KETOPROFEN IMPAIRS IMMUNOSUPPRESSION INDUCED BY SEVERE SEPSIS AND REVEALS AN IMPORTANT ROLE FOR PROSTAGLANDIN E2

The mechanism of immunosuppression induced by severe sepsis is not fully understood. The production of prostaglandin E-2 (PGE(2)) during sepsis is well known, but its role in long-term consequences of sepsis has not been explored. The current study evaluates the role of PGE(2) in the development of immunosuppression secondary to sepsis and its potential as therapeutic target. Cecal ligation and puncture was used as an experimental model for sepsis induction in Balb/c and C57BL/6 mice. Immunosuppression was evaluated by the response to secondary infection with Aspergillus fumigatus in sepsis survivors. The role of prostanoids was evaluated in vivo and in vitro by treatment with the cyclooxygenase inhibitor ketoprofen. Balb/c mice were more susceptible than C57BL/6 to severe sepsis and to secondary infection, with a greater mortality rate. Prostaglandin E-2 concentrations found in bronchoalveolar lavage in sham and cecal ligation and puncture group after fungal challenge were much higher in Balb/c than in C57BL/6 mice. Ketoprofen treatment improved survival of septic Balb/c mice subjected to secondary infection, while also enhancing macrophage phagocytosis and neutrophil recruitment to the lungs. We identified a pivotal role for PGE(2) acting on EP4 receptors in modulating cytokine production differentially by sham and septic macrophages. Furthermore, sepsis also altered key enzymes in PGE(2) synthesis and degradation. Our results indicate the involvement of PGE(2) in severe sepsis-induced immunosuppression. Inhibition of PGE(2) production represents an attractive target to improve innate immune response against secondary infection in the immunocompromised host.