Alterations in vascular response of the liver microcirculation is a major determinant of the liver's response to oxidative or inflammatory stress. This vascular response is mediated largely by the induction of the stress-related vasoregulatory genes: the endothelins and endothelin receptors and nitric oxide synthase (NOS). The long term objective of this proposal is to elucidate the mechanisms by which altered vascular responses modulate hepatic injury after clinically relevant stresses such as endotoxemia and sepsis. The short term objective is to test the hypothesis that that the hepatic vascular response to endotoxin or sepsis is mediated by upregulation of endothelin B receptors and the interaction of these receptors with nitric oxide synthase. To test this hypothesis, four specific aims are proposed: 1. Define the relative contribution of endothelin receptor subtypes in the microvascular response following stress.
This aim will use a series of specific endothelin agonists and antagonists to dissect out the specific contributions of endothelin receptor subtypes to the physiologic response 2. Determine cell-type distribution of altered expression of endothelins, endothelin receptors and NOS isoforms following stress conditions.
This aim will elucidate the specific cell types (endothelial cell, Kupffer cell, stellate cell, hepatocyte and neutrophil) that express specific endothelin receptors. Additionally, the acinar distribution of expression in specific cell types will be determined. 3. Test the hypothesis that altered regulation of eNOS contributes to the hyperse aboutzsitivity to endothelins.
This aim will first characterize the expression and activity of eNOS in specific cell types and acinar locations and then test the physiologic response to either over expression (using simvastatin or adenovirus gene transfer) or deletion (using mice with targeted mutations) to determine the role of NOS in modulating endothelin sensitivity follow endotoxin or sepsis. 4. Test whether manipulation of the expression or action of specific hepatic vascular stress proteins results in disruption of microregional balance between O2 supply and demand and hepatocellular injury.
This aim will evaluate the physiologic significance of the relationships among the constrictor / dilator balance characterized in aims 1-3. This will be accomplished using novel methodologies developed in the previous funding period to quantify the spatial distribution of oxygen delivery and metabolic response in the liver with high resolution in vivo.
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