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.

/pdf/hepatic-stellate-cells-protean-multifunctional-and-enigmatic-1ctrvjmfhn.pdf

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

Oxidative stress generated by an imbalance between reactive oxygen species (ROS) and antioxidants contributes to the pathogenesis of arthritis, cancer, cardiovascular, liver and respiratory diseases. Proinflammatory cytokines and growth factors stimulate ROS production as signaling mediators. Antioxidants such as N-acetylcysteine (NAC) have been used as tools for investigating the role of ROS in numerous biological and pathological processes. NAC inhibits activation of c-Jun N-terminal kinase, p38 MAP kinase and redox-sensitive activating protein-1 and nuclear factor kappa B transcription factor activities regulating expression of numerous genes. NAC can also prevent apoptosis and promote cell survival by activating extracellular signal-regulated kinase pathway, a concept useful for treating certain degenerative diseases. NAC directly modifies the activity of several proteins by its reducing activity. Despite its nonspecificity, ability to modify DNA and multiple molecular modes of action, NAC has therapeutic value for reducing endothelial dysfunction, inflammation, fibrosis, invasion, cartilage erosion, acetaminophen detoxification and transplant prolongation.

Molecular mechanisms of N-acetylcysteine actions.

Ionizing radiation-induced metabolic oxidative stress and prolonged cell injury

Stress-induced morphogenic responses: growing out of trouble?

The chemistry and biological activities of N-acetylcysteine

N-Acetylcysteine Induces Cell Cycle Arrest in Hepatic Stellate Cells through Its Reducing Activity

Prothrombin Kringle-2 Domain Has a Growth Inhibitory Activity against Basic Fibroblast Growth Factor-stimulated Capillary Endothelial Cells

Characteristics of six isoperoxidases from Korean radish root

Human Prothrombin Fragment 1 and 2 Inhibit bFGF-Induced BCE Cell Growth

In order to identify a fibrogenic factor associated with the potential of hepatic stellate cells (HSC) activation that arises during the CCl4-induced fibrogenic process, the relationship between the activation of HSC and levels of several fibrogenic factors were investigated. After isolation of HSC from the liver at different stages of CCl4 intoxication, the activation of HSC was assessed by the expression of alpha-smooth muscle actin. Levels of cytokines and oxidative stress in liver homogenates and plasma were measured by enzyme linked immunosorbent assay and the colorimetric method. In primary culture, HSC isolated from a rat liver were gradually activated in a time-dependent manner according to CCl4 administration. The progression of HSC activation was closely correlated with parameters related to oxidative stress in liver homogenates rather than the tissue levels of several cytokines. Also, the levels of antioxidants and arginase activity were inversely correlated with HSC activation. In plasma, the levels of oxidative stress and cytokines in CCl4-treated rat livers were not associated with the activation of HSC found during the CCl4-induced fibrogenic process. The relationship between HSC activation and oxidative stress was also confirmed through several factor-treated HSC cultures. In conclusion, the activation of HSC was accelerated according to CCl4 administration, and the progression of HSC activation is absolutely related to the oxidative stress. These results show that enhanced oxidative stress is an important signal for activation of HSC in experimental liver fibrogenesis.

Progression of hepatic stellate cell activation is associated with the level of oxidative stress rather than cytokines during CCl4-induced fibrogenesis.

Soung Soo Kim

Papers

N-Acetylcysteine Induces Cell Cycle Arrest in Hepatic Stellate Cells through Its Reducing Activity

Prothrombin Kringle-2 Domain Has a Growth Inhibitory Activity against Basic Fibroblast Growth Factor-stimulated Capillary Endothelial Cells

Characteristics of six isoperoxidases from Korean radish root

Human Prothrombin Fragment 1 and 2 Inhibit bFGF-Induced BCE Cell Growth

Progression of hepatic stellate cell activation is associated with the level of oxidative stress rather than cytokines during CCl4-induced fibrogenesis.