INFLAMMATION

INFLAMMATION. FEVER.

 

The inflammation is the most often pathological process, which arises in a human organism. It is a typical pathological process, which arises after damage of tissues and consists of three main vessel-tissues components: alteration, violation of microcirculation with exudation and emigration of leucocytes and proliferation. Inflammation, as typical pathological process has common regularities, which always are present and dont depend on the cause, localization, species of an organism and its individual features.

 

The suffix it is the common.

The suffix it means inflammation.

The inflammation can arise in various organs.

Examples of the localisation of inflammation

In langs

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Paronychia

Localised inflammation of the nail fold (paronychia) is relatively common in infants.  Before secondary infection (usually with Staphylococcus aureus or Streptococcus pyogenes) occurs, there is an initial separation of the skin from the nail fold.  This may be exacerbated by the baby sucking their fingers or by overzealous trimming of the infant's finger nails.

Most often, the infection can be treated with oral or - in severe cases - intravenous antibiotics (our first line is usually flucloxacillin).  Occasional infants may need drainage of large collections, which may be achieved by pushing the skin away from the nail fold.

 

Inflammation of the skin

 

 

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Each concrete case has its own features, but the scheme of the inflammatory reaction response will always be identical, that is typical.

The inflammation is the local process, but all organism reacts definitely too. Immune, endocrine and the nervous systems are main engaged systems inflammation.

Etiology of inflammation

The inflammation can arise as result of influence of any agent. Force and duration of such influence should be stronger, than adaptive possibilities of the tissue, organ. The external causes of an inflammation are classified as follows: the physical factors (foreign bodies, strong pressure on a tissue, high and low temperature, ionizing and ultra-violet rays, high and low barometric pressure, electrical current); chemical factors (acid, alkali, salts of heavy metals); biological factors (microorganisms bacteria, viruses, fungi; animal organisms worms, insects). The internal factors are the factors, which arise in organism, as the result of any other diseases, for example cholic acids, complex antigen-antibody and others.

 

 

 

Signs of inflammation

There are five classical local signs of the inflammation.

 

The Roman physician Celsus described four signs, such as: swelling (tumor), redness (rubor), heat (calor), pain (dolor)

 

 

 

Greek physician Galen added fifth sing loss of the function (functio laesa). Swelling is the result of the vessels permeability increase. Redness is the result of local arterial hyperemia.

 

 

Heat (the local rise of temperature) is the result of arterial hyperemia and impermanent intensification of metabolism in the center of inflammation. The pain is the result of the painful receptors irritation by biological active substances, metabolites, and pressing. The loss of the function is the result of the functional active tissue injury.

 

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1

 

3

2

 

Fig. Unchanged timpana

(1) and inflammation of timpana

(2), which is swollen and red.

 

GENERAL SIGNS OF INFLAMMATION

FIVER results from IL-1 influence on centre of thermoregulation (excreted by macrophages and neutrophyles)

 

 

LEUCOCYTOSIS is the result of leucocytes outcome from depot, leucocytes proliferation

 

PROTEINS OF AQUTE FASE of inflammation its content increases in the blood on 50 %, they are synthesized mainly in liver, play protective role (inhibitors of proteinases antitripsine; antioxidants haptoglobin, ceruloplasmin; IgG, - reactive protein)

 

ESR increases inflammation couses accumulation of big mass proteins in the blood (globulines, fibrinigen), they adsorb on erythrocytes, decrease surface negative charge and conduce erythrocytes aggregation

 

INTOXICATION is the result of necrotic substances income in the blood from area of inflammation

 

 

 

Increasing of ESR in blood testonduce

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Classification of an inflammation

Depending on clinical course, there are two kinds of inflammation:

Acute

Chronic

 

 

During the acute inflammation the pathological agent is destroyed completely and the process ends in liquidation of the inflammation and reparation of full value. The chronic inflammation develops as the result of persistent influence of the pathological agent on an organism, organ, and tissue, which cannot be destroyed and eliminated by the organism.

There are normoergic, hyperergic and hypoergic inflammation when taking into account intensity of local and general changes in organism. The normoergic inflammation is characterized by the adequate reaction of organism, as the response to the invasion of the pathological agent; the hyperergic inflammation is characterized by a very strong reaction of organism even on an insignificant influence of the pathological agent, the hypoergic inflammation is characterized by insignificant changes in tissues.

