A new role for an old drug: Ambroxol triggers lysosomal exocytosis via pH-dependent Ca²⁺ release from acidic Ca²⁺ stores

Cell Calcium. 2015 Dec;58(6):628-37. doi: 10.1016/j.ceca.2015.10.002. Epub 2015 Oct 27.

Abstract

Ambroxol (Ax) is a frequently prescribed drug used to facilitate mucociliary clearance, but its mode of action is yet poorly understood. Here we show by X-ray spectroscopy that Ax accumulates in lamellar bodies (LBs), the surfactant storing, secretory lysosomes of type II pneumocytes. Using lyso- and acidotropic substances in combination with fluorescence imaging we confirm that these vesicles belong to the class of acidic Ca(2+) stores. Ax lead to a significant neutralization of LB pH, followed by intracellular Ca(2+) release, and to a dose-dependent surfactant exocytosis. Ax-induced Ca(2+) release was significantly reduced and slowed down by pretreatment of the cells with bafilomycin A1 (Baf A1), an inhibitor of the vesicular H(+) ATPase. These results could be nearly reproduced with NH3/NH4(+). The findings suggest that Ax accumulates within LBs and severely affects their H(+) and Ca(2+) homeostasis. This is further supported by an Ax-induced change of nanostructural assembly of surfactant layers. We conclude that Ax profoundly affects LBs presumably by disordering lipid bilayers and by acting as a weak base. The pH change triggers - at least in part - Ca(2+) release from stores and secretion of surfactant from type II cells. This novel mechanism of Ax as a lysosomal secretagogue may also play a role for its recently discussed use for lysosomal storage and other degenerative diseases.

Keywords: Alzheimer's disease; Autophagy; Host defense; Inflammation; Lysosomal storage disease; Mucus; Neurodegeneration; Parkinson's disease; Secretory lysosome.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alveolar Epithelial Cells
  • Ambroxol / pharmacology*
  • Animals
  • Calcium / metabolism*
  • Cell Separation / methods
  • Exocytosis / drug effects*
  • Exocytosis / physiology
  • Hydrogen-Ion Concentration
  • Lysosomes / drug effects*
  • Rats, Sprague-Dawley
  • Secretory Vesicles / drug effects*

Substances

  • Ambroxol
  • Calcium