Cell apoptosis: why doesn't it always work? Morphological manifestations of apoptosis Importance of apoptosis
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What is apoptosis?
Apoptosis- physiological cell death, which is a kind of genetically programmed self-destruction.The term "apoptosis" in translation from Greek means "falling". The authors of the term gave such a name to the process of programmed cell death because it is with it that the autumn fall of withered leaves is associated. In addition, the name itself characterizes the process as physiological, gradual and absolutely painless.
In animals, the most striking example of apoptosis is, as a rule, the disappearance of the tail in a frog during metamorphosis from a tadpole to an adult.
As the frog grows up, its tail completely disappears, as its cells undergo gradual apoptosis - programmed death, and the absorption of destructed elements by other cells.
The phenomenon of genetically programmed cell death occurs in all eukaryotes (organisms whose cells have a nucleus). Prokaryotes (bacteria) have a kind of analogue of apoptosis. We can say that this phenomenon is characteristic of all living things, with the exception of such special precellular life forms as viruses.
Both individual cells (usually defective) and whole conglomerates can undergo apoptosis. The latter is especially characteristic of embryogenesis. For example, the experiments of researchers have shown that due to apoptosis during embryogenesis, the membranes between the toes on the feet of chickens disappear.
Scientists argue that in humans, congenital anomalies such as fused fingers and toes also occur as a result of disruption of normal apoptosis in the early stages of embryogenesis.
The history of the discovery of the theory of apoptosis
The study of the mechanisms and significance of genetically programmed cell death began in the sixties of the last century. Scientists were interested in the fact that the cellular composition of most organs throughout the life of an organism is practically the same, but the life cycle of various types of cells is significantly different. In this case, a constant replacement of many cells occurs.Thus, the relative constancy of the cellular composition of all organisms is maintained by the dynamic balance of two opposite processes - cell proliferation (division and growth) and physiological death of obsolete cells.
The authorship of the term belongs to British scientists - J. Kerr, E. Wiley and A. Kerry, who were the first to put forward and substantiate the concept of a fundamental difference between the physiological death of cells (apoptosis) and their pathological death (necrosis).
In 2002, scientists from the Cambridge laboratory, biologists S. Brenner, J. Sulston and R. Horwitz, received the Nobel Prize in Physiology or Medicine for the disclosure of the main mechanisms of genetic regulation of organ development and the study of programmed cell death.
Today, tens of thousands of scientific works are devoted to the theory of apoptosis, revealing the main mechanisms of its development at the physiological, genetic and biochemical levels. An active search for its regulators is underway.
Of particular interest are studies that enable the practical application of the regulation of apoptosis in the treatment of oncological, autoimmune, and neurodystrophic diseases.
Mechanism
The mechanism of development of apoptosis is not fully understood to date. It has been proven that the process can be induced by low concentrations of most substances that cause necrosis.However, in most cases, genetically programmed cell death occurs when signals are received from molecules - cellular regulators, such as:
- hormones;
- antigens;
- monoclonal antibodies, etc.
It is characteristic that a signal for the development of apoptosis can be both the presence of activating substances and the absence of some compounds that prevent the development of programmed cell death.
The response of a cell to a signal depends not only on its strength, but also on the general initial state of the cell, the morphological features of its differentiation, and the stage of the life cycle.
One of the basic mechanisms of apoptosis at the stage of its implementation is DNA degradation, resulting in nuclear fragmentation. In response to DNA damage, defense reactions are triggered to repair it.
Unsuccessful attempts to restore DNA lead to a complete energy depletion of the cell, which becomes the immediate cause of its death.
The mechanism of apoptosis - video
Phases and stages
There are three physiological phases of apoptosis:1. Signal (activation of specialized receptors).
2. Effector (the formation of a single pathway of apoptosis from heterogeneous effector signals, and the launch of a cascade of complex biochemical reactions).
3. Dehydration (lit. dehydration - cell death).
In addition, two stages of the process are morphologically distinguished:
1.
