Hydrogen Sulfide Modulates Hepatic Oxygen Availability and Microcirculation during Sepsis

1 online resource (156 pages) : PDF

2012

University of North Carolina at Charlotte

A mismatch between O2 supply and demand leads to the development of tissue hypoxia which contributes to hepatic dysfunction and injury during sepsis. Previously, we reported that hepatic microcirculatory failure is a major contributor to hypoxia and hepatic dysfunction during sepsis. Recent evidence suggests that hepatic H2S levels are increased during sepsis. Moreover, the inhibition of endogenous H2S synthesis significantly improves survival in septic mice; however, the exact mechanism is not known. The present study was designed to investigate the effect of H2S on hepatic O2 availability and microcirculation during sepsis. We hypothesized that H2S contributes to hepatic dysfunction during sepsis by reducing hepatic oxygen availability, via O2 dependent oxidation of H2S, and by potentiating microvascular dysfunction. We demonstrate that the liver is a central regulator of H2S via mitochondrial oxidation during sepsis. Additionally, we show that the oxidation of H2S lowers hepatic O2 levels in vivo. In the second half of this study, we demonstrate that H2S differentially affects the hepatic vascular response to phenylephrine and endothelin-1 which suggests that H2S differentially affects presinusoidal and sinusoidal sites in the hepatic microcirculation. Using intravital microscopy, we show that portal infusion of H2S is associated with sinusoidal constriction and that inhibition H2S synthesis attenuates the sensitization of the sinusoids to the constrictor effect of endothelin-1 which improves perfusion. We conclude that the contribution of H2S to hepatic tissue hypoxia and microcirculatory dysfunction is partially responsible for its detrimental effects during sepsis.

doctoral dissertations

Biology
Physiology

Ph.D.

Endotoxemia
Hydrogen Sulfide
Hypoxia
Liver
Microcirculation
Sepsis

Biology

Clemens, Mark

Dreau, Didier
Bost, Kenneth
Mukherjee, Pinku
Gibas, Cynthia

Thesis (Ph.D.)--University of North Carolina at Charlotte, 2012.

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Norris_uncc_0694D_10376

http://hdl.handle.net/20.500.13093/etd:48