Prostacyclin synthase deficiency exacerbates inflammatory reactions in lipopolysaccharide-induced sepsis in vivo

Abstract Objectives Sepsis is an inflammatory disorder characterized by life-threatening organ dysfunction resulting from a dysregulated host response to infection. In contrast, prostacyclin (PGI 2 ) is a bioactive lipid produced by PGI synthase (PGIS) and is known to play important roles in inflammatory reactions as well as cardiovascular regulation. However, little is known about the roles of PGIS and PGI 2 in sepsis. Methodology Sepsis was induced by intraperitoneal injection of 5 mg/kg lipopolysaccharide (LPS) in wild type (WT) or PGIS knockout (KO) mice. Selexipag, a selective PGI 2 receptor (IP) agonist, was administered 2 h before LPS injection and again given every 12 h for 3 days. Results Intraperitoneal injection of LPS induced diarrhea, shivering and hypothermia. These symptoms were more severe in PGIS KO mice than in WT mice. The expression of Tnf and Il6 genes was notably increased in PGIS KO mice. In contrast, over 95% of WT mice survived 72 h after the administration of LPS, whereas all of the PGIS KO mice had succumbed by that time. The mortality rate of LPS-administrated PGIS KO mice was improved by selexipag administration. Conclusion Our study suggests that PGIS-derived PGI 2 negatively regulates LPS-induced symptoms via the IP receptor. Selexipag shows promise for the clinical treatment of human sepsis.