First stage - preapoptosis... At this stage, the size of the cell decreases due to its shrinkage, reversible changes occur in the nucleus (compaction of chromatin and its accumulation along the periphery of the nucleus). In the case of exposure to some specific regulators, apoptosis can be stopped, and the cell will resume its normal life.
2.
The second stage is actually apoptosis. Inside the cell, gross changes occur in all of its organelles, but the most significant transformations develop in the nucleus and on the surface of its outer membrane. The cell membrane loses the villi and the usual folding, bubbles form on its surface - the cell seems to boil, and as a result breaks down into the so-called apoptotic bodies, which are absorbed by tissue macrophages and / or neighboring cells.
The morphologically determined process of apoptosis usually takes from one to three hours.
Cell necrosis and apoptosis. Similarities and differences
The terms necrosis and apoptosis denote the complete cessation of cell activity. However, apoptosis means physiological death, and necrosis means its pathological death.Apoptosis is a genetically programmed termination of existence, that is, by definition, it has an internal cause of development, while necrosis occurs as a result of the influence of superstrong external factors in relation to the cell:
- lack of nutrients;
- poisoning with toxins, etc.
In addition, cell death during the processes of necrosis and apoptosis differs morphologically - the first is characterized by its swelling, and in the second, the cell shrinks and its membranes are compacted.
During apoptosis, cell organelles die, but the membrane remains intact, so that the so-called apoptotic bodies are formed, which are subsequently absorbed by specialized cells - macrophages or neighboring cells.
With necrosis, a rupture of the cell membrane occurs, and the contents of the cell are released outside. An inflammatory reaction begins.
If a sufficiently large number of cells have undergone necrosis, inflammation manifests itself with characteristic clinical symptoms known from ancient times, such as:
- pain;
- redness (vasodilation in the affected area);
- swelling (inflammatory edema);
- local and sometimes general temperature rise;
- more or less pronounced dysfunction of the organ in which necrosis occurred.
Biological significance
The biological significance of apoptosis is as follows:
1. The implementation of the normal development of the body during embryogenesis.
2. Prevention of proliferation of mutated cells.
3.
Regulation of the immune system.
4.
Prevention of premature aging of the body.
This process plays a leading role in embryogenesis, since many organs and tissues undergo significant transformations during embryonic development. Many birth defects result from inadequate apoptosis.
As a programmed self-destruction of defective cells, this process is a powerful natural defense against cancer. So, for example, the human papillomavirus blocks cell receptors responsible for apoptosis and, thus, leads to the development of cancer of the cervix and some other organs.
Due to this process, the physiological regulation of T-lymphocyte clones, which are responsible for the cellular immunity of the body, takes place. Cells that are unable to recognize proteins of their own body (and about 97% of them mature in total) undergo apoptosis.
Lack of apoptosis leads to severe autoimmune diseases, while its intensification is possible in immunodeficient conditions. For example, the severity of the course of AIDS correlates with the intensification of this process in T-lymphocytes.
In addition, this mechanism is of great importance for the functioning of the nervous system: it is responsible for the normal formation of neurons, and it can also cause early destruction of nerve cells in Alzheimer's disease.
One of the theories of the aging of the organism is the theory of apoptosis. It has already been proven that it is he who underlies the premature aging of tissues, where cell death remains irreparable (nervous tissue, myocardial cells). On the other hand, insufficient apoptosis can contribute to the accumulation of aging cells in the body, which normally physiologically die off and are replaced by new ones (early aging of connective tissue).
The role of apoptosis theory in medicine
The role of the theory of apoptosis in medicine lies in the possibility of finding ways to regulate this process for the treatment and prevention of many pathological conditions caused by a weakening or, conversely, an increase in apopoptosis.Research is being carried out simultaneously in many directions. First of all, it should be noted scientific research in such an important field of medicine as oncology. Since tumor growth is caused by a defect in the genetically programmed death of mutated cells, the possibility of specific regulation of apoptosis, with an increase in its activity in tumor cells, is being studied.
