Auxiliary antioxidants.

Components: ascorbic acid, sulphur contained substances – glutathione, cystine, cysteine.

Assignment: regeneration of "true" antioxidants.

Breaches: hypovitaminosis C, violations of pentose cycle, deficiency of sulphur contained substances.

11.9. What can be a cause of the LPO activation?

Activation the LPO occurs:

1) At extended formation of primary free radicals (ultra-violet and ionizing radiation, hyperoxia, a poisoning with four-chloride carbon, hypervitaminosis D, etc.);

2) At violation of functioning of antioxidant systems (insufficiency of enzymes - superoxiddismutase, catalase, glutathioneperoxidase, glutathionereductase; deficiency of copper, iron, selenium; hypovitaminosis Е, C; violations of pentose cycle).

11.10. What mechanisms breach the barrier function of cellular membranes in case of activation of LPO?

I. The ionophores mechanism is caused by formation of the substances possessing properties of ionophores in cells, i.e. the substances, capable to facilitate diffusion of ions through a membrane due to formation of complexes of an ion and ionophore, taking place through its layers. During activation of the LPO among intermediate products of its reactions there are substances - ionophores in relation to ions of calcium and hydrogen. As a result of it permeability of cellular membranes to these ions rises.

II. The mechanism of electric breakdown is connected to existence of electric membrane potential on many membranes (plasmatic, internal mitochondrial). As a result of occurrence hydrophilic products of the LPO, electric-isolation properties of a hydrophobic layer of cellular membranes are broken that result in electric breakdown of a membrane, i.e. to its electromechanical break with formation of new transmembrane channels of ionic conductivity.

11.11. How does the matrix function of membranes brakes during activation of the LPO?

The essence of matrix function of lipid of bilayer membranes is that membrane enzymes and some specialized proteins are built in it.

In the LPO process, activity of the membrane enzymes is broken as changes in their lipid microenvironment which determine properties of protein molecules. Besides during reactions of LPO, occurs formation of "cross-links" between molecules of protein and phospholipids, and also oxidation of sulphhydrilic groups of the active centers that results to irreversible

11.12. How does the increased activity of phospholipases promote damage of cellular membranes?

In pathogenesis of cell damage, the great value is played by the excessive activation of phospholipase А₂ - the enzyme which carries out the hydrolytic cleaving of cell membrane phospholipids to nonsaturated fatty acids and lysophospholipides. Their molecules have only one fatty acid “tail”, that’s why it has ability to form a micelle and is strong detergent. Their detergent effect causes injuring of the cell membranes in conditions of excessive activation of phospholipase A₂, caused by high concentration of calcium ions in cytoplasm of the cells.

11.13. Under what conditions free fatty acids can make the detergent action on cellular membranes?

Detergent action of free fatty acids (FFA) is shown in increase of their contents in a cell that can be caused:

a) amplified receipt of FFA in cells at hyperlipacidemia (for example, activation of lipolysis in fat tissue at stress or diabetes mellitus);

b) releasing of FFA in lysosomes from triglyceride parts of lipoproteins, arrived in a cell from blood plasma (for example, hyperlipoproteinemia at atherosclerosis);

c) releasing of FFA from phospholipids membranes under action of membrane phospholipases;

d) violations of using of FFA as energy source (reduction of activity of enzymes of р-oxidation and pentose cycle, for example, at hypoxia).

To prevent damaging action of surplus of fatty acids, the cell has system of enzymes which transform free fatty acids into the form of triglycerides. This triglycerides in cytoplasm of cells agglomerate in fatty drops, i.e. it causes the fatty dystrophy of cells.

11.14. In what cases calcium ions are involved in pathogenesis of cell injury? What effects of calcium ions lead to injury of cellular structures?

Damage of cellular structures can be caused by increasing of concentration of Са²⁺ ions in cytoplasm of cells. Such situation arises or is as a result of superfluous receipt of Са²⁺ ions in cytoplasm (hypercalciemia, increase of permeability of a plasmatic membrane), or as a result of violation of the mechanisms providing removal of Са²⁺ ions from cytoplasm (violation of Са-pumps, the Na-Ca-exchange mechanism, Са-accumulated function of mitochondrions).

Increase of concentration of Са²⁺ ions in cytoplasm causes: contracture of fibrillar structures of a cell (myofibrils, elements of cytoskeleton); activation of phospholipase A₂; dissociation of oxidation and phosphorylation.

