Galactomannan and Zymosan Block the Epinephrine-Induced Particle Transport in Tracheal Epithelium

Abstract

BackgroundCiliary beating by respiratory epithelial cells continuously purges pathogens from the lower airways. Here we investigated the effect of the fungal cell wall polysaccharides Galactomannan (GM) and Zymosan (Zym) on the adrenergic activated particle transport velocity (PTV) of tracheal epithelium.MethodsExperiments were performed using tracheae isolated from male C57BL/6J mice. Transport velocity of the cilia bearing epithelial cells was measured by analysing recorded image sequences. Generation of reactive oxygen species (ROS) were determined using Amplex Red reagents. PCR experiments were performed on isolated tracheal epithelium to identify adrenergic receptor mRNA.ResultsThe adrenergic receptors α1D, α2A, β1 and β2 have been identified in isolated tracheal epithelium. We found epinephrine responsible for an increase in PTV, which could only be reduced by selective β-receptor-inhibition. In addition, either GM or Zym prevented the epinephrine induced PTV increase. Furthermore, we observed a strong ROS generation evoked by GM or Zym. However, epinephrine induced increase in PTV recovered in the presence of GM and Zym after application of ROS scavengers.ConclusionBoth GM or Zym trigger reversible ROS generation in tracheal tissue leading to inhibition of the β-adrenergic increase in PTV.

A fixed 20:1 combination of cafedrine/theodrenaline increases cytosolic Ca2+ concentration in human tracheal epithelial cells via ryanodine receptor-mediated Ca2+ release

“…Although these effects were attributed to theodrenaline alone, we did not observe similar effects in human tracheal epithelial cells. These observations are in line with the data reported by Weiterer et al, who reported the exclusive presence of the α1D-adrenergic receptor subtype in murine tracheal epithelium 26 . However, murine particle transport velocity was independent from α-adrenergic receptor activation.…”

“…However, murine particle transport velocity was independent from α-adrenergic receptor activation. Therefore, we conclude that α-receptor activation might occur in human tracheal epithelial cells following the administration of cafedrine/theodrenaline, but no influence on [Ca 2+ ] i or mucociliary clearance could be detected in light of the available in-vitro data 26 . The theophylline component of cafedrine and theodrenaline is believed to inhibit PDE, which should lead to the persistence of second messengers, such as cGMP and cAMP, improving cardiac inotropy 14 .…”

Echinocandins Accelerate Particle Transport Velocity in the Murine Tracheal Epithelium: Dependency on Intracellular Ca 2+ Stores

“…The mucociliary clearing system is an important mechanism that functions to disburden the airway surface area of the lung from debris and pathogen particles ( 49 , 50 ). Besides bacterial and viral pathogens as well as the fungal cell wall, the polysaccharides galactomannan and zymosan can inhibit the PTV via reversible ROS generation in the tracheal tissue ( 51 ). Echinocandins are antifungal agents recommended for the empirical and specific treatment of invasive Candida and Aspergillosis infections and are widely used in clinical practice ( 52 , 53 ).…”

“…The effects of all three echinocandins appeared to be similar in a dose-dependent manner. Thus, we elucidated according to the signal pathway how echinocandins enhance the PTV; specifically, different signal pathways are described to alter the mouse tracheal PTV, including membrane-bound receptors, intracellular signal cascades, ROS generation, and intracellular Ca 2+ homeostasis ( 13 , 51 ). Subsequently, we used pharmacological inhibitors to identify the underlying mechanism of a caspofungin-induced increase of the PTV and whether membrane-bound receptors are involved in echinocandin-induced PTV.…”

A 20:1 synergetic mixture of cafedrine/theodrenaline accelerates particle transport velocity in murine tracheal epithelium via IP3 receptor-associated calcium release

“…Second, ciliary cells are sensitive to local temperature, acid-base balance, humidity, mechanical stress, cytokines released during infection, and paracrine effects mediated by adjacent cells, like mast cells and macrophages ( Sanderson and Dirksen, 1986 ; Kilgour et al, 2004 ; Sutto et al, 2004 ; Salathe, 2007 ; Weiterer et al, 2014 ; Perniss et al, 2020 ). Third, the formation of reactive oxygen species and pathogenic bacterial or fungal components mediates opposing effects and may lead to a reduction in CBF with consequent impaired mucociliary clearance ( Burman and Martin, 1986 ; Weiterer et al, 2015 ). Furthermore, congenital impairment of the coordination of mucociliary clearance can result in severe diseases, like primary cilia dyskinesia, where recurrent infections occur due to ineffective clearance ( Horani and Ferkol, 2021 ).…”