Echinocandins Accelerate Particle Transport Velocity in the Murine Tracheal Epithelium: Dependency on Intracellular Ca2+ Stores

Abstract

The mucociliary clearance of lower airways is modulated by different physiologic stimuli and also by pathophysiologic agents like polluting substances or pharmaceutical molecules. In the present investigation, we measured the particle transport velocity (PTV) of mouse tracheae as a surrogate for mucociliary clearance. In mouse tracheal preparations, we detected a sustained increase in the PTV under the application of the echinocandins caspofungin, anidulafungin, and micafungin. In further experiments, we observed the effects of echinocandins on the PTV were dependent on intracellular Ca²⁺ homeostasis. In Ca²⁺-free buffer solutions, the amplitude of the echinocandin-evoked rise in the PTV was significantly reduced relative to that in the experiments in Ca²⁺-containing solutions. Depletion of intracellular Ca²⁺ stores of the endoplasmic reticulum (ER) by caffeine completely prevented an increase in the PTV with subsequent caspofungin applications. Mitochondrial Ca²⁺ stores seemed to be unaffected by echinocandin treatment. We also observed no altered generation of reactive oxygen species under the application of echinocandins as probable mediators of the PTV. Consequently, the observed echinocandin effects on the PTV depend upon the Ca²⁺ influx and Ca²⁺ contents of the ER. We assume that all three echinocandins act intracellularly on ER Ca²⁺ stores to activate Ca²⁺-dependent signal transduction cascades, enhancing the PTV.

Keywords: antifungal agents; echinocandins; intracellular calcium; mucociliary clearance; particle transport velocity.