11.15. What are the reasons of the changes in the content of sodium and potassium in cells? What the role of such changes in pathogenesis of cell injury?

Alignment of concentration of Na⁺ and K⁺ ions on both sides of a plasmatic membrane (increase in content Na⁺ and reduction of the content K⁺ in cytoplasm) in the basis can have two mechanisms: 1) amplified diffusion of ions through plasmatic membrane on an existing concentration both electric gradient and 2) breaches of mechanisms of active transport of Na⁺ and K⁺ (Na-K-pump).

The first mechanism is realized in states of the common breaches of water and electrolyte balance (hypernatriemia, hypokaliemia) and violations of barrier function of a plasmatic membrane (increase of its ionic permeability).

Dysfunction Na-K-pump can be caused by deficiency of ATP in cells, by increasing of cholesterol content in lipid bilayer of membranes (for example, at atherosclerosis), action of lot of specific inhibitors of Na-K-ATP-ase (for example, strophanthine).

Changes in the contents of Na⁺ and K⁺ ions causes: loss of electric membrane potential (rest potential) by cell; b) edema of a cell; c) osmotic stretching of cellular membranes that is accompanied by increase of their permeability.

11.16. What are the reasons of the development of the intracellular acidosis and what changes in a cell can be connected with it?

The development of intracellular acidosis can be result of:

1) Excessive receipt of Н⁺ ions in a cell from the extracellular environment (decompensated gas or nongas acidosis);

2) Excessive formation of acidic compounds in the cell at activation of glycolysis (a dairy acid), breaches of pentose cycle (three- and dicarbonic acids), hydrolytic splitting of phospholipids cellular membranes (free fatty acids, a phosphoric acid), etc.;

3) Violation of linkage of free Н⁺ ions as a result of insufficiency of buffer systems of a cell;

4) Violations of removing of Н⁺ ions from cells during breaches of the Na-H-exchange mechanism, and also in cases of disturbances of local blood circulation in a tissue.

Endocellular acidosis causes: changes conformation of protein molecules with their violation of enzymatic, contractile and other properties; b) increase of permeability of cellular membranes; c) activation of hydrolytic enzymes of lysosomes.

11.17. What changes of protein molecules take part in pathogenesis of cell injury?

Protein mechanisms of cell injury are include:

1) inhibition of enzymes (convertible and irreversible);

2) denaturation, i.e. violation of native structures of albumin molecules as a result of changes of secondary and tertiary structures of protein molecules, caused by breaking of covalent connections;

3) proteolysis, carried out under action of proteolytic enzymes of lysosomes(cathepsins) and Са-activating proteases. In the result of proteolysis can appear peptides with properties of biologically active substances (BAS). Releasing of BAS from the damaged cells can lead to the local and the general reactions of organism (an inflammation, a fever).

11.18. Which violations of functioning of the cell genetic apparatus can cause the cell damage?

The so-called nucleic mechanisms caused by violations of some processes can be a basis of the cell damage:

1) violations of replication of DNA: denaturation of DNA, damage of DNA-replication enzyme system, deficiency of triphosphnucleotids - ATP, GTP, TTP and CTP;

2) violations of transcription: mutational defects of a genic matrix, inhibition of DNA-dependent RNA- polymerase, antibiotics and toxins, violations of posttranscriptional updatings information RNA: non-alignment "cap" by the head end of a molecule, violation of formation of poly-A-tail, violation of splicing;

3) violations of translation: deficiency or qualitative changes information, ribosome or transport RNA, and also ribosome enzymes and nonenzyme proteins; deficiency of free amino acids and ATP; inhibition of process by antibiotics and microbe toxins.

11.19. What universal mechanisms of increase of permeability of cellular membranes can have place under cell injury?

Increase of permeability of cellular membranes can be caused by: 1) activation of lipid peroxide oxidation; 2) activation of phospholipases; 3) an osmotic stretching of membranes; 4) adsorption of proteins (polyelectrolytes) on a membrane; 5) changes of a phase condition of membrane lipids (acidosis, changes of temperature).

11.20. What violations can develop in cells as the result of damage of its organoids (a plasmatic membrane, mitochondrions, endoplasmic reticulum, lysosomes)?