During the inflammation one of stages of an inflammation can prevail, therefore there can be alterative inflammation, exudative inflammation and proliferative inflammation. The alterative inflammation is characterized by hard damage of tissues (dystrophy, necrosis), the exudative inflammation is characterized by derivation of big quantity of exudates, and the proliferative inflammation is characterized by reproduction of cells.

 

Pathogenesis of inflammation

 

The inflammation, as typical pathological process, consists of three stages: the first is the alteration stage; the second is violation of microcirculation with exudation and emigration of leucocytes in the center of an inflammation and the third proliferation.

The first stage is a stage, with which all forms of an inflammation begin. This stage is characterized by the violation of cells structure and function, of fibrous structures, of the microcirculatory system, nervous derivations. The damages of tissues are characterized by the disorder of proteins, fats, and carbohydrates metabolism, physical-chemical and morphological changes of tissues. The more complicated protein fibrous derivations (collagen, elastin) n also be destroyed. Necrobiosis and necrosis can take place in tissues. It is the reversible (sublethal) damage of cells, if they can adapt and restore their structure and function, and the irreversible (lethal) damage of cells, which is characterized by irrevocable change of cells structure.

There are two type of the alteration: primary and secondary.

: n	 Primary alteration is the result of pathological agent influence on a tissue 
n	Secondary alteration is the consequence of the primary alteration and that arises even at the absence of the damaging agent. Metabolism disorder (local acidosis, hyperosmia, hyperoncia), violation of microcirculation, free radicals formation, biological active substances action, lysosomal enzymes (damaged cells origin) conduce its development

 

 

The primary alteration is the result of the influence of the pathological (flogogenic) agent on a tissue. Metabolic and structural changes arise therefore. Various cells react differently: some cells perish, others remain alive, and others become activated. The activated cells are responsible for the creation of following stages of an inflammation.

The secondary alteration is the consequence of the primary alteration and it arises even at the absence of the damaging agent.

The signs of cells damage are the follows: the lessening 2; limitation or termination of 2 consumption by cells; the decrease of and D and the increase of the inorganic phosphorus concentration; the intensification of glycolysis, which cause the accumulation of lactic acid and piruvate acid; the decrease of cells . The decrease of concentration reduces the activity of ionic pumps of cells membranes, the parity of Na, K, Ca and Mg in cytoplasm is violated, and the activity of biochemical systems of cells is violated too. Then content of water in cells changes, the synthesis of protein decreases, the density of cytoplasm raises, the amount of + increases, the outlines of the cell change. These changes are reversible.

The constant deficiency of energy provokes the rise of permeability of organelles membranes and swelling of the cell takes place. These changes are the result of the significant damage of cells membrane structures. Free radicals and peroxides play the significant role in this process. They are the result of hypoxia of the damaged tissues and the violation of biochemical processes in cells. The accumulation of free radical substances exceeds the possibility of the cell to neutralize them. Therefore these substances damage membrane structures of the cell.

Especially dangerous is a damage of lysosomic membranes. Enzymes, which are localized in lysosomes, can acts on all kinds of macromolecules of cytoplasm. Primary lysis of the cell can be result of the lysosome membrane destruction by the pathological agent. Lysosome enzymes can get in the intracellular space. The secondary lysis of cells is the result of destruction of lysosomal membrane by free radicals. There is protein complex in blood of the man, which consists from 20 proteins (complements system). These proteins are activated during the invasion of microorganisms, promote damage of cells membranes and stimulate the protective phagocytic response. The main task of the complements system is destruction of all foreign agents, which get or derivate in human organism. These proteins, as well as lysosomes enzymes, promote development of the first stage of an inflammation. The damage of cells is accompanied by disorder of metabolism. Lisosomal enzymes uncontrol destroy of carbohydrates, proteins, fats, nuclear acids, and the activity of enzymes of glycolysis raises.

The consumption of oxygen in this stage of inflammation is increased. But it lasts not for long (2-3 hours). Then the alteration of cells provokes the damage of mytochondries membranes. The Krebs cycle is violated; the derivation is sharply oppressed, so the energy deficiency and accumulation of toxic substances, such as polypeptides, fatty acids, and ketone bodies take place. Simultaneously derivation of 2 is violated, and the respiratory coefficient decreases.

The inflammation always begins with the rise of metabolism. The main characteristic of this stage is the activation of metabolism; this is process of substances disintegration and as result destruction of glycoproteins and glicosaminoglicans complexes, formation of free aminoacids, polypeptides. Some of these substances are mediators of inflammation, and determine dynamics of inflammatory process.

