Cellular proliferation- an increase in the number of cells through mitosis,

leading to tissue growth, as opposed to another way of increasing it

masses (eg, edema). Nerve cells lack proliferation.

In the adult body, developmental processes continue, associated

with cell division and specialization. These processes can be both normal

minimal physiological, and aimed at restoring the

ganism due to violation of its integrity.

The importance of proliferation in medicine is determined by the ability of the cell

current of different tissues to division. The healing process is associated with cell division

wounds and tissue restoration after surgical operations.

Cell proliferation is the basis of regeneration (restoration)

lost parts. The problem of regeneration is of interest to

dicina, for reconstructive surgery. Distinguish between physiological,

reparative and pathological regeneration.

Physiological- natural regeneration of cells and tissues in

ontogenesis. For example, a change in erythrocytes, skin epithelial cells.

Reparative- recovery after damage or death of cells;

current and tissues.

Pathological- proliferation of tissues that are not identical to healthy tissues;

yum. For example, the growth of scar tissue at the site of the burn, cartilage - on

the fracture site, the multiplication of connective tissue cells at the site of

cervical tissue of the heart, cancer.

Recently, it has been customary to separate the cells of animal tissues according to the method

ability to be divided into 3 groups: labile, stable and static.

TO labile include cells that are quickly and easily renewed

during the life of the body (blood cells, epithelium, mucous

stand gastrointestinal tract, epidermis, etc.).

TO stable include cells of organs such as the liver, pancreas

duct gland, salivary glands, etc., which show limited

new ability to divide.

TO static include cells of the myocardium and nervous tissue, which

rye, according to most researchers, do not share.

The study of cell physiology is essential for understanding it

togenetic level of organization of living things and mechanisms of self-regulation

cells that ensure the integral functioning of the whole organism.

Chapter 6

GENETICS HOW THE SCIENCE. REGULARITIES

INHERITANCE SIGNS

6.1 Subject, tasks and methods of genetics

Heredity and variability are fundamental

properties of the living, since they are characteristic of living beings of any level of the organ-

nization. The science that studies the laws of heredity and variability

news is called genetics.

Genetics as a science studies heredity and hereditary

fickleness, namely, it deals with following problems:

1) storage of genetic information;

2) transfer of genetic information;

3) the implementation of genetic information (its use in a specific

signs of a developing organism under the influence of the external environment);

4) change in genetic information (types and causes of changes,

mechanisms).

The first stage in the development of genetics - 1900-1912. Since 1900 - re-

coverage of the laws of G. Mendel by scientists H. De Vries, K. Correns, E. Cher-

poppy seeds. Recognition of the laws of G. Mendel.

The second stage 1912-1925 - creation of the chromosome theory by T. Mor-

Ghana. The third stage 1925-1940 - the discovery of artificial mutagenesis and

genetic processes of evolution.

The fourth stage 1940–1953 - research on gene control

physiological and biochemical processes.

The fifth stage from 1953 to the present is the development of molecular

biology.

Some information on the inheritance of traits was known

a very long time ago, however, the scientific basis for the transmission of signs was first

are outlined by G. Mendel in 1865 in the work: "Experiments on plant

hybrids ". These were progressive ideas, but contemporaries did not give

the meaning of its discovery. The concept of "gene" did not exist at that time, and G. Men-

del talked about the "hereditary inclinations" contained in the reproductive cells

kah, but their nature was unknown.

In 1900, independently of each other, H. De Vries, E. Cermak and K. Cor-

rens rediscovered the laws of G. Mendel. This year is considered the year of birth

denya genetics as a science. In 1902 T. Boveri, E. Wilson and D. Setton de-

They made an assumption about the relationship of hereditary factors with chromosomes.

In 1906 W. Betson introduced the term "genetics", and in 1909 W. Johansen -

"gene". In 1911, T. Morgan and colleagues formulated the main

genius of the chromosomal theory of heredity. They proved that genes

located at specific loci of chromosomes in a linear order,

the development of a certain feature.

The main methods of genetics: hybridological, cytological and

mathematical. Genetics also actively uses methods of other related

sciences: chemistry, biochemistry, immunology, physics, microbiology, etc.