The action of some chemotherapeutic drugs widely used in oncology is based on the intensification of apoptosis processes. Since tumor cells are more prone to this process, a dose of a substance is selected that is sufficient for the death of pathological cells, but relatively harmless for normal ones.
It is also extremely important for medicine to study the role of apoptosis in the degeneration of the tissue of the heart muscle under the influence of circulatory failure. A group of Chinese scientists (Lv X, Wan J, Yang J, Cheng H, Li Y, Ao Y, Peng R) have published new experimental data that prove the possibility of artificially reducing apoptosis in cardiomyocytes with the introduction of certain inhibitor substances.
If theoretical studies on laboratory facilities can be applied in clinical practice, this will be a big step forward in the fight against coronary heart disease. This pathology ranks first among the causes of death in all highly developed countries, so it would be difficult to overestimate the transition from theory to practice.
Another very promising direction is the development of methods for regulating this process to slow down the aging of the body. Theoretical studies are carried out in the direction of creating a program that combines an increase in the activity of apoptosis of senescent cells, and a simultaneous increase in the proliferation of young cellular elements. Certain advances have been made here at a theoretical level, but there is still a long way to go from theory to practical solutions.
In addition, large-scale scientific research is carried out in the following areas:
- allergology;
- immunology;
- therapy of infectious diseases;
- transplantology;
Our cells are suicidal
Moreover, they can commit suicide for the slightest reason: overheating, radiation exposure, hypoxia ... They even have their own antidepressants!
Cells constantly receive a signal from other cells: "live-live-live" and its interruption immediately leads to death.
But sometimes a completely different message comes from the “neighbors”.
Cells closely monitor each other, and in case of inappropriate behavior, they send a signal of apoptosis - programmed death.
A biological cell is a complex and extremely interesting object, in essence it is a whole organism that is born, breathes, feeds, multiplies and dies.
But this is not surprising, because a huge part of living things on our planet consists of only one cell.
It is worth distinguishing between apoptosis and necrosis, which is cell death as a result of injury and damage.
The main difference is that during apoptosis, which does not happen by chance, apoptotic bodies are formed from the remnants of cells, which are eaten by phagocytes called for this, which prevents inflammation and poisoning of neighboring cells, and with necrosis, the death of cells and whole tissues occurs, accompanied by severe inflammation.
An interesting fact is that the term "apoptosis" meant falling of petals and leaves in plants (ancient Greek ἀπόπτωσις - falling leaves).
Conventionally, three stages of apoptosis can be distinguished: initiation or receipt of a signal, the effector stage, in which degradation processes are triggered and, in fact, the process of destruction and degradation - the formation of apoptotic bodies followed by eating by macrophages.
There are 2 ways of initiation: mitochondrial and external signal
Mitochondria are the energy stations of our body, where the process of cellular respiration actually takes place with the conversion of oxygen into water.
In school textbooks, mitochondria were depicted as such elongated ovals scattered throughout the cell. But it is not so.
If you look at a section of a cell, then you will really see such a picture, but with a three-dimensional reconstruction of cells using these thin sections, scientists discovered that there is only one mitochondirium in the cell, but it has a complex curved structure, so on the sections we see its various outgrowths.
Mitochondria are surrounded by two cell membranes and between them are proteins of apoptosis or apoptotic proteins that break free when the outer membrane is ruptured or pores are formed in it.
Actually, this is the key phase of the onset of apoptosis.
The released proteins through a series of biochemical reactions activate caspases - enzymes that destroy other proteins.
Caspases begin to destroy everything around me, destroying all the basic cellular structures.
In the process of destruction of the mitochondrial membrane, not only proteins are released, but water also begins to actively enter the mitochondria, causing it to swell.
The second pathway of the onset of apoptosis is signaling.
