Purinergic P2X7 receptor antagonist ameliorates intestinal inflammation in postoperative ileus

Abstract Postoperative ileus (POI) is gastrointestinal motility dysfunction after abdominal surgery caused by mechanical stress to intestine. It occurs nausea and vomiting, and lead to lower QOL during hospitalization for patients. It is regarded as a problem because it costs medical expenses due to long hospitalization. The intestinal inflammation caused by macrophage and neutrophil is thought to be important of the mechanism of POI. In tissue injury or inflammation, adenosine triphosphate (ATP) is released from injured cell. Purinergic P2X7 receptor (P2X7R) is expressed on inflammatory cells and ATP induces the secretion of inflammatory mediators through P2X7R. P2X7R antagonist is thought to be important in the first step of inflammation, and it is confirmed that P2X7R antagonist showed anti-inflammatory effects in chemically-induced colitis models. Therefore, we hypothesized that P2X7R has important function in POI and examined the effect of P2X7R antagonist in mouse POI model. As a result, P2X7R antagonist A438079 ameliorated macrophage and neutrophil infiltration in POI. The impairment of intestinal transit was improved by P2X7R antagonist. It tended to ameliorate the increase of IL-6, IL-1β and TNF-α mRNA expression in intestinal muscularis caused by POI. P2X7R expressed on both infiltrated and resident macrophages in the inflamed ileal muscle layer. In conclusion, P2X7R antagonist showed the anti-inflammatory effect through P2X7R on macrophages, and it may be the target to treat POI.