Endocrine, paracrine and autocrine regulation. Normally, cells divide exclusively under the influence of various factors of the internal environment of the body (and external - in relation to the cell). This is their fundamental difference from transformed cells dividing under the influence of endogenous stimuli. There are two types of physiological regulation - endocrine and paracrine. Endocrine regulation is carried out by specialized organs (endocrine glands), including the pituitary gland, adrenal glands, thyroid, parathyroid, pancreas and gonads. They secrete the products of their activity into the blood and have a generalized effect on the entire body.
Paracrine regulation is characterized by the fact that in the same tissue, neighboring cells act on each other through secreted and diffused active substances. These mitogenic stimulants (polypeptide growth factors) include epidermal growth factor, platelet growth factor, interleukin-2 (T-cell growth factor), nerve growth factor, and many others.
Autocrine regulation characteristic of tumor cells differs from paracrine regulation in that the same cell is both the source of the growth factor and its target. The result is an incessant, self-sustaining mitogenic "excitation" of the cell, leading to unregulated reproduction. In this case, the cell does not need external mitogenic stimuli and becomes completely autonomous.
Transfer of a mitogenic signal is a multi-stage process. Depending on the type of cell and on the specific mitogenic stimulus, one of the many signaling pathways is realized. The so-called MAP kinase cascade is described below as a "prototype".
Growth factors (regulators of proliferation) are secreted by some cells and act in a paracrine manner on others. These are small proteins. The EGF (epidermal growth factor) polypeptide chain consists, for example, of 53 amino acids. There are several families of growth factors, a representative of each of which is united by structural and functional similarities. Some of them stimulate proliferation (for example, EGF and PDGF, platelet-derived growth factor, platelet-derived growth factor), while others (TGF-p, TNF, interferons) suppress it.
The receptors are located on the cell surface. Each cell has its own receptor repertoire and, accordingly, its own special set of responses. A very functionally important family is formed by the so-called tyrosine kinase receptors (TCR), which have enzymatic (protein kinase) activity. They consist of several domains (structural and functional blocks): extracellular (interacting with a ligand - in this case with a growth factor), transmembrane and submembrane, with tyrosine protein kinase activity. Depending on the structure, TCRs are subdivided into several subclasses.
Upon binding to growth factors (for example, EGF), receptor molecules dimerize, their intracellular domains approach each other and induce intermolecular autophosphorylation at tyrosine. This transmembrane signal transfer is the beginning of a wave of "excitation", which then propagates in the form of a cascade of phosphorylation reactions into the cell and eventually reaches the chromosomal apparatus of the nucleus. TCRs have tyrosine kinase activity, but as the signal moves into the cell, the type of phosphorylation changes to serine / threonine.
Ras proteins. One of the most important is the signaling pathway involving Ras proteins (this is a subfamily of so-called G-proteins that form complexes with guanyl nucleotides; Ras-GTP is the active form, Ras-GDP is inactive). This pathway - one of the main pathways in the regulation of cell division in higher eukaryotes - is so conservative that its components are capable of replacing the corresponding homologues in the cells of Drosophila, yeast, and nematodes. It mediates numerous signals emanating from the environment and functions, apparently, in every cell of the body. Ras acts as a kind of turnstile through which almost any signal entering the cell must pass. The critical role of this protein in the regulation of cell division has been known since the mid-1980s, when an activated form of the corresponding gene (Ras oncogene) was found in many human tumors. Activation of an oncogene (oncogenes are genes that cause unregulated cell division) is one of the main events of carcinogenesis. This is such a damage to the normal gene involved in the regulation of cell reproduction (protooncogene - a normal cell gene capable of inducing tumor growth when the structure is disturbed), which makes it permanently working (active) and, thereby, inducing an equally continuous (unregulated) cell division. Since many cellular genes (protooncogenes) are involved in the regulation of cell reproduction, damage to which can potentially cause tumor growth, therefore, there are also many (several tens, and possibly hundreds) of oncogenes.
In a specific situation of the Ras-mediated signaling pathway (for example, when EGF interacts with the receptor), dimerization of the latter leads to autophosphorylation of one of the tyrosine residues in its submembrane domain. As a result, self-assembly (“recruiting” into a complex) of a number of proteins located downstream of the signaling pathway (adapter protein Grb2, protein Sos1) becomes possible. This multiprotein complex is localized in the plasma membrane.
MAP kinase cascade. MAP-kinases (mitogen activated protein kinases) - serine / threonine protein kinases, activated as a result of mitogenic stimulation of the cell. The kinase cascade arises as a result of the sequential activation of one enzyme by another, which is "higher" in the signaling pathway. As a consequence of the stimulation of the Ras protein and the formation of a submembrane complex, the activity of two cytoplasmic serine / threonine MAP kinases (also known as ERK1 and ERK2, extracellular signal-regulated protein kinases 1 and 2) increases, which move from the cytoplasm to the cell nucleus, where they phosphorylate key transcription factors - proteins that regulate the activity of various genes.
Transcription activation. The group of genes that determine the entry of the cell into the S phase is activated by the AP-1 transcription factor - a complex of Jun and Fos proteins (the genes coding for them - c-Jun and c-Fos, are among the protooncogenes; c - from cell, denotes their cellular origin in contrast to viral oncogenes v-Jun and v-Fos). These transcription factors can interact with each other to form a variety of homo- and heterodimers that bind to certain regions of DNA and stimulate RNA synthesis on genes adjacent to these regions. MAP kinases increase AP-1 activity in two ways:
mediated, activating genes encoding these transcription factors, and thereby increasing their content in the cell;
direct, phosphorylating their constituent serine and threonine residues.
As a result of gene activation, proteins are produced that are necessary for DNA synthesis and subsequent mitosis. Some of the newly formed proteins (Fos, Jun, Myc), known as immediateearly proteins, perform regulatory functions; by binding to specific regions of DNA, they activate adjacent genes. Another group consists of enzymes such as thymidine kinase, ribonucleotide reductase, dihydrofolate reductase, thymidylate synthase, ornithine decarboxylase, DNA polymerase, topoisomerases and enzymes that are directly related to DNA synthesis. In addition, overall protein synthesis is enhanced, since all cellular structures are reproduced with each doubling cycle.
Implementation of the mitogenic signal. The result of the transfer of the mitogenic signal is the implementation of a complex program of cell division.
Cell cycle. Cells can be in one of three states - in the division cycle, in the resting stage with the preservation of the possibility of returning to the cycle, and, finally, in the stage of terminal differentiation, in which the ability to divide is completely lost. Only those cells that have retained the ability to divide can form tumors.
The doubling cycle of different human cells varies from 18 hours (bone marrow cells) to 450 hours (colon crypt cells), on average 24 hours.Mitosis (M) and DNA synthesis (phase S), between which two intermediate (gap) are distinguished period - G1 and G2, the most noticeable; during interphase (the period between two divisions), the cell grows and prepares for mitosis. During the G1 phase, there is a moment (the so-called restriction point R) when the choice is made between entering the next division cycle or entering the G0 resting stage. The entry of a cell into the cycle of division is a probabilistic process determined by a combination of a number of conditions (internal and external); however, once the selection is made, the subsequent steps are automatic. Although a cell can become blocked at one stage or another in the division cycle, this can usually be due to some special circumstance.
Particularly important in the cycle are the moments when the cell enters the DNA synthesis phase (G / S phase boundary) and mitosis (G2 / M phase boundary), where a kind of "checkpoints" operate, which in the first case check the integrity of DNA ( its readiness for replication), and in the second - the completeness of replication. Cells with damaged or under-replicated DNA are blocked at the boundary of the corresponding phases, which prevents the transmission of defects in its structure to the offspring in the form of mutations, deletions and other disorders. A certain system of supervision, apparently existing in the cell, induces a DNA repair system, after the completion of which the movement of the cell along the cycle can be continued. An alternative to repair is apoptosis, which radically eliminates the risk of a clone of defective (potentially tumor) cells in the body. The specific choice depends on many conditions, including the individual characteristics of the cell.
The process of DNA replication is complex and time-consuming (it takes several hours), since all the genetic material of a cell must be reproduced absolutely exactly. If any deviations occur in it, the cell is blocked on the approach to mitosis (at the G2 / M phase boundary) and may also undergo apoptosis. The protective value of checkpoints can hardly be overestimated, since their functional defects ultimately result in both tumor transformation of the cell and the progression of an already formed tumor.
Cyclic reactions. There are two families of proteins that "move" the cell cycle - cyclin (cyclin) -dependent serine / threonine protein kinases (Cdk, cyclin-dependent kinases) and the cyclins themselves. Cyclins regulate the activity of Cdk and thus their ability to modify target structures directly involved in the metamorphosis of the cycle. With their participation, such important stages of the cycle as the disintegration of the nuclear membrane, condensation of chromatin, the formation of the spindle, and a number of others are carried out. Cdk are active only in combination with one of the cyclins. In this regard, the assembly and activation of numerous Cdkcyclin complexes, as well as their dissociation, are key moments of the cell cycle.
As their name suggests, cyclins are synthesized and disintegrated at strictly defined points in the cycle, which are different for different cyclins. There are three main classes of them: dL cyclins, which are necessary for the passage of GyS, S-cyclins - for the passage of the S-phase, and G2 (or mitotic) - cyclins for entering mitosis. There are also several Cdk families in mammalian cells that are involved in different regulatory influences. Removal of one or another cyclin from the intracellular environment strictly at a certain moment is just as important as its appearance (elimination of cyclins from the intracellular environment is achieved both by their degradation and by a synthesis block), for example, in mitosis (at the border of meta- and anaphase) as a result proteolysis, one of the cyclins is rapidly degraded; if this does not happen, then mitosis cannot be completed and the separation of daughter cells does not occur.
Advancement in the S phase requires the activation of kinases Cdk2, Cdk4, and Cdk6, which interact with H-phase cyclins (in particular, with cyclin D). The complex of Cdc2 with the first dLphase cyclin induces transcription of the gene of the next cyclin, etc., moving the cells further and further along the cycle. At the very beginning, Cdc2-cyclin D is replaced by Cdc2-cyclin E, which, in turn, is replaced by Cdc2-cyclin A, which activates the DNA synthesis apparatus. When the cell enters the S-phase, dL cyclines degrade and reappear only in the G1 phase of the next cycle.
Checkpoints (English). Any stressful effect (for example, lack of nutrients, hypoxia, especially DNA damage) blocks movement 'along the cycle at one of the two checkpoints mentioned above. During these stops, oversight mechanisms are activated that can:
detect DNA damage;
transmit a signal of distress that blocks DNA synthesis, or
mitosis;
activate the mechanisms of DNA repair.
This ensures the stability of the genome. As mentioned above, the G / S control mechanism blocks DNA replication and activates repair processes (or induces apoptosis), while the G2 / M control mechanism inhibits mitosis until replication is complete. Defects in these mechanisms can lead to the appearance of daughter cells with a damaged genome.
The checkpoint mechanism involves the Cdk-cyclin complexes and a number of additional proteins - Rb, p53, and others. Their combination forms a system of "brakes" that prevent the cell from dividing in the absence of adequate stimuli. The genes encoding these proteins are called suppressor genes. The special significance of this system lies in the fact that the cancerous transformation of the cell becomes possible only after its inactivation. In a somatic cell, there are two alleles of each of the genes, including suppressor genes, and, therefore, two independent events are required for their inactivation (for example, deletion of one allele and mutation of another). It is for this reason that "sporadic" tumors appear relatively rarely (the likelihood of several independent mutations occurring in one cell, affecting the same locus of both chromosomes, is relatively small), and "familial" tumors are extremely frequent (in "cancer" families one of two the inherited alleles of a particular suppressor gene are initially defective). In the latter case, the system of "brakes" in all cells of a given organism is provided with only one normal allele, which sharply reduces its reliability and increases the risk of a tumor. This is exactly what happens in hereditary retinoblastoma (deletion of one Rb allele) and other hereditary syndromes (deletion or damage of one allele p53 or other suppressor genes).
In cells with defective or absent p53 suppressor protein, the GyS checkpoint is defective. This is manifested in the fact that DNA damage induced by ionizing radiation or in any other way does not lead to cell retention at the G 1 / S phase boundary or capoptosis. As a result, the population accumulates cells with multiple violations of the DNA structure; genome instability appears and grows over time, which contributes to the emergence of new cell clones. Their natural selection underlies the tumor progression - the constant "drift" of the tumor towards ever greater autonomy and malignancy.
Apoptosis (or programmed cell death) is a widespread biological phenomenon of cellular “suicide”, which is induced either by various external stimuli or by insoluble “internal” conflicts (for example, the inability to repair DNA damage). The role of apoptosis is great not only in morphogenetic processes during embryogenesis (organ formation, replacement of some tissues with others, resorption of temporary organs, etc.), but also in maintaining tissue homeostasis in an adult organism.
In the regulation of tissue homeostasis, cell death performs a function complementary to mitosis. In tumor cells, the cell death program is in most cases blocked, which makes a significant contribution to the increase in tumor mass.
Apoptosis mechanisms. Of fundamental importance is the fact that the mechanisms of apoptosis are extremely conservative and retain their basic regularities in organisms that are very far in evolutionary terms. This circumstance made it possible to identify genes in mammals (in particular in humans) that are homologous to genes for apoptosis in nematodes, an organism in which the genetic system governing this process was first discovered and studied.
As a result, genes of the Bcl-2 family were identified in mammals. The role of Bc1-2 itself and some of its homologues is anti-apoptotic (preventing cell death), while in other family members, for example, Bax, it is pro-apoptotic. Proteins Bax and Bc1-2 are capable of complexation with each other. The fate of a given cell is decided depending on the relative intracellular content of pro- and anti-apoptotic proteins. The mechanism of action of proteins of the Bcl-2 family is not completely clear.
Of great functional importance is the mechanism of apoptosis induced through specific receptors CD95 (a 45 kDa transmembrane receptor protein, which, when bound to a specific ligand or antibodies, transmits a signal to apoptosis) and TNF-R (tumor necrosis factor receptor, tumor necrosis factor receptor). These receptors, united by the similarity of extracellular domains, are part of a large family. Ligands (molecules that specifically interact with TNF-R and CD95 receptors) are TNF and CD95-L, respectively, which are transmembrane proteins, but can also function in a soluble, "free" form. Of particular interest from an oncological point of view is TNF, a cytokine produced by many cells (macrophages, monocytes, lymphoid cells, fibroblasts) in response to inflammation, infection, and other stressful influences. It induces a wide range of sometimes opposite reactions, including fever, shock, tumor necrosis, anorexia; as well as immunoregulatory shifts, cell proliferation, differentiation and apoptosis. In this case, apoptosis is mediated by the specific cysteine ​​protease ICE, which destroys many intracellular target proteins. Overexpression of ICE in the cell induces apoptosis. size = 5 face = "Times New Roman">