On the surface of cells there are cell death receptors, special ligands produced by other cells (some of them are activated macrophages, which later eat up the remains), bind to these ligands and activate them.
Receptors are a large molecule that sits in the cell membrane and protrudes from both sides: into the cell and out.
From the outside, the ligand sits down and a signal is transmitted to the inside of the receptor throughout the receptor.
At the second stage of apoptosis - effector, it is no longer so important how the cell received the signal.
At this stage, a real apocalypse begins inside and caspases play the main role in it.
The second important element of this stage is the flavoprotein AIF, which leaves the mitochondria and activates endonucleases - proteins that destroy the cell's DNA.
In fact, after this station, the cell is a city after a nuclear bombing.
During the destruction of the mitochondrial membrane, the entire energy complex is also released, which provoke the formation of reactive oxygen species inside the cell.
Free radicals start chain reactions that destroy the contents of the cell.
At this point, they can no longer be contained by antioxidants.
After that, the third and last stage begins - degradation.
The cell loses its shape and shrinks due to the destruction of the cell skeleton.
Macrophages are already on duty around the dying cell, ready to pounce on the remains.
In the process of the cell, signal proteins appear on the surface of the membrane, which attract hungry macrophages, and now, they are already absorbing the remains of a dead relative.
But cells also have antidepressants that keep these processes under control, preventing them from responding to the slightest stress - these are inhibitors of apoptotic proteins.
But, as soon as the mitochondrial membrane begins to release the precursors of the apocalypse, the SMAC protein also breaks free, which deactivates these inhibitors and they become useless.
After this stage, apoptosis is difficult to stop.
Do not think that apoptosis is an exclusively gloomy negative phenomenon of our body.
With the help of apoptosis, the correct number and ratio of various cells in the body is maintained
Apoptosis plays an important role in our development: for example, the separation of fingers and toes is a consequence of programmed cell death.
When children erupt, even before a tooth appears, the process of death of gum cells begins, so that it is easy for the tooth to come out.
The tadpole's tail also does not fall off with the appearance of legs, but degrades with the help of the same phenomenon.
Apoptosis is indispensable in preventing the development of cancerous tumors.
During our normal life, a huge number of cells in the body undergo pathological changes and are reborn into potentially cancer cells.
Neighboring cells, like the grandmothers on the benches near the entrance, closely monitor their neighbors and, in case of inadequate behavior, send the cell an apoptosis signal even before it multiplies and becomes dangerous.
For this reason, over the past 20 years, interest in apoptosis has greatly increased as a means of preventing and combating malignant tumors.
It is a natural process in the body. It includes a controlled sequence of events in which the cell signals self-destruction. Apoptosis helps control the natural process of cell division through.
Why do cells undergo apoptosis?
There are several cases when cells need to self-destruct. For example, the natural process of menstruation involves the breakdown and removal of tissue from the uterus. Cells can also undergo damage or some types of infection. One way to remove these cells without harming healthy cells is through apoptosis.
What Happens During Apoptosis?
Apoptosis is a complex process that involves many events. During apoptosis, the cell triggers a process from within, which allows it to commit suicide. When the cell experiences some type of significant stress, such as DNA damage, signals are released that activate to release apoptosis-inducing proteins.
As a result, the cell undergoes a reduction in size as its cellular components both break down and condense. Bubbles appear on the surface, increasing its permeability. The cell then divides into smaller fragments called apoptotic bodies. These fragments are enclosed in membranes so as not to damage neighboring cells.
Then phagocytic cells, such as, engulf and destroy the apoptotic bodies without causing an inflammatory response. Apoptosis can also be triggered externally by chemicals that bind to specific receptors on the cell's surface. This is a pathway used by some white blood cells to activate apoptosis in infected cells.
Apoptosis and cancer
Some cancers persist as a result of the cell's inability to undergo apoptosis. Tumor viruses change cells by integrating their genetic material with the host cell's DNA. These viruses initiate the production of proteins that stop the process of apoptosis. An example of this can be seen with papilloma viruses, which are associated with cervical cancer. Cancer cells that do not develop from viral infection can also produce substances that inhibit apoptosis and promote uncontrolled growth. Radiation and chemical therapy is used to induce apoptosis in some cancers.