Violations of barrier function of a plasmatic membrane results in alignment of concentration gradients of substances existing in norm: in a cell enter ions Na⁺, Ca²⁺, Cl^-, and from cell exit ions K⁺, Mg²⁺, inorganic phosphate, low and high-molecular organic substances (AMP, ADP, intermediate products of a cellular metabolism, enzymes). With damages of fibres and the glycoprotein complexes which have been built in a plasmatic membrane, violations of systems of active transport of substances (Na-K-, Са-pumps are connected; Na-Ca-and Na-H-metabolic mechanisms); changes of specific ionic channels (Na-, K-, Са-channels); breaches of the cellular receptors perceiving external regulatory-coordinating signals (α-and β-adrenoreceptors, m- and n-cholinergic receptors, etc.); violations of intercellular interactions; changes of antigenic properties of a cell.

Damage of mitochondrions is accompanied by inhibition of processes of cellular breath, or by the effect of decoupling of processes of oxidation and phosphorylation. Both in this and in the other case result of mitochondrion dysfunction will be the decreasing of power cell supply.

Damage of rough endoplasmic reticulum leads to disaggregation of the polysomes, and as a result - damage of protein biosynthesis in cells takes place. As a result of damage of smooth endoplasmic reticulum and its enzyme systems, occur the disturbances of processes of detoxication, microsome oxidations, etc. Some cells (for example muscular) louse ability to deposit Са²⁺ ions in endoplasmic (sarcoplasmic) reticulum, that leads to realization of so-called calcium mechanisms of cell injury.

The increasing of permeability of lysosome membranes results in releasing of hydrolytic enzymes in cytoplasm. And activation of these enzymes causes the terminal changes of cell - its autolysis.

11.21. What mechanisms of cell death do exist? What is apoptosis?

There are two mechanisms of cell death distinguished:

1. Necrobiotic destruction comes under action of adverse external influences and is accompanied by decreasing of energy producing. The result of it are changes in cytoplasm, breaking of lysosomes with releasing of activated hydrolytic enzymes, which cause splitting and fragmentation of components of a cell (a nucleus, a plasmatic membrane, etc.), development of autolysis.

2. Apoptosis is an active energy-dependent process. In the beginning, due to activation of nucleases, occurs pyknosis and a fragmentation of nucleus; then remnants of nucleus removes from a cell and happens the secondary death of cytoplasm. Apoptosis is observed at a terminal differentiation of cells, a radiation injury, chronic hypoxia, action of T-lymphocytes-killers. It is connected to genetically determined program of destruction of cells.

11.22. What protective-compensatory mechanisms has damaged cell?

All variety protective-compensatory reactions of a cell in reply to its damage can be divided into two groups conditionally.

I. The reactions which are directed on recovering of the broken endocellular homeostasis:

a) activation of mechanisms of active transport of substances (Na-K-pump, Са-pump; Na-Ca-antiport (Na-Ca-exchange mechanisms), Na-H-antiport, microvesicular transport);

b) amplification of regeneration of antioxidants;

c) linkage of free fatty acids (synthesis of triglycerides);

d) activation of synthesis of proteins, nucleic acids, phospholipids, etc.

Indispensable condition of realization of these mechanisms is sufficient power supply of a cell. It is reached by increasing of intensity of a power exchange (activation of glycolysis, cellular breath, a pentose cycle) and redistribution of power resources available in a cell.

II. The reactions which directed on creation of functional rest of the damaged cell. Their purpose is to remove possible additional changes of endocellular homeostasis under action of physiological excitation factors (stabilization of damage) and to reduce to a minimum power expenses for performance of specific functions of a cell.

The examples of such reactions are: blockade of β-adrenoreceptors by prostaglandins, which forms by cells; b) inhibition of adenylatecyclase and increasing of activity of phosphodiesterase, which brake c-AMP; c) formation of adenosine (the natural calcium channel-blocking agent), etc.

11.23. What directions of pathogenetic treatment of the damaged cells do exist?

Main principles of treatment of the damaged cells are:

1) Restriction and suppression of molecular mechanisms of damage (blockade of Са-channels, application of antioxidants, inhibitors of phospholipase А₂ and proteases, activation of biosynthesis of proteins, etc.);

2) Providing of functional rest (a guarding mode, a diet, blockade of cellular receptors, etc.);

3) Energy and plastic maintenance of homeostatic mechanisms of cells (influence on peripheral blood circulation and microcirculation with the purpose of improvement of oxygen and nutrients supplying to the damaged cells, providing to cells the energy and plastic substrates).