1. Growth factors(macrophages, lymphocytes, fibroblasts, platelets, etc.) - stimulation of proliferation and limitation of apoptosis.

2. Keylons- glycoprotein tissue-specific growth inhibitors.

3. Fibronectin fibroblast chemoattractant.

4. Laminin- the main adhesive protein of the basement membranes.

5. Sindekan-integral proteoglycan of cell membranes, binds collagen, fibronectin and thrombospondin.

6. Thrombospondin- a glycoprotein, forms complexes with syndecan, collagen and heparin, plays an essential role in the assembly of bone tissue.

The formation and realization of the effects of biologically active substances (BAS) is one of the key links of inflammation. BAS provide the regular nature of the development of inflammation, the formation of its general and local manifestations, as well as the outcomes of inflammation. That is why biologically active substances are often referred to as "Inflammatory mediators".

Inflammatory mediators- These are local chemical signals formed, released or activated in the focus of inflammation, acting and destroyed also within the focus. Mediators (mediators) of inflammation are biologically active substances responsible for the occurrence or maintenance of certain inflammatory phenomena, for example, increased vascular permeability, emigration, etc.

These are the same substances that, under conditions of normal vital activity of the body, being formed in various organs and tissues in physiological concentrations, are responsible for the regulation of functions at the cellular, tissue level. In case of inflammation, being locally released (due to the activation of cells and liquid media) in large quantities, they acquire a new quality - inflammatory mediators. Almost all mediators are also modulators of inflammation, that is, they are able to enhance or weaken the severity of inflammatory phenomena. This is due to the complexity of their influence and their interaction both with the producing cells of these substances and among themselves. Accordingly, the effect of a mediator can be additive (additive), potentiating (synergistic) and weakening (antagonistic), and the interaction of mediators is possible at the level of their synthesis, secretion or effects.

The mediator link is the main one in the pathogenesis of inflammation. It coordinates the interaction of many cells - the effectors of inflammation, the change of cellular phases in the focus of inflammation. Accordingly, the pathogenesis of inflammation can be thought of as a chain of multiple intercellular interactions regulated by mediators-modulators of inflammation.

Inflammatory mediators determine the development and regulation of alteration processes (including changes in metabolism, physicochemical parameters, structure and function), the development of vascular reactions, fluid exudation and emigration of blood cells, phagocytosis, proliferation and reparative processes in the focus of inflammation.

Most mediators perform their biological functions by specifically acting on the receptors of target cells. However, some of them have direct enzymatic or toxic activity (for example, lysosomal hydrolases and active oxygen radicals). The functions of each mediator are regulated by the corresponding inhibitors.

Sources of inflammatory mediators can be blood plasma and cells participating in inflammation. In accordance with this, 2 large groups of inflammatory mediators are distinguished: humoral and cellular. Humoral

mediators are mainly represented by polypeptides that constantly circulate in the blood in an inactive state and are synthesized mainly in the liver. These mediators make up the so-called "Watchdog polysystem of blood plasma". Cell mediators can be synthesized de novo (for example, metabolites of arachidonic acid) or released from cell stores (for example, histamine). Sources of cellular mediators in the focus of inflammation are mainly macrophages, neutrophils and basophils.