Programmed cell death is an integral part of the life of any organism. If this process is violated, a number of serious diseases develop.
What is apoptosis?
Apoptosis is cell death that occurs as a result of programmed processes occurring in the cell at the molecular level. During apoptosis, the cell divides into several parts surrounded by a cell membrane, after which the cell fragments are digested by special cells by macrophages for several minutes (usually up to 90 minutes).
The phenomenon of programmed cell death is characteristic of all living beings, including humans. Several tens of billions of cells die in the human body every day. The destroyed cells are subsequently replaced by new cells formed by cell division (mitosis).
What is the role of apoptosis?
Self-elimination of cells unnecessary for the body is an extremely important process for the normal functioning of any organism. One of the main functions of apoptosis is to maintain the constancy of the cell population. When a new cell population is formed (for example, some immune cells), it must be taken into account that a number of cells will be necessarily defective. That is, the body needs to carry out cell selection to preserve only those cells that will fully cope with their functions. In the rest, the defective cells, the self-destruct program starts.
Apoptosis also plays an important role in infection with infectious agents, in particular viral ones. When it enters a cell, the virus begins to multiply rapidly, after which the cell bursts and millions of viral particles attack other cells. In the course of evolution, living organisms have learned to deal with such a phenomenon. So a number of viruses cause a number of changes in the cell, which are perceived as a signal for self-destruction. Thus, by destroying the infected cell, the body does not allow the virus to spread.
When apoptosis doesn't work
Many molecular processes are involved in the regulation of apoptosis, the coordinated action of which leads to the death of cells "unwanted" by the body. However, due to certain reasons, not yet completely clear, there is a violation of apoptotic regulation. Insufficient synthesis of apoptotic proteins and enzymes, as well as the effect of specific substances, leading to a decrease in the apoptotic activity of the cell, can lead to a failure in the system.
To date, it is known that one of the regulators of apoptosis is the p53 protein. In the presence of a number of defects in the cell, in particular, breakdowns of the genetic material, the p53 protein triggers a chain of molecular processes leading to the development of apoptosis. Mutation of the p53 protein makes it impossible to perform its main function - triggering cell death.
Viruses can also prevent programmed cell death. For example, in genetic the material of some viruses can be encoded with specific proteins that inhibit cell apoptosis. In other cases, a viral infection stimulates the production of anti-apoptotic proteins in the cell itself. Thus, the virus turns off the cell apoptosis program and can multiply uncontrollably.
There are several variants of apoptosis disorders:
- Excessive apoptosis is a pathological phenomenon that leads to excessive death of the cell population. This phenomenon is observed in HIV infection, some forms of hepatitis, chronic myocardial ischemia, neurodegenerative and other diseases.
- Insufficient apoptosis, in which the number of dying cells is clearly less than the number of newly formed cells.
- Incomplete apoptosis, in which the destruction of apoptotic fragments by the cells of the immune system does not occur.
What does the impairment of apoptosis lead to?
Activated Protein C May Inhibit Apoptosis
Regulating the processes of programmed cell death may be the key to creating a new effective treatment for stroke.
American scientists have successfully tested on mice a substance that has already found application in
Today it is known that impaired regulation of apoptosis can lead to a number of immunological and tumor diseases. Under normal conditions, a strict selection of newly formed immune cells takes place in the human body, since some of them may be reactive with respect to the body's own cells. If the process of self-destruction of such immune cells is disrupted, then diseases develop.
Dysregulation of apoptosis in cell populations leads to the development of a number of tumor processes. In particular, it has been proven that a mutation of the p53 protein or a violation of its synthesis in the body can lead to the development of hormone-dependent carcinoma of the breast, ovary and prostate gland. Similar disorders have also been identified with the development of lymphomas.