The accumulation of partly-oxidated products in cytoplasm, as the result of violation of Krebs cycle, is accompanied by the development of metabolic acidosic (decrease of ) and the conditions which are necessary for enzymes systems operation are also violated. The tissue destruction is accompanied by the release of Na+, K+, Ca2+ out the cells and the rise of osmotic pressure (hyperosmia, the increase of proteins concentration, as the result of katabolism intensification, causes the oncotic pressure increase (hyperonkia). The swelling, pain, violation of organs functions are the result of these changes.

The secondary alteration is the result of disorder metabolism, the derivation of free radicals, the influence of lysosomic enzymes, local acidosis, hyperonkia, hyperosmia and the influence of an inflammation mediators (biological active substances, which generate in inflammation area).

Mediators of the inflammation are united in groups of substances with defined chemical structure: biogenic amines (histamine, serotonine); polipeptides (bradykinine, kallidine); proteins (complements system and lysosomal enzymes); derivatives of arachidonic acid (prostaglandines and leucotriens).

 

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Mediators of the inflammation are divided into humoral mediators (proteins of complements system, bradykinine, kallidine) and cellular ones (histamine, serotonine, lymphokines, prostaglandines). This classification is based on an origin of these substances. Humoral mediators are characterized by the widespread effects, spectrum of their influence is very wide.

The effects of cellular mediators are local. Histamine (most important mediator) is found in high concentration in platelets, basophils and mast cells granules together with heparine and factor of thrombocytes activation. The effects of histamine are mediated by histamine receptors (1 and 2).

The main effects of histamine are the result of irritation 1-histamine receptors of vessel wall (especially in venous). Histamine causes vasodilation and increased permeability of capillaries (main effects of histamine), promotes emigration of leucocytes, stimulates phagocytosis, increases adhesive property of vessels endothelium, causes a pain.

The neurons, labrocytes, basophiles and thrombocytes contain of serotonin, which couses arterioles constriction, shortening of venules walls myocytes and promote the stagnation of blood in venous.

There are three most important blood systems, which play main role during inflammation:

kinines,

hemostasis,

fibrinolysis

complements systems.

The II factor of blood coagulation activates derivation such kinines as the bradykinine and kallidine. Their main effects are pain, dilatation of vessels, rise of vascular wall permeability, activation of hemostasic and fibrinolysis systems.

 

 

The system of hemostasis and fibrinolysis directly participate in the generation of highly active mediators. The appearance of fibrinopeptides promotes the increase of microvessels permeability, activation of chemotaxis. Plasmine plays the main role in the system of fibrinolysis; it promotes the derivation of biological active substances, which increase of vessels permeability.

The system of complement is the complex of plasma proteins (C1-C9). Their main function is the destruction of alien and own changed cells. Activated 2 operates as kinines; 3 raises vascular permeability and stimulates the motion of phagocytes; 5 has properties of 3 (but is more active) and stimulates the selection of leucocytes of lysosomic enzymes; 5-9 is provided by the reactions of alien and own cells lysis; 5 stimulates the splitting of arachidonic acid and the synthesis of leucotriens, promotes the forming of oxygen radicals and hydroperoxides of lipids.

Derivatives of arachidonic acid include prostaglandines (PG), thromboxan A2 (TXA2) and leucotriens (LT). PG and TXA2 are formed as the result of splitting of arachidonic acid, which is allocated from phospholipids of membranes cells, by cycloxigenase. Endothelial cells of vessels synthesize PG, thrombocytes synthesize TXA2. PG2 promotes the dilatation of vessels and the increase of their permeability, and also stimulates the excretion of histamine. Leucotriens are formed as the result of splitting of arachidonic acid by lipoxygenase. The leucotriens L4, LD4, L4 are excreted from labrocytes and basophiles and promote the increase of permeability of vessels (especially of venules). L4 is excreted by endotheliocytes and promotes chemotaxis of leucocytes, causes adhesion and aggregation of neutrophiles.

 

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Lymphocytes excret lymphokines, which play main role during the immune inflammation. Among them, lymphotoxines realize killer activity of monocytes and lymphocytes and destroy cells-target. The migration-inhibiting factor (MIF) promotes accumulation leucocytes-phagocytes in the center of the inflammation. The factors of blasttransformation provide the reproduction of immunocytes and the excretion of interleukines (IL-1, IL-2, IL-3 etc.). Very important for immune inflammation is an interferone. This protein brakes compilation m-RNA of viruses or cells, this effect promotes the oppression of cells reproduction. The effects of interferone can be realized by means prostaglandins. Sensibilizated T- and B-lymphocytes excret γ-interferone, which regulates the macrophagocytes activity.

