Vascular mediators in the injured liver

Rockey, Don C.

doi:10.1053/jhep.2003.50044

Cited by 154 publications

(149 citation statements)

References 92 publications

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“…This finding was expected in animals with chronic liver injury and has been documented by others. 7,19 However, when ADMA was added, in BDE rats the pre-existing endothelial dysfunction was further aggravated and resulted in paradoxical vasoconstriction, which is in agreement with an environment where vasoconstrictors highly upregulated 1,24,29,30 and where an already dysfunctional eNOS is impeded further or even completely inhibited. In contrast, in TAAinduced rats with cirrhosis the decreased vasorelaxing capacity was not impaired further, which supports the hypothesis of a decreased eNOS enzyme level as a causative factor.…”

Section: Discussionsupporting

confidence: 64%

A role for asymmetric dimethylarginine in the pathophysiology of portal hypertension in rats with biliary cirrhosis

Laleman¹,

Omasta²,

Casteele³

et al. 2005

Hepatology

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Reduced intrahepatic endothelial nitric oxide synthase (eNOS) activity contributes to the pathogenesis of portal hypertension (PHT) associated with cirrhosis. We evaluated whether asymmetric dimethylarginine (ADMA), a putative endogenous NOS inhibitor, may be involved in PHT associated with cirrhosis. Two rat models of cirrhosis (thioacetamide [TAA]-induced and bile duct excision [BDE]-induced, n ‫؍‬ 10 each), one rat model of PHT without cirrhosis (partial portal vein-ligated [PPVL], n ‫؍‬ 10), and sham-operated control rats (n ‫؍‬ 10) were studied. We assessed hepatic NOS activity, eNOS protein expression, plasma ADMA levels, and intrahepatic endothelial function. To evaluate intrahepatic endothelial function, concentration-effect curves of acetylcholine were determined in situ in perfused normal rat livers and livers of rats with TAAor BDE-induced cirrhosis (n ‫؍‬ 10) that had been preincubated with either vehicle or ADMA; in addition, measurements of nitrite/nitrate (NOx) and ADMA were made in perfusates. Both models of cirrhosis exhibited decreased hepatic NOS activity. In rats with TAA-induced cirrhosis, this decrease was associated with reduced hepatic eNOS protein levels and immunoreactivity. Rats with BDE-induced cirrhosis had eNOS protein levels comparable to those in control rats but exhibited significantly higher plasma ADMA levels than those in all other groups. In normal perfused liver, ADMA induced impaired endothelium-dependent vasorelaxation and reduced NOx perfusate levels, phenomena that were mimicked by N G -nitro-L-arginine-methyl ester. In contrast to perfused livers with cirrhosis induced by TAA, impaired endothelial cell-mediated relaxation in perfused livers with cirrhosis induced by BDE was exacerbated by ADMA and was associated with a decreased rate of removal of ADMA (34.3% ؎ 6.0% vs. 70.9% ؎ 3.2%). In conclusion, in rats with TAA-induced cirrhosis, decreased eNOS enzyme levels seem to be responsible for impaired NOS activity; in rats with biliary cirrhosis, an endogenous NOS inhibitor, ADMA, may mediate decreased NOS activity. (HEPATOLOGY 2005;42:1382-1390

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Section: Discussionsupporting

confidence: 64%

A role for asymmetric dimethylarginine in the pathophysiology of portal hypertension in rats with biliary cirrhosis

Laleman¹,

Omasta²,

Casteele³

et al. 2005

Hepatology

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“…The effects of ET-1 are mediated through two G protein-coupled receptors. Receptor types A and B have been identified in both quiescent and activated stellate cells (245,289,535,537). The relative prevalence of ET A and ET B receptors changes with stellate cell activation (495).…”

Section: Biology Of Membrane Receptorsmentioning

confidence: 99%

“…Contractility of stellate cells may be a major determinant of early and late increases in portal resistance during liver fibrosis. The collagenous bands typical of end-stage cirrhosis contain large numbers of activated stellate cells (534,536,537). These impede portal blood flow by constricting individual sinusoids and by contracting the cirrhotic liver.…”

Section: Perpetuationmentioning

confidence: 99%

Hepatic Stellate Cells: Protean, Multifunctional, and Enigmatic Cells of the Liver

