Translating an understanding of the pathogenesis of hepatic fibrosis to novel therapies

Abstract

The response to injury is one of wound healing and fibrogenesis, which ultimately leads to fibrosis. The fibrogenic response to injury is a generalized one across virtually all organ systems. In the liver, the injury response, typically occurring over a prolonged period of time, leads to cirrhosis (although it should be pointed out that not all patients with liver injury develop cirrhosis). The fact that many different diseases result in cirrhosis suggests a common pathogenesis. The study of hepatic fibrogenesis over the past 2 decades has been remarkably active, leading to a considerable understanding of this process. It clearly has been shown that the hepatic stellate cell is a central component in the fibrogenic process. It also has been recognized that other effector cells are important in the fibrogenic process, including resident fibroblasts, bone marrow-derived cells, fibrocytes, and even perhaps cells derived from epithelial cells (ie, through epithelial to mesenchymal transition). A key aspect of the biology of fibrogenesis is that the fibrogenic process is dynamic; thus, even advanced fibrosis (or cirrhosis) is reversible. Together, an understanding of the cellular basis for liver fibrogenesis, along with multiple aspects of the basic pathogenesis of fibrosis, have highlighted many exciting potential therapeutic opportunities. Thus, although the most effective antifibrotic therapy is simply treatment of the underlying disease, in situations in which this is not possible, specific antifibrotic therapy is likely not only to become feasible, but will soon become a reality. This review highlights the mechanisms underlying fibrogenesis that may be translated into future antifibrotic therapies and to review the current state of clinical development.

Figure 1. Liver injury and fibrogenesis

In the liver, many different types of injury (i.e., chronic hepatitis, ethanol, metabolic disease, biliary tract disease, iron, copper, etc…) lead to hepatocyte injury, and then typically an inflammatory response. This injury process is complicated, but in aggregate, it stimulates a wound healing response, which involves a number of different systems. Paramount in this process is often including recruitment of inflammatory cells. Among other properties, inflammatory cells produce a variety of mediators, cytokines, and other factors, which in turn are responsible for stimulation and/or recruitment of other cells. Key among these other cells include effector cells, highlighted in the figure and including stellate cells, fibrocytes, fibroblasts, and even fibroblasts derived though epithelial to mesenchymal transition (EMT). These effectors produce extracellular matrix proteins (see text), and importantly interact with other cells in the wounding mileu. Additionally, it is important to emphasize that many forms of injury lead to activation and transformation of other cells in the liver, such as endothelial and bile duct epithelial cells. Injury to these cells in turn leads to a variety of downstream effects. Each injured endothelial bile duct epithelial cells are capable of stimulatulation of effector cells to produce extracellular matrix consitutents.

Figure 2. Stellate cell activation

A key pathogenic feature underlying liver fibrosis and cirrhosis is activation of hepatic stellate cells (note that activation of other effector cells is likely to parallel that of stellate cells). The activation process is complex, both in terms of the events that induce activation and the effects of activation. Multiple and varied stimuli participate in the induction and maintenance of activation, including, but not limited to cytokines, peptides, and the extracellular matrix itself. Recently, signaling through TLR4 on stellate cells has been identified as important in activation. Key phenotypic features of activation include production of extracellular matrix, loss of retinoids, proliferation, of upregulation of smooth muscle proteins, secretion of peptides and cytokines (which have autocrine effects on stellate cells and paracrine effects on other cells such as leukocytes and malignant cells), and upregulation of various cytokine and peptide receptors. Additionally, evidence indicates that stellate cells exhibit several cell fates, highlighted at the bottom of the figure, and each of these appear to play a role in the biology of fibrogenesis.