Oxidative stress is a host defense mechanism whose involvement in maintaining homeostasis and/or inducing disease has been widely investigated over the past decade. Various reactive oxygen species (ROS) have been defined and the enzymes involved in generating and/or eliminating them have been widely studied. In this review we briefly discuss general mechanisms of oxidative stress and the oxidative stress response of the host. We focus primarily on hydrogen peroxide and summarize the systems involved in its formation and elimination. We describe mechanisms whereby hydrogen peroxide and other ROS can modify protein conformation and, thus, alter protein function, and describe a group of transcription factors whose biological activity is modulated by the redox state of cells. These basic aspects of oxidative stress are followed by a discussion of mechanisms whereby hydrogen peroxide and other ROS can modulate some physiological and pathological processes, with special emphasis on wound healing and scarring of the liver.

Ethanol induces liver fibrosis by several means that include, among others, the direct fibrogenic actions of acetaldehyde and the induction of an oxidative stress response. However, the mechanisms responsible for these activities, and the possible connections between oxidative stress and acetaldehyde-induced fibrosis are not well understood. In this communication we investigated the molecular mechanisms whereby acetaldehyde induces mouse ␣1(I) procollagen (col1a1) gene expression in cultured hepatic stellate cells. Transfection assays using reporter plasmids driven by different segments of the col1a1 promoter localized an acetaldehyde-responsive element (AcRE) between nucleotides ؊370 and ؊345. We also show that acetaldehyde enhances binding of a CCAAT/enhancer binding protein-␤ (C/EBP␤)-containing complex to this element, and that this effect is due, at least in part, to an increase in the concentration of nuclear p35C/EBP␤ protein. Although this element overlaps to a previously described transforming growth factor ␤1 (TGF-␤1)-responsive element, the stimulatory effect of acetaldehyde is not mediated through this cytokine, because addition of neutralizing anti-TGF-␤1 antibodies does not prevent acetaldehyde-elicited col1a1 up-regulation. On the other hand, this effect is blocked by the addition of catalase, an H 2 O 2 scavenger. Moreover, this ethanol metabolite stimulates production of H 2 O 2 in stellate cells. Thus, these results suggest that acetaldehyde-induced col1a1 up-regulation is mediated, at least in part, through H 2 O 2 . Altogether, these data suggest that the ؊370 to ؊344

Collagen degradation by matrix metalloproteinases is the limiting step in reversing liver fibrosis. Although collagen production in cirrhotic livers is increased, the expression and/or activity of matrix metalloproteinases could be normal, increased in early fibrosis, or decreased during advanced liver cirrhosis. Hepatic stellate cells are the main producers of collagens and matrix metalloproteinases in the liver. Therefore, we sought to investigate whether they simultaneously produce alpha1(I) collagen and matrix metalloproteinase-13 mRNAs. In this communication we show that expression of matrix metalloproteinase-13 mRNA is reciprocally modulated by tumor necrosis factor-alpha and transforming growth factor-beta1. When hepatic stellate cells are co-cultured with hepatocytes, matrix metalloproteinase-13 mRNA is up-regulated and alpha1(I) collagen is down-regulated. Injuring hepatocytes with galactosamine further increased matrix metalloproteinase-13 mRNA production. Confocal microscopy and differential centrifugation of co-cultured cells revealed that matrix metalloproteinase-13 is localized mainly within hepatic stellate cells. Studies performed with various hepatic stellate cell lines revealed that they are heterogeneous regarding expression of matrix metalloproteinase-13. Those with myofibroblastic phenotypes produce more type I collagen whereas those resembling freshly isolated hepatic stellate cells express matrix metalloproteinase-13. Overall, these findings strongly support the notion that alpha1(I) collagen and matrix metalloproteinase-13 mRNAs are reciprocally modulated.