The possibility of influencing the apoptotic system is one of the directions in the search for drugs for cancer. However, in some cases, stimulation of apoptotic activity, on the contrary, is detrimental to the body. In this regard, scientists and physicians are actively studying the nature of this phenomenon, hoping in the future to obtain a tool with which it would be possible to control apoptosis.
Or avoidance of programmed cell death of tumor cells is the most important property of the malignant phenotype.
Normally, the apoptotic program is present in a latent form in all cells of the body, since it is quite obvious that DNA damage constantly occurs in the body under the influence of various factors during the passage of the cell through the cell cycle, i.e. mutations occur.
It is known that 10 16 cell divisions occur in the human body during life. Spontaneous mutations occur with a frequency of 10 6 per gene per cell cycle.
Thus, during a person's life, each gene may well undergo mutation about 10 billion times (10 16 x 10 6 = 10 10), and up to 1 million somatic mutations occur in the body every day.
And among them, there are undoubtedly possible leading to cancer. From this perspective, the problem with cancer is not so much why it occurs, but why it occurs so rarely.
And cancer occurs, despite the constant exposure to carcinogenic factors, relatively rarely because the body has defense mechanisms aimed at maintaining the normal genotype of the cell. It should be noted that the fate of cells with certain genetic damage can be different.
Some of the mutated cells die due to vital damage to their genome, some are restored, some are destroyed by the body itself through apoptosis, and, finally, some of the mutated cells will survive and in the process of reproduction can become a source of accumulation of potentially oncogenic mutations and the development of cancer.
Normally, the genetic fund of a cell, despite its fragility, is protected by a powerful enzymatic apparatus, which often ensures recognition of mutated and altered DNA regions and their restoration.
DNA repair consists in cutting out mutated nucleotides using endo- and exonucleases, synthesizing a normal DNA region with the participation of DNA polymerase, and inserting the restored region into the DNA chain under the action of the ligase enzyme. Thus, the original genetically programmed nucleotide sequence of the damaged strand is recreated (Fig. 3.12).
Figure 3.12. Reparation scheme for DNA damage and mutation formation [Novik AL, 2004].
If the activity of the repair-restoration systems is insufficient and DNA damage persists, then programmed cell death is induced in such cells, which leads to the destruction, including of mutant cells capable of malignant transformation.
Apoptosis (from the Greek apoptosis - shedding) - programmed cell death or "death of a cell as a result of self-destruction" - an active, genetically controlled process. The term was proposed by Kerr J. et al. (1972) to denote the changes occurring in a cell during its physiological death and leading to a decrease in the number of cells, as opposed to mitosis, which provides an increase in their number.
The biological significance of apoptosis
The biological significance of apoptosis is that it is a key mechanism for maintaining genetic homeostasis, which the body uses to remove cells whose survival is undesirable: foreign, defective ones with breakdowns in the genome; mutant or infected with a virus; with inadequate specificity of receptors for various regulators of vital activity, etc.In the body, in every unit of time, millions of cells complete their cycle, work out their "age". To prevent the "clogging" of the organism from the "spent", "worn out" cells that have managed to fulfill their function, a special mechanism of their elimination - apoptosis - has been developed in the course of evolution.
The ability to trigger self-destruction (apoptosis) is an essential property of cells to maintain tissue homeostasis by maintaining a certain balance between proliferation (mitosis) and death.
Apoptosis plays an extremely important role in embryogenesis, in particular in the regulation of the amount of mesodermal tissue during the formation of organs and the skeleton. The apoptotic mechanism also underlies the destruction of alien cells by immune cells.
Cell death by the type of apoptosis occurs in many physiological processes: age-related involution of organs (thymus), atrophy (of the prostate gland after castration), regression of hyperplasia, normal functioning of the ovaries and testes, and, finally, in the destruction of mutant cells.
