Impact of PAR2 on Tight Junctions and Esophageal Mucosal Inflammation in Rats with Gastroesophageal Reflux Disease

Gastric content reflux activates protease-activated receptor 2 (PAR2), which is a critical step in the pathophysiological mechanisms underlying gastroesophageal reflux disease (GERD). Claudins serve as the primary constituents of tight junctions (TJs). They are in charge of the barrier and polarity of epithelial cells, and the disruption of their function can lead to chronic inflammation. The present research is designed to investigate whether PAR2 influences TJs in the development of GERD.

GERD models were established both in vivo and in vitro. Rabeprazole and/or GB-88 (a PAR2 inhibitor) were administered. The expression of PAR2, Claudin-1, and Claudin-4, M1 macrophages, transepithelial electrical resistance (TEER), Interleukin-8 (IL-8), and Interleukin-1β (IL-1β) were measured. Furthermore, cells were treated with SLIGKV-NH2 (a PAR2 agonist) and GB-88 to verify the impact of PAR2 on TJs.

Rabeprazole improved pathological changes, decreased the concentration of IL-8 and IL-1β, and inhibited the accumulation of M1 macrophages in GERD rats. Rabeprazole inhibited the expression of PAR2 and enhanced Claudin-1 and Claudin-4 in vivo. GB-88 declined PAR2 and the concentration of IL-8 and IL-1β, and increased Claudin-1, Claudin-4, and TEER in vitro. The combination of GB-88 and rabeprazole was more effective in restoring Claudin-4.

In GERD, elevated PAR2 expression impaired esophageal mucosal barrier function by downregulating and inducing the redistribution of Claudin-1 and Claudin-4, while promoting M1 macrophage-mediated secretion of IL-8 and IL-1β.