The deposition of lanthanum carbonate may activate macrophages to induce gastrointestinal mucosal injury in patients with chronic kidney disease: an in vitro caco-2/THP-1 macrophage coculture model study

Abstract

The aim of this study was to investigate the effect and possible underlying mechanism of La₂(CO₃)₃ deposition on GI mucosal inflammation. Our results showed that La₂(CO₃)₃ can dissolve in artificial gastric fluids and form lanthanum phosphate (LaPO₄) precipitates with an average size of about 1 μm. To mimic the intestinal mucosa and epithelial barrier, we established a Caco-2/THP-1 macrophage coculture model and a Caco-2 monoculture model, respectively. Our findings demonstrated that the medium of THP-1 macrophages stimulated by LaPO₄ particles can damage the Caco-2 monolayer integrity in the coculture model, while the particles themselves had no direct impact on the Caco-2 monolayer integrity in the monoculture model. We measured values of trans-epithelial electrical resistance and detected images using a laser scanning confocal microscope. These results indicate that continuous stimulation of LaPO₄ particles on macrophages can lead to a disruption of intestinal epithelium integrity. In addition, LaPO₄ particles could stimulate THP-1 macrophages to secrete both IL-1β and IL-8. Although LaPO₄ particles can also promote Caco-2 cells to secrete IL-8, the secretion was much lower than that produced by THP-1 macrophages. In summary, the deposition of La₂(CO₃)₃ has been shown to activate macrophages and induce damage to intestinal epithelial cells, which may exacerbate inflammation in patients with chronic kidney disease. Therefore, patients taking lanthanum carbonate, especially those with gastrointestinal mucosal inflammation, should be mindful of the potential for drug deposition in the GI system.

Graphical abstract

A schematic diagram of the effect and possible underlying mechanism of the deposition of La₂(CO₃)₃ on GI mucosal inflammation.