Apoptosis activation mechanism
Mature differentiated cells in their normal state are resistant to the induction of apoptosis, but become sensitive to it after their activation. This activation is caused by various external influences through specific receptors and intracellular signals caused by the expression of some protooncogenes.They can be physiological - activation of special killer cytokines, changes in hormonal status (cyclical changes in the endometrium, etc.), and non-physiological - intracellular damage or unfavorable conditions (lack of growth factors, DNA damage, hypoxia, etc.).
In the mechanisms of apoptosis activation, two main stages are distinguished: the induction phase (decision-making) and the execution phase (execution of the sentence). In the first phase, the apoptosis sensor system monitors deviations from the norm in the intra- and extracellular environment and determines the further fate of the cell: live or die.
The class of sensors are cell surface receptors that bind signals for survival or death. Various cytokines act as such signals.
When abnormalities are detected (for example, DNA damage, lack of growth factors, hypoxia, etc.), the second phase of apoptosis, the execution of the sentence, is triggered by means of sensory regulators. It begins with the activation of caspases + enzymes of the cysteine proteinase family (the so-called execution caspases).
There are two fundamentally different pathways for caspase activation. One of them is triggered in response to an active death signal transmitted by specific killer cytokines of the TNF (tumor necrosis factor) group to the corresponding receptors (the most studied Fas), called death receptors.
Apoptosis caused by activated death receptors is called instructive apoptosis. In the second pathway of caspase activation, mitochondria play a key role - mitochondrial apoptosis.
At the same time, various damaging effects cause an increase in the permeability of the mitochondrial membrane and the release of mitochondrial proteins (mainly cytochrome C) into the cytoplasm, which activate caspases through the corresponding cascade of reactions.
Proteins of the bcl-2 family, which have either proapoptotic or antiapoptotic activities, play a key role in the regulation of mitochondrial membrane permeability for cytochrome C.
Thus, in response to damage in human cells, there are two mechanisms that trigger apoptosis: instructive, caused by death receptors, and mitochondrial, caused by increased membrane permeability. There is mutual regulation between them, which makes it possible to more reliably achieve the final effect.
As a result, caspases activated in one way or another proteolytically cleave key structural components of the cell, which leads to DNA fragmentation and cell destruction. In this case, the cytoplasmic and nuclear skeletons are destroyed, chromosomes are degraded, the nucleus is fragmented, but without rupture of the cell membrane.
Therefore, such a cell can be utilized by phagocytes and neighboring cells, and even their massive death does not lead to any pathological processes. The proteolysis process lasts 30-120 minutes, then the shriveled cell is absorbed by macrophages and usually disappears within 24 hours (Fig. 3.13).
Rice. 3.13. Phagocytosis of an apoptotic cell by a macrophage [Filchenkov AA, Stoika RS, 1999]. 1 - fragmented core; 2 - fragments of cytoplasm (apoptotic bodies); 3 - fragments of an apoptotic cell are captured by a macrophage.
The task of apoptosis is to utilize cell fragments until its contents enter the extracellular environment and cause an inflammatory process. External morphological manifestations of apoptotic cell death in the form of karyopycnosis (shrinking of the nucleus), karyorrhexis (disintegration of the nucleus into parts), condensation (compression) of the cell, etc. have been known for a long time and only recently has it been shown that these are partial manifestations of apoptosis. No inflammatory process occurs around the cells that underwent apoptosis.
Cell death by the type of apoptosis should be distinguished from necrosis - another form of cell death in the body. Necrosis is initiated by nonphysiological agents, and apoptosis is initiated by both physiological and nonphysiological. Unlike necrosis, apoptosis occurs not only in pathologically altered tissues, but also in normal tissues.
Necrosis occurs when cells are exposed to extreme factors and therefore can be called pathological death. In necrosis, morphological changes as a reaction to lethal cell damage almost always begin with damage to the plasma membrane, which does not occur with apoptosis.
