Medicine of the Future in America

Category Archives: Apoptosis

Liver cell death: PERSPECTIVES

The current goals of research done in this field are to further elucidate the mechanisms governing the cellular response to apoptotic stimuli. A number of intracellular pathways are involved. The manipulation of these intracellular responses may alter the course of liver diseases. For example, liver function could be maintained in patients with cholestatic disorders with the inhibition of hepatocyte apoptosis. It is not always possible to address the underlying cause of liver disease (eg, in cases of autoimmune or chronic viral hepatitis); therefore, finding ways to make hepatocytes resistant to apoptotic signals may be useful in mitigating the liver injury. Continue reading

Liver cell death: Clinical importance of apoptosis in liver diseases (Part 3)

toxic mushroom poisoningThere is some evidence that toxic mushroom poisoning (mediated by Amanita phalloides toxin) involves apoptosis. Indeed, amanitin is a transcriptional blocker (see above) and has been shown in vitro to cause all the characteristics of hepatocyte apoptosis. Besides these observations, there is experimental evidence that drugs can trigger hepatocyte apoptosis by directly activating the caspase cascade or by sensitizing hepatocytes to the lethal effects of cytokines. However, there have been few pathological studies assessing the amount of hepatocyte apoptosis in biopsy samples of drug-induced liver injury. Continue reading

Liver cell death: Clinical importance of apoptosis in liver diseases (Part 2)

As previously described, the presence of the Fas ligand on the surface of the lymphocyte can activate Fas receptors normally expressed on the hepatocyte plasma membrane. There are several reports describing an increased expression of Fas in human specimens of chronic hepatitis C and B. Lymphocytes can also use the perforin-granzyme pathway to deliver their death signal. On the other hand, the role of viruses in the induction of apoptosis is controversial. Some authors have demonstrated that HCV proteins can induce apoptosis, whereas others have postulated that these proteins have the capacity to block the apoptotic signal generated by cytokines. Thus far, experimental models of HCV infection or replication have not shown evidence of increased hepatocyte cell death. Continue reading

Liver cell death: Clinical importance of apoptosis in liver diseases (Part 1)

inactive alcoholic liver diseaseThe relevance of studying apoptosis and of trying to change the apoptotic response in liver diseases depends on the actual occurrence of this type of cell death and its importance relative to other forms of cell death. This can be expected to vary widely depending on the etiology of the liver injury.

There is accumulating evidence that hepatocyte apoptosis is significant in alcoholic liver disease. Surgical specimens from patients with inactive alcoholic liver disease reveal increased numbers of acidophilic bodies, which are considered apoptotic (see below). Apoptotic hepatocytes have been reported in liver biopsy material from patients with alcoholic hepatitis. There is experimental evidence that chronic ethanol feeding increases hepatocyte apoptosis in animals. Furthermore, Fas ligand upregulation has been described in the liver and the plasma in cases of alcohol-induced liver disease. Recent evidence has linked the upregulation of the Fas ligand with increased hepatocyte apoptosis. Continue reading

Liver cell death: Experimental models of hepatocyte apoptosis

There are a number of experimental models of hepatocyte apoptosis. Maybe the best known, and the one that has generated the widest interest, is the mouse model of massive liver apoptosis after the intraperitoneal injection of Fas antibodies. These antibodies bind to the Fas receptor and, instead of preventing its activation (as is the case for other antibodies such as the anti-TNF-a antibodies), they induce oligomerization of the Fas receptors and their consequent activation. When injected in vivo, this causes a rapid and massive liver injury characterized by overwhelming apoptosis. Other liver cells, such as endothelial cells, are also injured and there is some debate about the exact sequence of pathological events. Nevertheless, this model has been used to assess the capacity of agents to block hepatocyte apoptosis and has demonstrated the importance of the Fas system in this process. Continue reading

Liver cell death: Caspases – The executioners of apoptosis

The intracellular execution of apoptosisThe intracellular execution of apoptosis is driven by a recently identified class of proteases. Proteases are enzymes whose function is to cut proteins. Some proteases are nonspecific: they cut all sorts of proteins at a variety of cleavage sites. Such are the pancreatic enzymes, whose role is to render large proteins small enough to be absorbed by the intestinal mucosa. Other proteases are very specific and will cleave only proteins that have a particular shape or amino acid sequence. The latter group includes proteases involved in the apoptotic process. They have been given the name caspases because they are rich in Cysteine amino acids, they recognize a special target sequence that contains ASPartic acid and they are proteASES. Continue reading

Liver cell death: The role of mitochondria

The importance of mitochondria in the apoptotic process was first suspected when Bcl-2 was found to be localized to the outer membrane of these organelles. Mitochondria possess a membrane that is rich in enzymes that play a major role in the oxygenation of cells (ie, for the genesis of ATP). The activity of these enzymes depends on the maintenance of an electrochemical gradient between the inner membrane and the mitochondrial matrix. Therefore, the intermitochondrial space needs to be isolated from the cell cytoplasm. Members of the Bcl-2 family govern the permeability of the outer membrane to ions. A number of other proteins are structurally similar to Bcl-2; they form the large family of Bcl-2-related proteins. Some of these are antiapoptotic (like Bcl-2 itself), whereas others promote apoptosis by binding Bcl-2 and blocking its activity at the outer mitochondrial membrane. Continue reading

Liver cell death: T cell-induced apoptosis

extracellular eventA good example of an extracellular event that leads to apoptosis is the killing of target cells by activated T lymphocytes that have recognized foreign antigens expressed on the surface of an infected cell. The lymphocyte binds the target cell through specific receptors with the help of human leukocyte antigen molecules expressed by the target cell. The lymphocyte can deliver the ‘kiss of death’ by means of two distinct pathways. First, the Fas ligand, which is expressed on the surface of the T lymphocyte, can bind the Fas death receptor when it is expressed on the surface of the target cell. The Fas receptor is constitutively expressed on hepatocytes. This leads to the activation of the intracellular apoptotic cascade (see below). Alternatively, the lymphocyte can literally drill a hole in its target cell by using a protein that is appropriately named ‘perforin’. Perforin is present in the secretory granules of activated lymphocytes. Continue reading

Liver cell death: Death receptors

It is somewhat surprising to learn that almost every cell possesses death receptors on its surface. Fortunately, the expression of these receptors differs among various tissues. Moreover, cells possess many antiapoptotic survival receptors that can block the transmission of the message derived from the activation of death receptors. Nevertheless, one must recognize that cell death occurs continuously throughout life. For example, there is a degree of cell turnover taking place in almost every tissue (eg, liver and gastrointestinal mucosa). This requires the organized loss of a definite number of cells, which is currently thought to occur by apoptosis. Figure 3 is a schematic representation of the hepatocyte death receptors. Continue reading

Liver cell death: Characteristics of the apoptotic process

The morphological characteristics of apoptotic cells are a decrease in cell volume; condensation and fragmentation of the nuclei; and fragmentation of the cell into small bodies that remain surrounded by plasma membranes (Figure 1). Not all apoptotic cells exhibit these morphological features. This fact makes it difficult to determine the number of apoptotic cells in tissue specimens. Furthermore, apoptotic bodies have a short lifespan because they are readily eliminated by macrophages and/or neighbouring cells. Some of the best pathological examples of apoptosis can be observed in cases of chronic hepatitis C and B (Figure 2). Continue reading

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