Of the humoral mediators of inflammation, the most important are derivatives of complement. Among almost 20 different proteins formed during the activation of complement, its fragments C5a, C3a, C3b and the C5b-C9 complex are directly related to inflammation. Moreover, C5a and, to a lesser extent, C3a are mediators of acute inflammation. C3b opsonizes the pathogenic agent and, accordingly, promotes immune adhesion and phagocytosis. The C5b-C9 complex is responsible for the lysis of microorganisms and pathologically altered cells. The source of complement is blood plasma and, to a lesser extent, interstitial fluid. Enhanced delivery of plasma complement to tissue is one of the important uses of exudation. C5a, formed from it in plasma and tissue fluid under the influence of carboxypeptidase N, C5a des Arg and C3a increase the permeability of postcapillary venules. At the same time, C5a and C3a, being anaphylatoxins (i.e., histamine liberators from mast cells), increase permeability both directly and indirectly through histamine.The effect of C5a des Arg is not associated with histamine, but is neutrophil-dependent, i.e. permeability factors released from polymorphonuclear granulocytes - lysosomal enzymes and non-enzymatic cationic proteins, active oxygen metabolites. In addition, C5a and C5a des Arg attract neutrophils. In contrast, C3a has practically no chemotactic properties. The active components of the complement release not only histamine and granulocyte products, but also interaeukin-1, prostaglandins, leukotrienes, a factor that activates platelets, and synergistically interact with prostaglandins and substance P.

Kinin- vasoactive peptides formed from kininogens (alpha2-globulins) under the influence of kallikreins in plasma (nonapeptide bradykinin) and in tissue fluid (decapeptide lysilbradykinin, or kallidin). The triggering factor for the activation of the kallikrein-kinin system is the activation of the Hageman factor (factor XII of blood coagulation) in tissue damage, which converts prekallikreins into kallikreins.

Kinins mediate the expansion of arterioles and an increase in venule permeability by contraction of endothelial cells. They contract the smooth muscle of the veins and increase intracapillary and venous pressure. Kinins inhibit the emigration of neutrophils, modulate the distribution of macrophages, stimulate the migration and mitogenesis of T-lymphocytes and the secretion of lymphokines. They also enhance fibroblast proliferation and collagen synthesis and, therefore, may be important in reparative phenomena and in the pathogenesis of chronic inflammation.

One of the most significant effects of kinins is the activation of reflexes by irritating the endings of the sensory nerves and thus mediating inflammatory pain. Kinins cause or enhance the release of histamine from mast cells, the synthesis of prostaglandins by many types of cells, therefore some of their main effects - vasodilation, smooth muscle contraction, pain - are associated with the release of other mediators, especially prostaglandins.

Activation of the Hageman factor triggers not only the process of kinin formation, but also blood coagulation and fibrinolysis. In this case, such mediators as fibrinopeptides and fibrin degradation products are formed, which are powerful hematractants. In addition, fibrinolysis and the formation of blood clots in the vessels of the focus are essential both in the pathological and protective phenomena of inflammation.

Of the cellular mediators, of primary interest are eicosanoids since most likely they are the central mediator of the inflammatory response. This is evidenced by the long-term maintenance of the production of eicosanoids in the focus, their close relationship with the key event of the inflammatory process - leukocyte infiltration, the powerful anti-inflammatory effect of inhibitors of their synthesis.

The main role in the production of eicosanoids in the focus of inflammation is played by leukocytes, especially monocytes and macrophages, although they are formed by almost all types of nuclear cells upon stimulation of the latter. The predominant eicosanoids in the focus of inflammation are almost always prostaglandin (PG) E2, leukotriene (LT) B4, and 5-hydroxyeicosatetraenoic acid (5-HETE). Thromboxane (Tx) A2, PGF2alpha, PGD2, prostacyclin (PG12), LTS4, LTD4, LTE4, and other GETE are also formed, albeit in a smaller amount.

The main effects of eicosanoids in inflammation are on leukocytes. PG, TCS and especially LT are powerful hematractants and thus play an important role in the mechanisms of self-maintenance of leukocyte infiltration. PGs themselves do not increase vascular permeability, but, being strong vasodilators, increase hyperemia and, consequently, exudation. LTV4, JITD4, LTE4 increase vascular permeability by direct contraction of endothelial cells, and LTV4 - as a neutrophil-dependent mediator. PH and LT are important in the genesis of inflammatory pain. At the same time, PGE2, without having direct painful activity, increases the sensitivity of the receptors of afferent pain nerve endings to bradykinin and histamine. PGE2 is a potent antipyretic agent, and the fever of inflammation may be due in part to its release. PGs play a key role in modulating the inflammatory process, carrying out a bidirectional regulation of exudation, emigration and degranulation of leukocytes, phagocytosis. For example, PGE is able to potentiate the development of edema caused by histamine or bradykinin, while PGF2alpha, on the contrary, can weaken. A similar relationship between PGE and PGF2alpha also applies to leukocyte emigration.

An especially wide range of interactions with other inflammatory mediators is characteristic of RT. They synergistically interact in relation to bronchospasm with histamine, acetylcholine, PG and TCS, stimulate the release of PG and TCS. The modulatory function of eicosanoids is carried out through changes in the ratio of cyclic nucleotides in cells.

Sources histamine are basophils and mast cells. Serotonin(neurotransmitter) in humans, in addition to a small amount in mast cells, it is also found in platelets and enterochromaffin cells. Due to its rapid release during the degranulation of mast cells , the ability to change the lumen of microvessels and cause direct contraction of endothelial cells of venules, histamine and serotonin are considered the main mediators of initial microcirculatory disorders in the focus of acute inflammation and the immediate phase of increasing vascular permeability. Histamine plays a dualistic role in both blood vessels and cells. Through the H2 receptors, it dilates the arterioles, and through the H1 receptors, it narrows the venules and, thus, increases the intracapillary pressure. Through Hi-receptors, histamine stimulates, and through H1-receptors inhibits the emigration and degranulation of leukocytes. In the normal course of inflammation, histamine acts primarily through the H1 receptors on neutrophils, limiting their functional activity, and through the H1 receptors on monocytes, stimulating them. Thus, along with pro-inflammatory vascular effects, it has anti-inflammatory cellular effects. Serotonin also stimulates monocytes at the site of inflammation. Histamine carries out bi-directional regulation of proliferation, differentiation and functional activity of fibroblasts and, therefore, may be of importance in reparative phenomena. The modulatory effects of histamine are also mediated by cyclic nucleotides.

As for the interactions of biogenic amines in the focus of inflammation, it is known that histamine through Hi-receptors can trigger or enhance the synthesis of prostaglandins, and through H-receptors - to inhibit. Biogenic amines interact both with each other and with bradykinin, nucleotides and nucleosides, substance P in increasing vascular permeability. The vasodilating effect of histamine is enhanced in combination with acetylcholine, serotonin, bradykinin.

The main source lysosomal enzymes in the focus of inflammation are phagocytes - granulocytes and monocytes-macrophages. Despite the great importance in the pathogenesis of inflammation of phagocytosis, phagocytes are primarily mobile carriers of mediator-modulators secreted extracellularly. The release of lysosomal contents is carried out during their chemotactic stimulation, migration, phagocytosis, damage, death. The main components of lysosomes in humans are neutral proteinases - elastase, cathepsin G and collagenases contained in primary, azurophilic, neutrophil granules. In the processes of antimicrobial protection, including inflammation, proteinases belong to the “second order” factors after oxygen-dependent (myeloperoxidase - hydrogen peroxide) and oxygen-independent mechanisms such as lactoferrin and lysozyme. They provide mainly the lysis of already killed microorganisms. The main effects of proteinases are mediation and modulation of inflammatory phenomena, including damage to one's own tissues. The mediator and modulatory effects of proteinases are carried out in relation to vascular permeability, emigration, phagocytosis.

