Liver injury following ischemia, inflammation or other conditions associated with shock remains a serious clinical problem. A growing body of recent evidence points to the microcirculation as a primary target for pathology which may be the major factor in determining the severity of liver injury. Nevertheless, the mechanisms by which microvascular injury occurs are not well understood. Recent evidence indicates that the probable target vessel for microvascular injury in the liver is the sinusoid. Classically, decreased sinusoidal flow has been considered to be the result of either shutdown of larger vessels upstream or overt injury to the sinusoids. Recently, however, it has been shown that the sinusoids are capable of active, graded and reversible constriction thus contributing directly to regulation of sinusoid perfusion. The long range goal of this proposal is, thus, to test the hypothesis that sinusoidal constriction contributes to a heretofore unknown mechanism for regulating functional liver perfusion and that dysregulation of this system is a major determinant of hepatic microvascular injury following ischemia or inflammation.
Four specific aims are proposed to test this hypothesis. First, determine which physiologic vasoactive substances act at sinusoidal resistance sites. Second, test whether control of individual sinusoid perfusion by sinusoidal constriction is an actively regulated mechanism in the normal liver.
This aim will also test whether sinusoidal resistance regulation is an important mechanism for local matching of perfusion to metabolic demand. Third, test whether dysregulation of this system via an imbalance in the local expression of constrictor and dilator substances (e.g. endothelin and nitric oxide) may contribute to microvascular failure following ischemia or inflammation. Finally, we will test whether an increase in contractile responsiveness of the sinusoid via activation of sinusoidal lining cells also contributes to increased sinusoidal constriction leading to microvascular injury following ischemia or inflammation. These studies will focus on the activity of the hepatic stellate cells as the primary effector of sinusoid constriction but will also test the possible contribution of kupffer cells as intermediaries or amplifiers in the constrictor response to exogenous vasoactive substances or endogenous responses following stress. These studies will use a combination of intravital microscopy both in vivo and in isolated perfused livers to quantitate the microvascular responses along with Norther and Western blot analysis, immunohistochemistry, and in situ hybridization to determine the level and localization of vasoactive substances and markers of effector cell activation. Ultimately, these studies should contribute substantially to the understanding of how sinusoidal perfusion is regulated in the normal liver and how alterations in this regulation can lead to liver injury.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Surgery, Anesthesiology and Trauma Study Section (SAT)
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Doo, Edward
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University of North Carolina Charlotte
Schools of Arts and Sciences
United States
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