Inflammatory modulation of hepatocyte apoptosis by nitric oxide: in vivo, in vitro, and in silico studies.
Nitric oxide (NO*) and its reaction products are key players in the physiology and pathophysiology of inflammatory settings such as sepsis and shock. The consequences of the expression of inducible NO* synthase (iNOS, NOS-2) can be either protective or damaging to the liver. We have delineated two distinct hepatoprotective actions of NO*: the stimulation of cyclic guanosine monophosphate and the inhibition of caspases by S-nitrosation. In contrast, iNOS/NO* promotes hepatocyte death under conditions of severe redox stress, such as hemorrhagic shock or ischemia/reperfusion. Redox stress activates an unknown molecular switch that transforms NO*, which is hepatoprotective under resting conditions, into an agent that induces hepatocyte death. We hypothesize that the magnitude of the redox stress is a major determinant for the effects of NO* on cell survival by controlling the chemical fate of NO*. To address this hypothesis, we have carried out studies in relevant in vivo and in vitro settings. Moreover, we have constructed an initial mathematical model of caspase activation and coupled it to a model describing some of the reactions of NO* in hepatocytes. Our studies suggest that modulation of iron, oxygen, and superoxide may dictate whether NO* is hepatoprotective or hepatotoxic.
Vodovotz
Yoram
Y
Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA. vodovotzy@msx.upmc.edu
Kim
Peter K M
PK
Bagci
Elife Zerrin
EZ
Ermentrout
G Bard
GB
Chow
Carson C
CC
Bahar
Ivet
I
Billiar
Timothy R
TR
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D020169:Caspases / Q000378:metabolism; D004789:Enzyme Activation; D005609:Free Radicals / Q000378:metabolism; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000166:cytology / Q000502:physiology*; D007249:Inflammation / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D009569:Nitric Oxide / Q000737:chemistry / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010100:Oxygen / Q000378:metabolism
D005609:Free Radicals; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D020169:Caspases; D010100:Oxygen