Liver disease, in some form, affects approximately 30 million Americans and is the 9th leading cause of death in the United States. While there are many different causes of liver disease, such as viral infection, obesity, alcohol and hereditary conditions, the progression of liver damage, eventually leading to liver failure, follows a common pathway. Understanding the chain of events involved in this pathway provides a unique opportunity for therapeutic intervention regardless of the underlying nature of the disease.
Chronic liver disease damages hepatocytes, the main cell type in the liver. These cells are responsible for hundreds of critical metabolic functions performed by the liver. Damage to these cells and the surrounding tissue establishes a state of inflammation in the liver called hepatitis. Inflammation further exacerbates damage to the liver and initiates a process of wound healing to cope with the ongoing damage. This process involves the production of a number of proteins called extracellular matrix proteins, which form the “scaffold” that maintains the structural integrity of the liver. In the case of chronic liver disease, in which the inflammation is persistent, mechanisms that would normally terminate this wound healing process are overridden. Over time, the loss of hepatocytes and ongoing fibrogenesis results in cirrhosis. These processes and the key cells involved are represented graphically in Figure 1.
There are four basic cell types that reside in the liver which are important in the initiation and progression of liver damage. These cells, shown in Figure 1, are the hepatocyte, the stellate cell, the Kupffer cell and the liver endothelial cell. These so-called resident cells control many of the key functions in the liver, as well as its response to injury. A brief description follows.
Hepatocytes are the main cell type in the liver, representing approximately 80% of the total liver mass. It is unique in its ability to perform so many vital and diverse metabolic functions, including the regulation of cholesterol levels, synthesis of essential amino acids, vital blood clotting proteins, albumin and bile to name a few. In addition, hepatocytes store glucose in the form of glycogen, which plays a key role in maintaining proper blood glucose levels. These activities are in addition to its well known role in breaking down food into essential nutrients and as a filter of toxic substances.
The hepatocyte is also the primary target of many liver diseases, including viral infections, excessive fat accumulation (steatosis) and drug induced liver damage. Injury to these cells initiates the cycle of inflammation that in turn perpetuates further liver damage through the activation hepatic stellate cells.
Hepatic stellate cells reside in close proximity to the hepatocyte. Under normal conditions, these cells store approximately 80% of the body’s supply of vitamin A and a variety of other lipids. Under conditions of liver injury, these cells become activated, changing from cells that store lipids to cells that are highly responsive to a variety of external signals and synthesize and secrete extracellular matrix proteins and collagen. These hepatic stellate cells also begin to proliferate in response to factors such as PDGF, increasing their number in response to injury. Activated stellate cells are highly responsive to pro-fibrogenic factors such as TGF-ß. Activated hepatic stellate cells are the primary pro-fibrogenic cell in the liver and play a central role in the wound healing response.
Liver sinusoidal endothelial cells form the wall of the blood vessels (sinusoids) that carry blood throughout the liver. Liver sinusoidal endothelial cells comprise approximately 50% of the non-parenchymal hepatic cells. They separate the hepatocytes from the blood flowing through the sinusoids and play an important role in hepatic microcirculation. These cells form a single layer with spaces between each cell known as fenestra, that allow an efficient flow of essential materials to pass from the blood to hepatocytes and vice versa. In addition, these endothelial cells also express a wide variety of scavenger receptors, and control the exchange of material between the blood and the liver hepatocytes. These cells also are rich in lysosomal enzymes needed for degrading endocytosed material.
Kupffer cells are liver specific macrophages that adhere to the sinusoidal endothelium. These cells are responsible for clearing the blood of ingested bacterial pathogens and removing spent red blood cells from the circulation. These cells play an important role in the liver’s immune response to injury as they initiate and orchestrate a first response to pathogens. Therefore, these cells are a significant factor in the host resistance to primary and secondary infections. Kupffer cells facilitate and amplify the response by secreting of cytokines and chemokines that recruit and expand the population of other proinflammatory cells in the liver.
In addition to cells that specifically reside in the liver, an influx of non-resident cells, including neutrophils, T-cells and platelets, are recruited to the liver in response to liver damage. These cells also play an important role in the progression of liver damage, working in concert with resident liver cells.
An understanding of the relevant cell types and their involvement in the mechanistic pathway associated with liver damage enables the development of rational, effective and potentially broad based therapies to address liver damage associated with a variety of liver diseases. One attractive approach involves targeting a class of enzymes known as matrix metalloproteinases (MMPs). The role of MMPs in liver disease and the rationale for inhibiting this group of enzymes is presented below.