An increase in vascular permeability under the influence of lysosomal enzymes occurs due to lysis of the subendothelial matrix, thinning and fragmentation of endothelial cells and is accompanied by hemorrhage and thrombosis. Forming or cleaving the most important chemotactic substances, lysosomal enzymes are modulators of leukocyte infiltration. First of all, this concerns the components of the complement system and kallikrein-kinin.

Lysosomal enzymes, depending on the concentration, can themselves enhance or inhibit the migration of neutrophils. In relation to phagocytosis, neutral proteinases also have a number of effects. In particular, elastase can form C3b opsonin; C3b is also important for the adhesion of particles to the neutrophil surface. Consequently, the neutrophil provides itself with a mechanism for enhancing phagocytosis. Both cathepsin G and elastase increase the affinity of the Fc receptor of the neutrophil membrane for immunoglobulin complexes and, accordingly, enhance the efficiency of particle absorption.

Due to the ability of lysosomal enzymes to activate the complement system, kallikrein-kinin, coagulation and fibrinolysis, to release cytokines and lymphokines, inflammation develops and self-sustains for a long time.

The most important property non-enzymatic cationic proteins, contained in both azurophilic and specific granules of neutrophils, are their high microbicidal activity. In this respect, they are in synergistic interaction with the myeloperoxidase - hydrogen peroxide system. Cationic proteins are adsorbed on the negatively charged membrane of the bacterial cell by electrostatic interaction. As a result, the permeability and structure of the membrane are disturbed and the death of the microorganism occurs, which is a prerequisite for its subsequent effective lysis by lysosomal proteinases. Released extracellularly cationic proteins mediate an increase in vascular permeability (mainly by inducing mast cell degranulation and release of histamine), adhesion and emigration of leukocytes.

The main source cytokines(monokines) in inflammation are stimulated monocytes and macrophages. In addition, these polypeptides are produced by neutrophils, lymphocytes, endothelial and other cells. The best studied cytokines are interleukin-1 (IL-1) and tumor necrosis factor (TNF). Cytokines increase vascular permeability (in a non-nitrophil-dependent way), adhesion and emigration of leukocytes. Along with the pro-inflammatory properties, cytokines can also play a role in the direct defense of the body, stimulating neutrophils and monocytes to kill, absorb and digest invading microorganisms, as well as enhancing phagocytosis by opsonizing the pathogenic agent.

By stimulating wound cleansing, cell proliferation and differentiation, cytokines enhance reparative processes. Along with this, they can mediate tissue destruction (degradation of the cartilage matrix and bone resorption) and, thus, play a role in the pathogenesis of connective tissue diseases, in particular rheumatoid arthritis.

The action of cytokines also causes a number of metabolic effects that underlie the general manifestations of inflammation - fever, drowsiness, anorexia, metabolic changes, stimulation of hepatocytes for enhanced synthesis of acute phase proteins, activation of the blood system, etc.

Cytokines interact with each other, with prostaglandins, neuropeptides and other mediators.

A number of inflammatory mediators also include lymphokines- polypeptides produced by stimulated lymphocytes. The most studied lymphokines that modulate the inflammatory response are macrophage inhibiting factor, macrophage activating factor, interleukin-2. Lymphokines coordinate the interaction of neutrophils, macrophages and lymphocytes, thus regulating the inflammatory response in general.

Active oxygen metabolites, first of all, free radicals - superoxide anion radical, hydroxyl radical HO, perhydroxyl, due to the presence of one or more unpaired electrons in their outer orbit, have increased reactivity with other molecules and, therefore, a significant destructive potential, which is important in the pathogenesis of inflammation. The source of free radicals, as well as other oxygen-derived mediators and modulators of inflammation - hydrogen peroxide (H 2 0 2), singlet oxygen (f0 2), hypochlorite (HOC1) are: respiratory explosion of phagocytes during their stimulation, arachidonic acid cascade in the process of eicosanoid formation, enzymatic processes in the endoplasmic reticulum and peroxysomes, mitochondria, cytosol, as well as the self-oxidation of small molecules such as hydroquinones, leucoflavins, catecholamines, etc.

The role of active oxygen metabolites in inflammation consists, on the one hand, in increasing the bactericidal ability of phagocytes and, on the other hand, in their mediator and modulatory functions. The mediatory role of active oxygen metabolites is due to their ability to cause lipid peroxidation, oxidation of proteins, carbohydrates, and damage to nucleic acids. These molecular changes underlie the phenomena caused by active oxygen metabolites that are characteristic of inflammation - an increase in vascular permeability (due to damage to endothelial cells), stimulation of phagocytes.

Modulator role , active oxygen metabolites can be both in the enhancement of inflammatory phenomena (by inducing the release of enzymes and interaction with them in tissue damage; not only initiation, but also modulation of the arachidonic acid cascade), and in anti-inflammatory effects (due to inactivation of lysosomal hydrolases and other mediators of inflammation ).

Active oxygen metabolites are important in maintaining chronic inflammation.

Inflammatory mediators and modulators also include neuropeptides- substances released by C-fibers as a result of activation by an inflammatory agent of polymodal nociceptors, which play an important role in the emergence of axon reflexes in the terminal branches of primary afferent (sensory) neurons. The most studied are substance P, calcitonin-gene-linked peptide, neurokinin A. Neuropeptides increase vascular permeability, and this ability is largely mediated by mediators originating from mast cells. There are membrane contacts between nonmyelinated nerves and mast cells, which provide communication between the central nervous system and the focus of inflammation.

Neuropeptides synergistically interact to increase vascular permeability both among themselves and with histamine, bradykinin, C5a, a factor that activates platelets, leukotriene B4; antagonistically with ATP and adenosine. They also have a potentiating effect on the recruitment and cytotoxic function of neutrophils, enhance the adhesion of neutrophils to the venule endothelium. In addition, neuropeptides increase the sensitivity of nociceptors to the action of various mediators, in particular prostaglandin E2 and prostacyclin, thus participating in the reconstruction of inflammatory pain.

In addition to the above substances, inflammatory mediators also include acetylcholive and catecholamines, released upon excitation of choline and adrenergic structures. Acetylcholine causes vasodilation and plays a role in the axon-reflex mechanism of arterial hyperemia during inflammation. Norepinephrine and adrenaline inhibit the growth of vascular permeability, acting primarily as modulators of inflammation.

. Chapter II
Cell reproduction. Problems of cell proliferation in medicine.
2.1. Cell life cycle.
Cell theory says that cells emerge from cells by dividing the original. This position excludes the formation of cells from non-cellular matter. Cell division is preceded by the reduplication of their chromosomal apparatus, DNA synthesis in both eukaryotic and prokaryotic organisms.

The lifetime of a cell from division to division is called the cell or life cycle. Its value varies considerably: for bacteria it is 20-30 minutes, for a shoe 1-2 times a day, for an amoeba about 1.5 days. Multicellular cells also have different ability to divide. In early embryogenesis, they often divide, and in an adult organism, for the most part, they lose this ability, since they become specialized. But even in an organism that has reached full development, many cells must divide to replace worn-out cells that are constantly sloughing off and, finally, new cells are needed to heal wounds.

Consequently, in some populations of cells, division must occur throughout life. With this in mind, all cells can be divided into three categories:

1. By the time a child is born, nerve cells reach a highly specialized state, losing their ability to reproduce. In the process of ontogenesis, their number is continuously decreasing. This circumstance also has one good side; if the nerve cells were dividing, then the higher nervous functions (memory, thinking) would be disturbed.

