1. Mitochondria nitric oxide synthase in inflammation and septic shock Tu jie

2. Nitric Oxide a ubiquitous signaling molecule Chemical characters 2NO+O 2  2NO 2 NO 2 + NO 2  N 2 O 4 NO 2 +NO  N 2 O 3 [NO + ] + OH -  HNO 2  NO - 2 + H + [NO - 2 ] [NO + ] + H 2 O  2NO - 2 + 2H + [NO - 3 ] [NO + ] + H 2 O  NO - 2 + NO - 3 + 2H +

4. Biosynthesis of Nitric Oxide H2NH2N NH 2 + NH H+3NH+3NCOO - H2NH2NN-OH NH H+3NH+3NCOO - + NO NADPH BH 4 O 2 HEME Ca 2+ /CaM NOS L-arginine L-citrulline

5. Three isoforms of NOS

8. Cellular and mitochondrial production of NO A fourth type of NOS: mitochondrial NOS (mtNOS) 1. first observed in rat liver mitochondria by Ghafourifar group and Giulivi group, 1997-1998; 2. localize in the mitochondrial innermembrane

9. 3. mtNOS activity is substantial and modulated by calcium 4. mtNOS continously controls mitochondrial respiration Respiration of IM is markedly inhibited when mtNOS is stimulated （ trace b vs trace a)

10. InfectionSIRS Sepsis Trauma Burns Pancreatitis Inflammation and septic shock A combination of three clinical signs: vasodilation, hyperthermia, edema Myochondrial dysfunction The role of mtNOS in inflammation and septic shock Septic Shock septic shock: a major cause of death

11. NO production in inflammation and septic shock milestone: recognition of NO production by activated macrophages as part of the inflammatory process

13. The impairment by high NO concentration in septic shock To impair mitochondrial and cellular oxygen uptake with a simultaneous decrease in the rate of ATP synthesis To shift the main mitochondrial O 2 。－ metabolic route （ form peroxynitrite (ONOO-), an oxidizing free radical that can cause DNA fragmentation and lipid oxidation ）

16. Cyclosporin A (CsA) in ameliorating endotoxin-caused myocardial dysfunction and apoptosis in rats ( Fauvel H, Marchetti P, Obert G, et al. Protective effects of cyclosporin A from endotoxin-induced myocardial dysfunction and apoptosis in rats [J] Am J Respir Crit Care Med, 2002,165(4):449-55 )

17. Mitochondrial played a central role in the intracellular event associated with inflammation and septic shock The contributions of mtNOS and NOS cytosolic isoforms to the total production of NO constitute an open and challenging question Conclusion