1. Local Factors: Although each injurious agent could disturb the ecosystem of the liver by a different route, there are, however, common sets of responses that lead to excess deposition of extracellular matrix components. As illustrated in Figure 1, there are two key players in the fibrogenic process. These are: a) the stellate cells (HSC) that are activated to produce cytokines, growth factors and extracellular matrix components, including type I collagen and b) activated Kupffer cells (KC) (and other inflammatory cells) which secrete reactive oxygen intermediates and produce several cytokines and growth factors. Of all the cytokines and growth factors produced, transforming growth factor _ (TGF-_) and interleukin-6 are the two main fibrogenic cytokines. TGF-_ is produced by KC and HSC, it up-regulates the transcription of the _1(I) and _2(I) collagen genes and induces the expression of TIMP-1, a tissue inhibitor of metalloproteinases involved in collagen degradation. Moreover, TGF-_ induces its own mRNA and establishes key autocrine and paracrine loops to sustain high levels of this cytokine in local sites of liver injury and/or inflammation. IL-6 which is produced by HSC and KC, also induces the transcriptional activation of the type I collagen genes. However, while IL-6 is unable to induce its own mRNA in HSC from normal or cirrhotic livers, it up-regulates the expression of TGF-_ in HSC from cirrhotic livers. Accordingly, it enhances the fibrogenic actions of TGF-_. The molecular mechanisms by which TGF-_ up-regulates the expression of the type I collagen genes have not been completely defined. However, recent work from our laboratory indicates that reactive oxygen intermediates in general, and H2O2 in particular, are important mediators of TGF-_ actions in HSC.
2. Systemic Factors: It has been recently established that cytokines released during an acute phase response episode, mainly IL-6 and tumor necrosis factor-___TNF-___play a key role in liver regeneration and in fibrogenesis. In this regard, we have shown that a single acute phase episode suffices to increase the expression of _1(I) procollagen mRNA in rat liver, and that IL-6 is the cytokine responsible for this up-regulation. Moreover, repeated acute phase episodes in rats receiving CCl4 to produce cirrhosis, enhance the expression of _1(I) procollagen and TIMP 1 mRNAs and increase further the deposition of liver collagen (see Figure 2). In this regard, it is noteworthy to mention that many non-specific inflammatory stimuli are capable of inducing acute phase response episodes. Accordingly, they could play an important role in fibrogenesis by enhancing the production of liver collagen.
In spite of the complexity of the fibrogenic process, several investigators have dissected individual paths leading to activation of KC and HSC and to excess collagen deposition. Thus, the concept of antifibrogenic therapy that was introduced by our group in the early 1970’s could now become a reality in the 1990’s. A better knowledge of the fibrogenic routes could help in designing drugs that will specifically block single fibrogenic pathways. Thus, the development of combined therapies to block two or more fibrogenic routes, may prove to be more efficient and less toxic.
C = Control liver T = Liver from rats with weekly (x3) acute phase response episodes CCl4 = Liver from rats receiving weekly (3x) injections of CCl4 to produce fibrosis CCl4 + T= Liver from rats receiving the combined treatment (acute phase response and CCl4) for 3 weeks.
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