2. Another category of cells is also highly specialized, but due to their constant desquamation, they are replaced by new ones, and this function is performed by cells of the same line, but not yet specialized and have not lost the ability to divide. These cells are called renewing cells. An example is the constantly renewing cells of the intestinal epithelium, hematopoietic cells. Even bone cells are capable of forming from non-specialized ones (this can be observed during reparative regeneration of bone fractures). Populations of non-specialized cells that retain the ability to divide are usually called stem cells.

3. The third category of cells is an exception, when highly specialized cells, under certain conditions, can enter the mitotic cycle. These are cells with a long lifespan and where, after the complete completion of growth, cell division rarely occurs. An example is hepatocytes. But if 2/3 of the liver is removed from an experimental animal, then in less than two weeks it is restored to its previous size. The same are the cells of the glands that produce hormones: under normal conditions, only a few of them are able to reproduce, and under altered conditions, most of them can begin to divide.

The cell cycle means the repeated repetition of successive events that take a certain period of time. Cyclic processes are usually depicted graphically in the form of circles.

The cell cycle is divided into two parts: mitosis and the interval between the end of one mitosis and the beginning of the next - interphase. The autoradiography method made it possible to establish that during the interphase the cell not only performs its specialized functions, but also synthesizes DNA. This period of the interphase was called synthetic (S). It starts about 8 hours after mitosis and ends after 7-8 hours. The interval between the S-period and mitosis was called presynthetic (G1 - 4 hours) after synthetic, before mitosis itself - postsynthetic (G2). happening for about an hour.

Thus, four stages are distinguished in the cell cycle; mitosis, G1-period, S-period, G2-period.

The establishment of the fact of doubling in the interphase of DNA means that during its time the cell cannot perform specialized functions, it is busy building cellular structures, synthesizing building materials that ensure the growth of daughter cells, accumulating energy spent during mitosis itself, synthesizing specific enzymes for DNA replication ... Therefore, interphase cells in order to perform their functions predetermined by the genetic program (become highly specialized) must temporarily or permanently exit the cycle during the G0 period, or remain in the extended G1 (no significant differences in the state of the cells of the G0 and G1 periods were noted, since from G0 cells per cycle). It should be especially noted that in mature multicellular organisms, most of the cells are known to be in the G0 period.

As already mentioned, an increase in the number of cells occurs only due to the division of the original cell, which is preceded by a phase of accurate reproduction of genetic material, DNA molecules, chromosomes.

Mitotic division includes new states of cells: interphase, decondensed and already reduplicated chromosomes transform into the compact form of mitotic chromosomes, an achromatin mitotic apparatus is formed, which is involved in the transfer of chromosomes, chromosomes diverge to opposite poles and cytokinesis occurs. The process of indirect division is usually subdivided into the following main phases: prophase, metaphase, anaphase and telophase. The division is conditional, since mitosis is a continuous process and the phase change occurs gradually. The only phase that has a real beginning is anaphase, in which

the divergence of chromosomes begins. The duration of individual phases is different (on average, prophase and telophase - 30-40 ", anaphase and metaphase - 7-15"). By the beginning of mitosis, a human cell contains 46 chromosomes, each of which consists of 2 identical halves - chromatids (chromatids are also called S-chromosome, and a chromosome consisting of 2 chromatids - d-chromosome).

One of the most remarkable phenomena observed in mitosis is the formation of a fission spindle. It ensures the alignment of d-chromosomes in one plane, in the middle of the cell, and the movement of S-chromosomes to the poles. The spindle of division is formed by the centrioles of the cell center. Microtubules are formed in the cytoplasm from the protein tubulin.

In the G1-period, each cell contains two centrioles, by the time of the transition to the G2-period, a daughter centriole is formed near each centriole, and two pairs are formed in total.

In prophase, one pair of centrioles begins to move to one pole, the other to the other.

A set of interpolar and chromosomal microtubules begins to form between pairs of centrioles towards each other.

At the end of prophase, the nuclear envelope disintegrates, the nucleolus ceases to exist, chromosomes (d) spiralize, the division spindle moves to the middle of the cell, and the d-chromosomes find themselves in the spaces between the spindle microtubules.

During prophase, the D chromosomes undergo a condensation path from filamentous to rod-like structures. Shortening and thickening (d-chromosomes continue for some time in metaphase, as a result of which the metophase d-chromosomes have sufficient density. The centromere is clearly visible in the chromosomes, dividing them into equal or unequal arms, consisting of 2 adjacent S- At the beginning of the anaphase, the S chromosomes (chromatids) begin to move from the equatorial plane to the poles. Anaphase begins with the splitting of the centromeric region of each chromosome, as a result of which two S chromosomes of each d chromosome are completely separated from one another. Therefore, each daughter cell receives an identical set of 46 S chromosomes After centromere separation, one half of the 92 S chromosomes begins to move to one pole, the other half to the other.

Until today, it has not been precisely established under the influence of what forces the movement of chromosomes to the poles is carried out. There are several versions:

1. In the spindle of division there are actin-containing filaments (as well as other muscle proteins), it is possible that this force is generated in the same way as in muscle cells.

2. The movement of chromosomes is due to the sliding of chromosomal microtubules along continuous (interpolar) microtubules with opposite polarity (McItosh, 1969, Margolis, 1978).

3. The rate of movement of chromosomes is regulated by kinetochore microtubules in order to ensure orderly separation of chromatids. Most likely, all of the above mechanisms for the implementation of a mathematically accurate distribution of the hereditary substance among the daughter cells cooperate.

Towards the end of the anaphase and the beginning of the telophase, in the middle of the elongated cell, the formation of a constriction begins, it forms the so-called cleavage groove, which, deepening, divides the cell into two daughter cells. Actin filaments take part in the formation of the furrow. But as the furrows deepen, the cells are interconnected by a bundle of microtubules, called the median body, the rest of it is present for some time in the interphase. Parallel to cytokinesis, at each pole, chromosomes are despiralized in reverse order from the chromosomal to the nucleosomal level. Finally, the hereditary substance takes the form of lumps of chromatin, either tightly packed or decondensed. The nucleolus, the nuclear envelope surrounding chromatin and karyoplasm, is re-formed. Thus, as a result of mitotic cell division, the newly formed daughter cells are identical with each other and are a copy of the mother cell, which is important for the subsequent growth, development and differentiation of cells and tissues.
2.2. The mechanism of regulation of mitotic activity
Maintaining the number of cells at a certain, constant level provides overall homeostasis. For example, the number of erythrocytes and leukocytes in a healthy body is relatively stable, despite the fact that these cells die off, they are constantly replenished. Therefore, the rate of new cell formation must be regulated to match the rate of cell death.

To maintain homeostasis, it is necessary that the number of various specialized cells in the body and the functions that they must perform are under the control of various regulatory mechanisms that maintain all this in a stable state.

In many cases, the cells are given a signal that they must increase their functional activity, and this may require an increase in the number of cells. For example, if the Ca content in the blood falls, then the cells of the parathyroid gland increase the secretion of the hormone, the calcium level reaches normal. But if the animal's diet lacks calcium, then the additional production of the hormone will not increase the content of this element in the blood.In this case, the cells of the thyroid gland begin to rapidly divide, so that an increase in their number will lead to a further increase in the synthesis of the hormone. Thus, a decrease in one or another function can lead to an increase in the population of cells providing these functions.

