Blockade of purinergic receptors P2Y₁or P2Y₁₂prevents intestinal barrier damage and platelet sequestration in intra-abdominal sepsis in female mice

Intra-abdominal sepsis is a clinical syndrome with high mortality and no specific therapeutic options, in which a severe intestinal infection triggers a runaway immune response and disruption of the intestinal barrier. This then facilitates a feed-forward loop of inflammatory mediator release and intestinal epithelial damage. Preserving intestinal barrier integrity could break this cycle, restore balance in the immune system, and improve survival. Platelets, as key mediators of inflammation, contribute to sepsis by releasing cytokines and modulating immune responses. Our prior work demonstrated that blocking P2Y 1 or P2Y 12 receptors on platelets reduced cytokine secretion and enhanced bacterial clearance in a sex-dependent manner. However, the role of platelets in intestinal sepsis responses is unknown. This study addresses the underrepresentation of females in biomedical research by investigating sex-specific treatments for sepsis. Sepsis was induced in female C57BL/6J mice by cecal ligation and puncture (CLP) with sham surgery as control. Platelet secretion was inhibited using P2Y 1 (MRS2279, 10 mg/kg) or P2Y 12 (Ticagrelor, 30 mg/kg) antagonists administered intraperitoneally post-surgery. Ileums were collected 24 hours later to assess tissue damage on H&E stained slides, platelet infiltration (fluorescence microscopy), and P2Y 1 /P2Y 12 protein levels (western blotting). As expected, intestinal tissue damage and platelet infiltration were elevated in the CLP group compared to the sham control. Ticagrelor but not MRS2279 significantly reduced intestinal tissue damage and protein levels in treated septic mice (p<0.05). Blocking either P2Y 1 or P2Y 12 receptors reduced platelet infiltration (p<0.01). These findings suggest that Ticagrelor, a P2Y 12 antagonist, could be a therapeutic strategy to improve intestinal inflammation in septic females. National Institute of Health, grant AI156627-01 (EL) This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.