To provide an overview of current concepts of liver fibrosis, with special emphasis on the role of hepatic stellate cells (Ito cells, fat-storing cells or lipocytes) on collagen deposition
To review basic molecular mechanisms whereby the genes encoding the type I collagen chains are up regulated
To describe the contribution of non-specific, systemic events on liver fibrosis
To briefly indicate possible targets for anti-fibrogenic therapy.
The liver behaves as an ecological system in which all its elements contribute to the function of the organ. Injurious agents capable of inducing alterations in any of its cell populations, and/or in its extracellular matrix components will trigger an immediate response in an attempt to establish homeostasis. Irrespectively of the mechanisms induced, two main types of response are observed: there is either regeneration with complete restoration of liver architecture and function, or there is sustained scarring of the tissue that will result in fibrosis and organ failure. Many factors, including the genetic make-up of the individual, the nature of the injurious agent and the intensity and duration of the stimulus, will determine whether regeneration or scarring occurs. It is generally accepted that a single, strong injury capable of inducing a significant reduction in functional mass (>50%), will result in regeneration. However, if the injury is repetitive, of small intensity, and it is not accompanied by a significant loses of functional mass, scarring of the liver will be the predominant form of response. The molecular mechanisms involved in each type of response are currently unknown, but are under investigation in many laboratories around the world. Fibrosis that accompanies liver cirrhosis is characterized by excess deposition of most components of the extracellular matrix. However, type I collagen is the predominant type found in all terminal cirrhotic livers. Therefore, in this presentation, we shall analyze important mechanisms involved in excess collagen deposition in the liver, with special emphasis on type I. Collagen deposition is a complex process that depends on the amount of collagen produced and that, which is degraded by specific interstitial collagenases (metalloproteinases or MMPs). Accordingly, excess collagen deposition will result from an imbalance between its synthesis and its degradation.
Although local mechanisms triggered within the liver play a key role in liver fibrogenesis, nonetheless, systemic factors could influence the outcome of the disease. Figure 1 depicts some of the steps involved in upregulation of the type I collagen genes that could result in excess deposition of collagen. Although the figure was designed to explain how alcohol induces excess collagen deposition, with some minor modifications, it could be adapted for many liver injurious agents including virus, endotoxin and metals. The figure illustrates that both local and systemic factors contribute to excess collagen deposition in the liver. While the local events depend mostly on the nature of the injurious agent and on the cell type that is its primary target, systemic effects depend primarily on the intensity of the stimulus.
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