Prostacyclin synthase deficiency exacerbates systemic inflammatory responses in lipopolysaccharide-induced septic...

Sepsis is a systemic inflammatory disorder characterized by life-threateningorgan dysfunction resulting from a dysregulated host response to infection. Prostacyclin (PGI₂) 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 PGI₂ in systemic inflammatory responses such as septic shock.

Systemic inflammation was induced by intraperitoneal injection of 5 mg/kg lipopolysaccharide (LPS) in wild type (WT) or PGIS knockout (KO) mice. Selexipag, a selective PGI₂ receptor (IP) agonist, was administered 2 h before LPS injection and again given every 12 h for 3 days.

Intraperitoneal injection of LPS induced diarrhea, shivering and hypothermia. These symptoms were more severe in PGIS KO mice than in WT micqe. 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.

Our study suggests that PGIS-derived PGI₂ negatively regulates LPS-induced symptoms via the IP receptor. PGIS-derived PGI₂-IP signaling axis may be a new drug target for systemic inflammation in septic shock.