Barriolides: Non-antibacterial compounds with epithelial barrier enhancing properties and anti-inflammatory effects in vitro

Abstract

OBJECTIVE:
the macrolide antibiotic azithromycin (Azm) is well known for its antibacterial properties. On long term treatment, Azm mitigates non-infectious chronic airway diseases (CAD) like COPD but promotes macrolide resistant microorganisms. Our research on Azm led to the development of several 15-membered macrolides lacking antibacterial activity but augmenting epithelial integrity in vitro.

METHODS:
our compounds, known as “barriolides”, have been studied in several in vitro systems for their effects on bronchial epithelium. Using air-liquid interface cultures of several lung epithelial cell lines, we have shown that barriolides promote transepithelial electrical resistance and decreased permeability, similar to Azm.

RESULTS:
we have observed alterations by barriolides to intracellular lipid metabolism, enhanced expression of cell junction proteins, and altered gene regulation of several ontology groups including water loss and oxidative stress. Although several barriolides have overlapping effects, their gene signature in cells is unique to each. High magnification of the cells indicated an increase in multivesicular- and lamellar bodies, supporting the involvement of lipid metabolism. Anti-inflammatory potential was examined using isolated human macrophages and neutrophils. While there were some similarities to Azm, our lead compound displayed slight differences in its regulation of M1 macrophage polarisation. In neutrophils,
both native and stimulated, our lead compound reduced ROS and LL-37 release indicating its effects on tissue-damaging mediators.

CONCLUSIONS:
these data give support to the potential for barriolides to enhance respiratory epithelial barrier integrity, possibly via lipid metabolism, and to modulate inflammatory responses.