Granulocytes excret the platelet-activating factor, which stimulates the excretion serotonine, adrenalin from the thrombocytes. Main effects of the platelet-activating factor are the intensification of microvessels permeability, strengthens the exudation of the blood plasma and the emigration of leucocytes out the vessels.

Polymorphonuclearic leucocytes excrete kationic proteins, neutral and acidic proteases. Kationic proteins can release histamine and raise of vessels permeability, to strengthen the reactions of phagocytes. Neutral proteases (elastase, collagenase, katepsies) destroy the proteins of basal membrane and raise of vascular wall permeability. Acidic proteases acts in conditions of low and destroy membranes of microorganisms and own tissues.

Mediators of an inflammation, as the signals system, provide the exchange of the information between the cells, which cooperate and destroy the pathological agent. The system of mediators not only provokes various responses of tissues, but also is responsible for their interrelation.

Therefore inflammation has stereotyped components, such as alteration, vascular response, exudation, phagocytosis, and proliferation. The inflammation has some stages, which arise consistently. A principal value for each stage has the defined group of mediators. Histamine and serotonine play the main role on the initial stage of the acute inflammation development. These mediators increase the permeability of microvessels walls, strengthen the exudation, and start the system of kinines, complement and hemostasis. Then the cascade of reactions of arachidonic acid transformation and the derivation of prostaglandines and leucotriens is stimulated. Then the cellular mechanisms of protection start very actively. At the beginning, polimorphonuclearic leucocytes then monocytes and lymphocytes accumulate in the center of the inflammation, and the damaging agent or the products of tissues disintegration are destroyed and eliminated from an organism. The excretion of the inflammation mediators is cascade process. The question about the limitation of their excretion and action is really important. High concentration in blood can cause shock, collapse, DIC-syndrome. In the center of the inflammation, the substances, which block redundant accumulation and stop their influence, are excreted. Such processes take place during all stages of the inflammation.

All these substances are united in the system of antimediators. Enzymes are the main antimediators: histaminase destroys the histamine; carboxypeptidase destroys the kinines; esterases inhibits the complement proteins; prostaglandindehydrogenase destroys the prostaglandines; superoxyddismutase and catalase neutralize radicals of oxygen (eosinophiles are the important cells, which generate and delivery antimediators). Cortisole, cortisone, corticosterone have antimediators activity too. They weaken vascular reactions, stabilize membranes of microvessels cells, reduce the exudation and the emigration of leucocytes, weaken phagocytosis, reduce the excretion of histamine, stabilize of lysosomes membranes, reduce activity of lysosomic enzymes and the derivation of kinines and prostaglandines. These effects of corticosteroides doctors use for patients treatment. The inflammation is characterized by local violation of blood and lymph of circulation, especially microcirculation (in terminal vessels arterioles, metarterioles, capillaries and venules).

 

The most impotent mediator of the inflammation is HISTAMINE

Histamine is an organic nitrogen compound involved in local immune responses as well as regulating physiological function in the gut and acting as a neurotransmitter. Histamine triggers the inflammatory response. As part of an immune response to foreign pathogens, histamine is produced by basophils and by mast cells found in nearby connective tissues. Histamine increases the permeability of the capillaries to white blood cells and some proteins, to allow them to engage pathogens in the infected tissues.

Most histamine in the body is generated in granules in mast cells or in white blood cells called basophils. Mast cells are especially numerous at sites of potential injury the nose, mouth, and feet, internal body surfaces, and blood vessels. Non-mast cell histamine is found in several tissues, including the brain, where it functions as a neurotransmitter. Another important site of histamine storage and release is the enterochromaffin-like (ECL) cell of the stomach.

The most important pathophysiologic mechanism of mast cell and basophil histamine release is immunologic. These cells, if sensitized by IgE antibodies attached to their membranes, degranulate when exposed to the appropriate antigen. Certain amines and alkaloids, including such drugs as morphine, and curare alkaloids, can displace histamine in granules and cause its release. Antibiotics like polymyxin are also found to stimulate histamine release.

Histamine release occurs when allergens bind to mast-cell-bound IgE antibodies. Reduction of IgE overproduction may lower the likelihood of allergens finding sufficient free IgE to trigger a mast-cell-release of histamine.

Histamine exerts its actions by combining with specific cellular histamine receptors. The four histamine receptors that have been discovered in humans and animals are designated H1 through H4, and are all G protein-coupled receptors (GPCR).

