HIV protease inhibitors induce endoplasmic reticulum stress and disrupt barrier integrity in intestinal epithelial cells.

The integrity of the intestinal epithelial barrier plays a crucial role in maintaining symbiotic homeostasis between microbes in the gut lumen and eukaryotic cells. Disruption of intestinal epithelial barrier function occurs commonly under various pathological conditions, including trauma, inflammatory bowel disease, and drug-induced gastrointestinal toxicity, exhibiting increased intestinal epithelial paracellular permeability or "leakiness" of the intestinal mucosa. Endoplasmic reticulum (ER) stress has recently been linked to various pathological conditions, including intestinal inflammation. Our previous studies have shown that HIV protease inhibitors (PIs) induce ER stress and activate the unfolded protein response (UPR) in different types of cells, and HIV PI-induced UPR activation contributes to the disruption of barrier function in intestinal epithelial cells and the increase of intestinal permeability. This chapter will discuss the commonly used methods for analysis of ER stress activation and epithelial barrier function. Both in vitro cell culture models and in vivo animal models are useful tools to examine general drug-induced ER stress and intestinal barrier dysfunction.