled ENaC blockers with a reduced potential to induce hyperkalaemia provide a therapeutic strategy to improve mucosal hydration and MCC in the lungs of CF patients. The present study describes the preclinical profile of a novel ENaC blocker, NVP‐QBE170, designed for inhaled delivery, with a reduced potential to induce hyperkalaemia.