Role Of NAMPT In Development Of Immunosuppression In Polymicrobial Septic Mice

BACKGROUND:Sepsis is a common syndrome in patients with severe trauma, infection and major operations. It addresses a major challenge for trauma surgeons. Immunosuppression and the following secondary infection is the leading cause of sepsis-related in-hospital mortality. But to date, the underlying of sepsis-induced immunosuppression remains poorly understood. Nicotinamide phosphoribosyl transferase(NAMPT) is a multi-functional molecule. It is the speed-limiting enzyme in the salavage synthesis of NAD. It is also regarded as a pro-inflammatory cytokine. NAMPT can inhibit apoptosis of neutrophils and increases organ injury in clinical sepsis. However, the role of NAMPT in the development of immunosuppression of sepsis has not been well delineated.OBJECTIVE:(1) To elucidate the role of(NAMPT) in the development of immunosuppression in sepsis.(2) To investigate the effect of NAMPT inhibitor, FK866 on the survival of septic mice.METHODS: With the use of NAMPT inhibitor FK866 in CLP septic model, we observed the mortality rate of the mice.The delayed-type hypersensitivity(DTH) were examined to determine the immunological functions of T lymphocytes. ELISA, Immunohistochemistry and flow cytometry were performed to characterized and demonstrated the level of serum cytokines concentrations, Arginase-1 and inducible Nitric Oxide Synthetase(i NOS) production in liver and spleen, MDSC and Treg cells counts in animals.RESULTS: The survival of the severe septic mice were significantly improved by the inhibitor of NAMPT(p<0.05)(Figure.1-A).at the same time, FK866 attenuated systematic/circulated bacterial count, which indicate FK866 can elevate the resistance to the infection(Figure.1-B). The levels of the serum cytokines of the FK866 treated mice were lower than the CLP group, both 1 day and 3 days after CLP. During the 7th day, the mice treated with FK866 have a lower serum value of TNF-?and TGF-?(p<0.05), while the levels of the IFN-?, IL-6, IL-10 and PGE2 had no significant difference as compared to those of control group(p>0.05). The animals treated with FK866 had a higher proliferation and a small apotosis amounts of CD4+ T lymphocytes than the control group(CLP + vehicle)(p<0.05). Delayed-type hypersensitivity(DTH) can reflect the competences of T lymphocytes. The DTH response showed the mice treated with FK866 have a significant higher immunological capacities than the CLP mice. Immunohistochemistry revealed that the expressions of inducible nitric oxide synthetase(i NOS) were largely down-regulated both in spleens and livers than those of the control mice.We evaluated MDSC proportions in spleen, peripheral blood and bone marrows of animals during the study, which showed there are notable drops in animals treated with FK866 than control, in the 3rd day and 7th day after CLP, respectively. But had no significant difference in 1d day after CLP(p>0.05).CONCLUSIONS : NAMPT plays a pivotal role in the development of immunosuppression in sepsis. NAMPT inhibitor FK866 can enhance the survival, and partly restore T cell response of septic mice,. NAMPT may be used as a potential therapeutic target in sepsis.