[CITATION][C] Oxidative stress: does it 'initiate'hepatic stellate cell activation or only 'perpetuate'the process?
M Apte - Journal of gastroenterology and hepatology, 2002 - Wiley Online Library
M Apte
Journal of gastroenterology and hepatology, 2002•Wiley Online LibraryOxidative stress is thought to play an important role in the development of hepatic injury from
a variety of causes including alcohol abuse, viral infections, biliary obstruction (cholestasis),
and iron or copper overload. 1–3 The development of oxidative stress in these conditions is
usually a result of increased free radical generation combined with depleted antioxidant
defences in the organ. These events lead to a disturbance in cellular homeostasis including
DNA damage, activation of the glutathione redox cycle, depletion of adenosine triphosphate …
a variety of causes including alcohol abuse, viral infections, biliary obstruction (cholestasis),
and iron or copper overload. 1–3 The development of oxidative stress in these conditions is
usually a result of increased free radical generation combined with depleted antioxidant
defences in the organ. These events lead to a disturbance in cellular homeostasis including
DNA damage, activation of the glutathione redox cycle, depletion of adenosine triphosphate …
Oxidative stress is thought to play an important role in the development of hepatic injury from a variety of causes including alcohol abuse, viral infections, biliary obstruction (cholestasis), and iron or copper overload. 1–3 The development of oxidative stress in these conditions is usually a result of increased free radical generation combined with depleted antioxidant defences in the organ. These events lead to a disturbance in cellular homeostasis including DNA damage, activation of the glutathione redox cycle, depletion of adenosine triphosphate and nicotinamide adenine dinucleotide, and peroxidation of membrane lipids. Lipid peroxidation is a known association of liver fibrosis in chronic liver injury (regardless of etiology). 4 Consequently, several substances with antioxidant properties have been examined for their potential antifibrotic effects in both animal and human studies. These include:(i) α-tocopherol (vitamin E), shown to be effective in experimental models of liver fibrosis, although its value in humans is uncertain;(ii) silymarin (a plant flavanoid), shown to be antifibrotic in a rat model of biliary obstruction and also found to be of some benefit in patients with alcoholic liver disease; 5, 6 (iii) polyenylphosphatidylcholine (PPC), a polyunsaturated phospholipid found to have an antifibrogenic effect in alcoholic liver disease, possibly via reduced induction of the microsomal enzyme cytochrome P4502E1 and reduced oxidative stress; 7–9 (iv) S-adenosyl-L-methionine, a substrate for glutathione synthesis shown to attenuate liver fibrosis in experimental liver injury caused by alcohol, carbon tetrachloride (CCL4) or biliary obstruction, 10–12 which has also been used in patients with alcoholic liver disease, drug-induced liver disease and primary biliary cirrhosis; 13 and (v) compounds such as retinoids14 and the natural phenolic compounds resvatrol and quercetin, 15, 16 found to reduce liver fibrosis in experimental models.
It is now well-established that fibrogenesis in the liver is mediated by hepatic stellate cells (HSC) that have been activated during liver injury. 17 Hepatic stellate cells are located in the perisinusoidal space of Disse and act as storage sites for vitamin A. These cells are a major source of extracellular matrix (ECM) proteins in the liver and are also a source of the enzymes (matrix metalloproteinases) that degrade ECM. Therefore, HSC are thought to play a role in the maintenance of normal ECM in the liver by regulating the balance between its synthesis and degradation. During liver injury, activation of HSC occurs in two steps. 17–19 The first is the ‘initiation’of activation whereby the cells begin to lose vitamin A, display cytoplasmic extensions and exhibit increased expression of cell surface receptors for growth factors and cytokines. The second step is the ‘perpetuation’of activation involving a further change in morphology to a myofibroblast-like phenotype, with further loss of vitamin A, increased proliferation, and increased matrix synthesis. The consequence of these morphological and functional changes is a significant imbalance between ECM synthesis and degradation, with deposition of excessive amounts of ECM proteins (particularly fibrillar collagen) in the interstitium.
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