Hydrogen Sulfide Modulates Hepatic Oxygen Availability and Microcirculation during Sepsis

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Norris, E. (2012). Hydrogen Sulfide Modulates Hepatic Oxygen Availability and Microcirculation during Sepsis. Unc Charlotte Electronic Theses And Dissertations.
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Abstract

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.

Details
Author

Norris, Eric

Title

Hydrogen Sulfide Modulates Hepatic Oxygen Availability and Microcirculation during Sepsis

Physical Description

1 online resource (156 pages) : PDF

Date

2012

Degree Granting Institution

University of North Carolina at Charlotte

Abstract

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.

Genre

doctoral dissertations

Subjects--Topics

Biology
Physiology

Degree

Ph.D.

Keywords

Endotoxemia
Hydrogen Sulfide
Hypoxia
Liver
Microcirculation
Sepsis

Subject Area

Biology

Advisor(s)

Clemens, Mark

Committee Members

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

Degree Note

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

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Rights Holder Information

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Identifier

Norris_uncc_0694D_10376

Permalink

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