In people entering the highlands, the number of erythrocytes increases sharply (at an altitude of less than 02) in order to provide the body with the necessary amount of oxygen. Renal cells respond to a decrease in oxygen and increase the secretion of erythropoietin, which enhances hematopoiesis. After the formation of a sufficient number of additional erythrocytes, hypoxia disappears and the cells that produce this hormone reduce its secretion to the usual level.

Fully differentiated cells cannot divide, but nevertheless their number can increase due to the stem cells from which they originated. Nerve cells cannot divide under any circumstances, but they can increase their function by increasing their processes and multiplying the connections between them.

It should be noted that in adults, the ratio of the total sizes of various organs remains more or less constant. With an artificial violation of the existing ratio of the size of the organ, it tends to the norm (the removal of one kidney leads to an increase in the other).

One of the concepts explaining this phenomenon is that cell proliferation is regulated by special substances - keylons. It is assumed that they have specificity for cells of different types, organ tissues. It is believed that a decrease in the number of keylons stimulates cell proliferation, for example, during regeneration. Currently, this problem is being carefully studied by various specialists. Data have been obtained that keylons are glycoproteins with a molecular weight of 30,000 - 50,000.

2.3. Irregular types of cell reproduction
Amitosis... Direct division, or amitosis, is described earlier than mitotic division, but is much less common. Amitosis is cell division in which the nucleus is in an interphase state. In this case, there is no condensation of chromosomes and the formation of a fission spindle. Formally, amitosis should lead to the appearance of two cells, but most often it leads to the division of the nucleus and the appearance of two- or multinucleated cells.

The amitotic division begins with the fragmentation of the nucleoli, followed by the division of the nucleus by the constriction (or invagination). There can be multiple division of the nucleus, as a rule of unequal size (in pathological processes). Numerous observations have shown that amitosis is almost always found in cells that are dying, degenerating and are not capable of producing full-fledged elements in the future. So, normally, amitotic division occurs in the embryonic membranes of animals, in the follicular cells of the ovary, in the giant cells of trophoblasts. Amitosis has a positive value in the process of tissue or organ regeneration (regenerative amitosis). Amitosis in senescent cells is accompanied by disturbances in biosynthetic processes, including replication, DNA repair, and transcription and translation. The physicochemical properties of the proteins of the chromatin of cell nuclei, the composition of the cytoplasm, the structure and functions of organelles change, which entails functional disturbances at all subsequent levels - cellular, tissue, organ and organism. With the growth of destruction and extinction of restoration, natural cell death occurs. Often, amitosis occurs in inflammatory processes and malignant neoplasms (induced amitosis).

Endomitosis. When the cells are exposed to substances that destroy the spindle microtubules, division stops, and the chromosomes will continue the cycle of their transformations: replicate, which will lead to the gradual formation of polyploid cells - 4 p. 8 p., Etc. This transformation process is otherwise called endoreproduction. The ability of cells to endomitosis is used in plant breeding to obtain cells with a multiple set of chromosomes. For this, colchicine, vinblastine are used, destroying the threads of the achromatin spindle. Polyploid cells (and then adult plants) are large in size, the vegetative organs of such cells are large, with a large supply of nutrients. In humans, endoreproduction takes place in some hepatocytes and cardiomyocytes.

Another, rarer result of endomitosis is polytene cells. During polyteny in the S-period, as a result of replication and nondisjunction of chromosomal filaments, a multi-filamentous, polytene structure is formed. They differ from mitotic chromosomes by their large size (200 times longer). Such cells are found in the salivary glands of dipterans, in the macronuclei of ciliates. On polytene chromosomes, bulges are visible, puffs (transcription sites) - an expression of gene activity. These chromosomes are the most important object of genetic research.
2.4. Problems of cell proliferation in medicine.
It is known that tissues with a high rate of cell renewal are more sensitive to the effects of various mutagens than tissues in which cells are renewed slowly. However, for example, radiation damage may not appear immediately and does not necessarily weaken with depth, sometimes it even damages deep-lying tissues much more than superficial ones. When cells are irradiated with X-rays or gamma rays, gross violations occur in the life cycle of cells: mitotic chromosomes change shape, their breaks occur, followed by an incorrect connection of fragments, sometimes individual parts of chromosomes disappear altogether. Spindle anomalies may occur (not two poles in the cell, but three), which will lead to uneven separation of chromatids. Sometimes the damage to the cell (large doses of radiation) is so significant that all attempts of the cell to start mitosis are unsuccessful and division stops.

A similar effect of radiation is partly explained by its use in tumor therapy. The purpose of irradiation is not to kill tumor cells in interphase, but to make them lose their ability to mitosis, which will slow down or stop tumor growth. Radiation in doses that are not lethal to the cell can cause mutations, leading to increased proliferation of altered cells and give rise to malignant growth, as often happened with those who worked with X-rays without knowing their dangers.

Many chemicals, including drugs, affect cell proliferation. For example, the alkaloid, colchicine (contained in colchicum corms) was the first drug to relieve joint pain in gout. It turned out that it also has another effect - to stop division by binding to proteins with tubulins from which microtubules are formed. Thus, colchicine, like many other drugs, blocks the formation of the fission spindle.

On this basis, alkaloids such as vinblastine and vincristine are used to treat certain types of malignant neoplasms, being part of the arsenal of modern chemotherapeutic anticancer drugs. It should be noted that the ability of substances like colchicine to stop mitosis is used as a method for the subsequent identification of chromosomes in medical genetics.

Of great importance for medicine is the ability of differentiated (moreover, sex) cells to maintain their potency for proliferation, which sometimes leads to the development of tumors in the ovaries, on the section of which cell sheets, tissues, organs are seen, which are a "jumble". Scraps of skin, hair follicles, hair, ugly teeth, pieces of bones, cartilage, nerve tissue, eye fragments, etc. are revealed, which requires urgent surgical intervention.

2.5. Cell reproduction pathology
Mitotic cycle anomalies.. The mitotic rhythm, usually adequate to the need for the restoration of aging, dead cells, in conditions of pathology can be changed. A slowdown in the rhythm is observed in aging or low-vascularized tissues, an increase in rhythm in tissues with various types of inflammation, hormonal influences, in tumors, etc.

The cell is an elementary unit of all living things. There is no life outside the cell. Cell reproduction occurs only by division of the original cell, which is preceded by the reproduction of its genetic material. Cell division is activated as a result of exposure to external or internal factors. The process of cell division from the moment it is activated is called proliferation. In other words, proliferation is cell multiplication, i.e. an increase in the number of cells (in culture or tissue), occurring by mitotic divisions. The lifetime of a cell as such, from division to division, is usually called the cell cycle.

