PMCID: PMC5344436 DOI: 10.2147/DDDT.S125349
Our previous study indicated that overexpression of nicotinamide phosphoribosyltransferase (NAMPT) aggravated acute lung injury, while knockdown of NAMPT expression attenuated ventilator-induced lung injury. Recently, we found that meta-carborane-butyl-3-(3-pyridinyl)-2E-propenamide (MC-PPEA, MC4), in which the benzoylpiperidine moiety of FK866 has been replaced by a carborane, displayed a 100-fold increase in NAMPT inhibition over FK866. Here, we determined the effects of MC4 and FK866 on cecal ligation and puncture (CLP) surgery-induced sepsis in C57BL/6J mice. MC4 showed stronger inhibitory effects than FK866 on CLP-induced mortality, serum tumor necrosis factor α (TNFα) levels, pulmonary myeloperoxidase activity, alveolar injury, and interleukin 6 and interleukin1β messenger RNA levels. In vitro cell permeability and electric cell-substrate impedance sensing assays demonstrated that MC4 inhibited TNFα- and thrombin-mediated pulmonary endothelial cell permeability better than FK866. MC4 also exerted more potent effects than FK866, at concentrations as low as 0.3 nM, to attenuate TNFα-mediated intracellular cytokine expression, nicotinamide adenine dinucleotide (NAD+) and its reduced form NADH levels, and nuclear factor kappa B p65 phosphorylation and nuclear translocation in A549 cells. Our results strongly suggest that the newly developed MC4 is a more potent suppressor of CLP-induced pulmonary inflammation and sepsis than FK866, with potential clinical application as a new treatment agent for sepsis and inflammation.
Drug Des Devel Ther
Acrylamides; Acrylates; Animals; Boron Compounds; Cecum; Dose-Response Relationship, Drug; Humans; Ligation; Male; Mice; Mice, Inbred C57BL; Piperidines; Pneumonia; Sepsis; Structure-Activity Relationship; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha
NAMPT; pulmonary inflammation; sepsis
Huang, P., Lee, M., Sadrerafi, K., Heruth, D. P., Zhang, L. Q., Maulik, D., Ye, S. Q. MC-PPEA as a new and more potent inhibitor of CLP-induced sepsis and pulmonary inflammation than FK866. Drug Des Devel Ther 11, 629-641 (2017).