Due to the rupture of the membrane, water molecules and ions enter the cell from the extracellular space and cause swelling of the structures. At the same time, the ingress of the contents of the cytoplasm (including lysosomal enzymes) into the extracellular space causes tissue damage and the development of a pronounced inflammatory process, which does not occur during apoptosis.
In addition, single cells die off during apoptosis, and groups of them die off during necrosis. The destruction of cells by apoptosis, compared with necrosis, provides minimal tissue damage. There are other differences between these processes. Figure 3.14 shows schematically two forms of cell death.
Rice. 3.14. Schematic representation of two forms of cell death [according to Wyllle A. et al., 1998].
Like other physiological processes, apoptosis is regulated by a large number of genes. The key role in the initiation of the apoptosis program belongs to the p53 support gene. Due to its special significance, p53 was named the genome of the 20th century. p53 maintains the stability of the genetic apparatus and controls the cell cycle.
Normally, with damage to the DNA structure or other forms of genotoxic stress, rapid activation of p53 is noted. Its protein blocks the cell cycle in the G1 phase until DNA duplication and mitosis, initiates and participates in DNA repair processes. This allows the cell to repair the damaged section of DNA, which prevents the appearance of mutant cells.
In severe irreparable damage, p53 triggers the apoptosis program and thereby prevents pathological proliferation. It is important to emphasize that p53-dependent apoptosis eliminates from the body not only damaged cells, but also those cells in which unregulated stimulation of proliferation is observed.
If p53 is mutated, it is inactivated and stops triggering the apoptotic cascade, which allows cells with damaged DNA to survive during mitosis, and this in turn leads to the survival of cells undergoing tumor transformation (Figure 3.15).
Rice. 3.15. Regulatory effect of the p53 anti-oncogene. Gene damage creates conditions for abnormal cell proliferation.
It is assumed that the increase in the incidence of neoplasia with age is associated not with the accumulation of mutations in the cell genome, but with age-related disorders of the DNA repair system.
Naturally, apoptosis is regarded as a potent antitumor defense. Inhibition of the process greatly facilitates the transformation of a normal cell into a cancerous one, since various mutations will easily accumulate in cells incapable of apoptosis.
Such mutant cells, despite DNA damage, will continue to actively multiply. The accumulation of a critical number of mutations will inevitably lead to the appearance of a neo-pastic cell and the formation of a malignant tumor (Fig. 3.16).
Rice. 3.16. Violation of the processes of proliferation (P) and apoptosis (A) of cells during oncogenesis [Filchenkov AA, Stoika RS, 1999].
Acquired resistance to apoptosis is a hallmark of most, if not all tumor clones. Avoiding apoptosis dramatically increases the viability of a neoplastic cell, making it less sensitive to antitumor immunity factors and therapeutic effects. Tumor cells acquire resistance to apoptosis in various ways.
To date, it has been established that the loss of expression on the cell surface of the death receptor Fas can lead to a weakening of the induction of apoptosis; violation of the apoptogenic signal conduction to mitochondria and inhibition of the mitochondrial membrane permeability for cytochrome C; blocking of activation and / or a sharp decrease in the lifetime of the executing caspases.
Obviously, along with proteins that turn on apoptosis, there are proteins that prevent it, and there is a delicate balance between the two. The genes promoting apoptosis belong to the suppressor genes (except for p53, BAC, PML, etc.). Genes that block the work of this defense mechanism - to protooncogenes (BCL1, BCL2, etc.).
The latter, when activated, neutralize apoptotic activity and will sharply increase the appearance of constantly proliferating mutant cell clones, and, consequently, the likelihood of subsequent development of malignant tumors from them.
It is believed that the ratio of the number of different forms of BCL and p53 oncoproteins determines the rheostat of cell life and death. In this regard, it should be noted that due to the existence of the apoptosis mechanism, it is fundamentally impossible to achieve the immortality of the organism.
Over time, atrophy of the cells of organs, regulators of the body's vital functions occurs, and a number of diseases develop, which are united by the common name -