INTRODUCTION 3
CHAPTER I. Proliferation 4
Cell cycle 5
Cell cycle regulation 6
Exogenous regulators of proliferation 7
Endogenous regulators of proliferation 7
Regulatory pathways of CDK 8
Regulation G1 phase 10
S phase 11 regulation
Regulation G2 phase 12
Regulation of mitosis 12
DNA damage 13
1.10.1 Ways to repair double-stranded DNA breaks 13
1.10.2 Cellular response to DNA damage and its regulation 14
1.11. Tissue regeneration 15
1.11.1 Forms of regeneration 16
1.11.2. Regulation of tissue regeneration 17
CHAPTER II. APOPTOSIS 18
2.1. Characteristic signs of apoptosis 19
2.2. Apoptosis mechanism 19
2.3. The role of apoptosis in protection against cancer 20
2.4. Regulation of apoptosis 21
REFERENCES 24

The work contains 1 file

Russian State Pedagogical University named after A.I. Herzen

Faculty of Biology

COURSE WORK

Cell proliferation

SPb 2010
TABLE OF CONTENTS

INTRODUCTION 3

CHAPTER I. Proliferation 4

1. Cell cycle 5
2. Cell cycle regulation 6
3. Exogenous regulators of proliferation 7
4. Endogenous regulators of proliferation 7
5. Regulatory pathways of CDK 8
6. G1 phase regulation 10
7. S phase regulation 11
8. G2 phase regulation 12
9. Regulation of mitosis 12
10. DNA damage 13

1.10.1 Ways to repair double-stranded DNA breaks 13

1.10.2 Cellular response to DNA damage and its regulation 14

1.11. Tissue regeneration 15

1.11.1 Forms of regeneration 16

1.11.2. Regulation of tissue regeneration 17

CHAPTER II. APOPTOSIS 18

2.1. Characteristic signs of apoptosis 19

2.2. Apoptosis mechanism 19

2.3. The Role of Apoptosis in Protection Against Cancer 20

2.4. Regulation of apoptosis 21

BIBLIOGRAPHY 24

Introduction

The cell is an elementary unit of all living things. There is no life outside the cell. Cell reproduction occurs only by division of the original cell, which is preceded by the reproduction of its genetic material. Cell division is activated as a result of exposure to external or internal factors. The process of cell division from the moment of its activation is called proliferation. In other words, proliferation Is the multiplication of cells, i.e. an increase in the number of cells (in culture or tissue), occurring by mitotic divisions. The lifetime of a cell as such, from division to division, is usually calledcell cycle.

In the adult human body, cells of various tissues and organs have an unequal ability to divide. In addition, with aging, the intensity of cell proliferation decreases (i.e., the interval between mitosis ). There are populations of cells that have completely lost the ability to divide. These are, as a rule, cells that are at the terminal stage.differentiatione.g. mature neurons, granular blood leukocytes, cardiomyocytes ... In this respect, the immune system is an exception.B- and T-cells of memory, which, being in the final stage of differentiation, when a certain stimulus appears in the body in the form of a previously encountered antigen are able to begin to proliferate. The body has constantly renewing tissues - various types of epithelium, hematopoietic tissues. In such tissues, there is a pool of cells that are constantly dividing, replacing spent or dying cell types (for example,intestinal crypt cells, cells of the basal layer of the integumentary epithelium, hematopoietic cells bone marrow ). There are also cells in the body that do not multiply under normal conditions, but reacquire this property under certain conditions, in particular, if necessary. regeneration tissues and organs.

The process of cell proliferation is tightly regulated by the cell itself (regulation of the cell cycle, cessation or slowdown of synthesis autocrine growth factors and their receptors) and its microenvironment (lack of stimulating contacts with neighboring cells and matrix, cessation of secretion and / or synthesis paracrine growth factors). Violation of the regulation of proliferation leads to unlimited cell division, which in turn initiates the development of the oncological process in the body.

Proliferation

The main function associated with the initiation of proliferation is assumed byplasma membranecells. It is on its surface that events occur that are associated with the transition of resting cells to an activated state that precedes division. The plasma membrane of cells, due to the receptor molecules located in it, perceives various extracellular mitogenic signals and provides the transport of the necessary substances into the cell that are involved in the initiation of the proliferative response. Mitogenic signals can be contacts between cells, between a cell and a matrix, as well as the interaction of cells with various compounds that stimulate their entry into cell cycle , which are called growth factors. A cell that has received a mitogenic signal for proliferation starts the process of division.

Cell cycle

The entire cell cycle consists of 4 stages: presynthetic (G1),
synthetic (S), post-synthetic (G2) and mitosis proper (M).
In addition, there is a so-called G0-period characterizing
the state of rest of the cell. In the G1 period, cells have diploid
DNA content per nucleus. During this period, cell growth begins,
mainly due to the accumulation of cellular proteins, which is due to
an increase in the amount of RNA per cell. In addition, preparations for DNA synthesis begin. In the next S-period, there is a doubling of the number of DNA and, accordingly, the number of chromosomes doubles. The postsynthetic G2 phase is also called premitotic. In this phase, active synthesis occurs mRNA (messenger RNA). This stage is followed by actual cell division in two or mitosis.

Division of all eukaryotic cellsassociated with the condensation of doubled (replicated) chromosomes. As a result of the division, these chromosomes transferred to daughter cells. This type of eukaryotic cell division - mitosis (from the Greek mitos - threads) - is the only complete way to increase the number of cells. The process of mitotic division is divided into several stages: prophase, prometaphase, metaphase, anaphase, telophase.

Cell cycle regulation

The purpose of the regulatory mechanisms of the cell cycle is not to regulate the passage of the cell cycle as such, but to ensure, ultimately, the infallibility of the distribution of hereditary material in the process of cell reproduction. The regulation of cell reproduction is based on a change in the states of active proliferation andproliferative dormancy... Regulatory factors that control cell multiplication can be roughly divided into two groups: extracellular (or exogenous) or intracellular (or endogenous).Exogenous factorsare in the microenvironment of the cell and interact with the cell surface. Factors that are synthesized by the cell itself and act inside it refer to
endogenous factors... This subdivision is rather arbitrary, since some factors, being endogenous in relation to the cell producing them, can leave it and act as exogenous regulators on other cells. If regulatory factors interact with the same cells that produce them, then this type of control is called autocrine control. Under paracrine control, the synthesis of regulators is carried out by other cells.

Exogenous regulators of proliferation

In multicellular organisms, the regulation of the proliferation of various types of cells occurs due to the action of not one growth factor, but their totality. In addition, somegrowth factorsbeing stimulants for some types of cells, they behave like inhibitors in relation to others. Classicgrowth factorsrepresent polypeptides with a molecular weight of 7-70 kDa. To date, more than a hundred such growth factors are known.

PDGF platelets. Released upon destruction of the vascular wall, PDGF is involved in the processes of thrombus formation and wound healing. PDGF is a potent growth factor for resting fibroblasts ... Along with PDGF, epidermal growth factor ( EGF ), which is also able to stimulate the proliferation of fibroblasts. But, besides this, it also has a stimulating effect on other types of cells, in particular on chondrocytes.

A large group of growth factors are cytokines (interleukins, tumor necrosis factors, colony-stimulating factorsetc.). All cytokines are polyfunctional. They can both enhance and inhibit proliferative responses. So, for example, different subpopulations of CD4 + T-lymphocytes, Th1 and Th2 , producing a different spectrum of cytokines, are antagonists in relation to each other. That is, Th1 cytokines stimulate the proliferation of cells that produce them, but at the same time suppress Th2 cell division, and vice versa. Thus, the body normally maintains a constant balance of these two types of T-lymphocytes. The interaction of growth factors with their receptors on the cell surface leads to the launch of a whole cascade of events inside the cell. As a result, transcription factors are activated and the genes of the proliferative response are expressed, which ultimately initiates DNA replication and the entry of the cell into mitosis.

Endogenous regulators of the cell cycle

In normal eukaryotic cells, the passage of the cell cycle is tightly regulated. The reasononcological diseases is the transformation of cells, usually associated with violations of the regulatory mechanisms of the cell cycle. One of the main results of cell cycle defectiveness is genetic instability, since cells with impaired control of the cell cycle lose the ability to correctly duplicate and distribute theirgenome ... Genetic instability leads to the acquisition of new features that are responsible for tumor progression.