Friedman

2008

Physiological Reviews

2,390

2,549

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The hepatic stellate cell has surprised and engaged physiologists, pathologists, and hepatologists for over 130 years, yet clear evidence of its role in hepatic injury and fibrosis only emerged following the refinement of methods for its isolation and characterization. The paradigm in liver injury of activation of quiescent vitamin A-rich stellate cells into proliferative, contractile, and fibrogenic myofibroblasts has launched an era of astonishing progress in understanding the mechanistic basis of hepatic fibrosis progression and regression. But this simple paradigm has now yielded to a remarkably broad appreciation of the cell's functions not only in liver injury, but also in hepatic development, regeneration, xenobiotic responses, intermediary metabolism, and immunoregulation. Among the most exciting prospects is that stellate cells are essential for hepatic progenitor cell amplification and differentiation. Equally intriguing is the remarkable plasticity of stellate cells, not only in their variable intermediate filament phenotype, but also in their functions. Stellate cells can be viewed as the nexus in a complex sinusoidal milieu that requires tightly regulated autocrine and paracrine cross-talk, rapid responses to evolving extracellular matrix content, and exquisite responsiveness to the metabolic needs imposed by liver growth and repair. Moreover, roles vital to systemic homeostasis include their storage and mobilization of retinoids, their emerging capacity for antigen presentation and induction of tolerance, as well as their emerging relationship to bone marrow-derived cells. As interest in this cell type intensifies, more surprises and mysteries are sure to unfold that will ultimately benefit our understanding of liver physiology and the diagnosis and treatment of liver disease.

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“…10,154 As fibrosis advances, the collagenous bands typical of end-stage cirrhosis contain large numbers of activated stellate cells. 155 These cells progressively impede portal blood flow by both constricting individual sinusoids and by contracting the cirrhotic liver, mediated by pathways that allow interaction with the ECM. 156,157 At the same time, stellate cell density and coverage of the sinusoidal lumen increases.…”

Section: Perpetuating Pathwaysmentioning

confidence: 99%

“…156,157 At the same time, stellate cell density and coverage of the sinusoidal lumen increases. 10,153 Endothelin-1 and nitric oxide are the key opposing counter-regulators that control stellate cell contractility, in addition to angiotensinogen II, eicosanoids, atrial natriuretic peptide, somatostatin, and carbon monoxide, among others (see Rockey 155 and Reynaert et al 158 for reviews). Progressive development of intrahepatic shunts also is likely to require angiogenic responses driven by stellate cells.…”

Section: Perpetuating Pathwaysmentioning

confidence: 99%

Mechanisms of Hepatic Fibrogenesis

2008

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Substantial improvements in the treatment of chronic liver disease have accelerated interest in uncovering the mechanisms underlying hepatic fibrosis and its resolution. Activation of resident hepatic stellate cells into proliferative, contractile, and fibrogenic cells in liver injury remains a dominant theme driving the field. However, several new areas of rapid progress in the past 5-10 years also have taken root, including: (1) identification of different fibrogenic populations apart from resident stellate cells, for example, portal fibroblasts, fibrocytes, and bone-marrow-derived cells, as well as cells derived from epithelial mesenchymal transition; (2) emergence of stellate cells as finely regulated determinants of hepatic inflammation and immunity; (3) elucidation of multiple pathways controlling gene expression during stellate cell activation including transcriptional, posttranscriptional, and epigenetic mechanisms; (4) recognition of disease-specific pathways of fibrogenesis; (5) re-emergence of hepatic macrophages as determinants of matrix degradation in fibrosis resolution and the importance of matrix cross-linking and scar maturation in determining reversibility; and (6) hints that hepatic stellate cells may contribute to hepatic stem cell behavior, cancer, and regeneration. Clinical and translational implications of these advances have become clear, and have begun to impact significantly on the management and outlook of patients with chronic liver disease.The field of hepatic fibrosis is flourishing thanks to continued experimental advances complemented by exciting progress in the treatment of chronic liver disease. 1 Control of chronic hepatitis B and C by antiviral therapies has established that advanced fibrosis can regress in association with improved clinical outcomes, 2-4 thereby intensifying enthusiasm to uncover the mechanistic basis for hepatic fibrogenesis and its attenuation. At the same time, simple paradigms defining the cellular sources of extracellular matrix (ECM), and the roles of cytokines and paracrine interactions among resident liver cells and inflammatory cells have yielded a more nuanced understanding of how the liver responds to injury. These advances have had a collateral benefit towards understanding fibrosis in other organs, particularly the pancreas. 5 Thus, a review of the mechanisms underlying hepatic fibrosis is not only timely, but is more clinically relevant than ever. This article focuses on recent advances in the field, building on established principles from earlier reviews 6,7 while weaving in their clinical relevance, but also emphasizing the molecular subtleties that have emerged through continued progress in the field. General PrinciplesFibrosis, or scarring of the liver, is a wound-healing response that engages a range of cell types and mediators to encapsulate injury. Although even acute injury will activate mechanisms of fibrogenesis, the sustained signals associated with chronic liver disease caused by infection, Cirrhosis, the most advanced stage ...

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Vascular mediators in the injured liver

Cited by 154 publications

References 92 publications

A role for asymmetric dimethylarginine in the pathophysiology of portal hypertension in rats with biliary cirrhosis

A role for asymmetric dimethylarginine in the pathophysiology of portal hypertension in rats with biliary cirrhosis

Hepatic Stellate Cells: Protean, Multifunctional, and Enigmatic Cells of the Liver

Mechanisms of Hepatic Fibrogenesis

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