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Mitochondria nitric oxide synthase in inflammation and septic shock
Tu jie
Nitric Oxidea ubiquitous signaling molecule
Chemical characters
2NO+O2 2NO2
NO2 + NO2 N2O4
NO2 +NO N2O3
[NO+] + OH- HNO2 NO -
2+ H+
[NO -2 ] [NO+] + H2O 2NO -
2+ 2H+
[NO -3 ] [NO+] + H2O NO -
2+ NO -3 + 2H+
Biosynthesis of Nitric Oxide
H2N NH2
+
NH
H+3N COO-
H2N N-OH
NH
H+3N COO-
+ NONADPH
BH4
O2
HEME
Ca2+/CaM
NOS
L-arginine L-citrulline
Three isoforms of NOS
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
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)
Infection SIRS
Sepsis
Trauma
Burns
Pancreatitis
Inflammation and septic shock
• A combination of three clini
cal signs:
vasodilation, hyperthermia,
edema
• Myochondrial dysfunction
The role of mtNOS in inflammation and septic shock
Septic Shock
septic shock: a major cause of death
NO production in inflammation and septic shock• milestone: recognition of NO production by activated
macrophages as part of the inflammatory process
The impairment by high NO concentration in septic sho
ck
• To impair mitochondrial and cellular oxygen uptake with
a simultaneous decrease in the rate of ATP synthesis
• To shift the main mitochondrial O2。- metabolic route
( form peroxynitrite (ONOO-), an oxidizing free radical that can c
ause DNA fragmentation and lipid oxidation )
• 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)
Mitochondrial played a central role in the intracellula
r event associated with inflammation and septic sho
ck
The contributions of mtNOS and NOS cytosolic isofo
rms to the total production of NO constitute an open
and challenging question
Conclusion