Histamine biology is a series of weak interactions. In all of the known physiological reactions, the histamine backbone is unchanged.

In the H2 receptor mechanism, histamine is protonated at the end-chain amine group. This amine group interacts with aspartic acid in the transmembrane domains of cells. The other nitrogens in the molecule interact with threonine and aspartic acid in different transmembrane domains. This is a three-pronged interaction. It brings the transmembrane domains close to each other, causing a signal transduction cascade.

Histamine receptors in insects, like Drosophila melanogaster, are histamine-gated chloride channels that function in inhibition of neurons. Histamine-gated chloride channels are implicated in neurotransmission of peripheral sensory information in insects, especially in photoreception/vision. Two receptor subtypes have been identified in Drosophila: HClA and HClB. There are no known GPCRs for histamine in insects.

 

 

 

 

Another very impotent mediator of the inflammation is INTERLEUKINE-1

 

 

Julius Friedrich Cohnheim (July 20, 1839 August 15, 1884) has described the stages of disturbance of the microcirculation in the inflammation area.

At the Pathological Institute, Berlin (186568), Cohnheim was an outstanding pupil of Rudolf Virchow, founder of the science of pathology. While assisting him, Cohnheim also conducted extensive research into the causes of inflammation. By 1867, he confirmed earlier suspicions that the condition results from the passage of leukocytes (white blood corpuscles) through capillary walls and into tissues, and that pus consists mainly of the debris formed by disintegration of these leukocytes. He summarized his findings in Neue Untersuchungen über die Entzündung (1873; Recent Researches on Inflammation).

 

Cohnheim served as professor of pathology at the universities of Kiel (186872) and Breslau (187278), where in 1876 he witnessed Robert Kochs historic demonstration of the infectivity of anthrax bacilli. Cohnheims induction of tuberculosis in the anterior chamber of a rabbits eye one year later led to Kochs discovery of the tuberculosis bacillus.

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The first stage is the short-term spasm of vessels (arterioles), the second is the arterial hyperemia, the third stage is the venous hyperemia, the fourth stage is the prestasis, and the stasis is the fifth stage. Spasm (constriction) of arterioles is a result of vasoconstrictive adrenergic nerves stimulation by the catecholamines. Catecholamines stimulate a-adrenoreceptors and promote the contraction of smooth muscles of vascular wall. The duration of first stage is short, because the depot of catecholamines in the nervous endings is exhausted very fast and monoamineoxydase destrois the released mediators. The activation of cholinergic nerves and the excretion of acetylcholine promote the development of the second stage of microcirculation violation the arterial hyperemia. This mechanism is short-term, because acetylcholinesterase destrois acetylcholine. The significant duration of this stage is stipulated by the excretion of vasoactive mediators of the inflammation, which influences on the walls of arterioles and precapillaries (histamine, serotonine, bradykinine, kallidine, prostaglandines).

The change of metabolism in the inflammation area and the damage of cells promote the increase of lactic acid, adenosinemonophosphatic acids, potassium ions concentration and the violation of the functional condition of the connective tissue, surrounding the vessels. The connective tissue becomes less elastic and it promotes the extension of vessels.

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VIOLATION OF MICROCIRCULATION AND BLOOD CIRCULATIONS IN AREA OF INFLAMMATION

The effects of arterial hyperemia are the increase of blood flow speed, the increase of functioning capillaries amount, and the rise of blood pressure, strengthens of the tissues oxygenation.

Arterial hyperemia

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Arterial hyperemia promotes the derivation of the oxygen radicals for the protection of the organism against the microorganisms, forming of humoral plasma factors of the organism protection (complement, properdine, fibronectine), causes the movement of leucocytes into the area of injury. Arterial hyperemia causes the redness and warmth of the injurious area.

Venous hyperemia is characterized by the deceleration of blood circulation, the change of blood viscosity (its a result of exudation), and the chaotic placement of blood cells. Blood becomes very viscous; erythrocytes swell and move slowly, sometimes they stick in capillaries.

The development of venous hyperemia is promoted by three groups of factors: intravascular, vascular, extravascular.

 

 

Intravascular factors are follows: erythrocytes swelling and blood viscousness, which are the result of the increase vessels permeability; the forming of mycrothrombuses, the disposition of the leucocytes near the vessel wall.

Vascular factors: the development of venous hyperemia is promoted by the increase of endoteliocytes sizes and as a result the diameter of capillaries decreases. The elasticity of venal and lymph vessels decreases as a result of collagen and elastine destroy caused by lysosomic enzymes. Extravascular factors: edematic fluid easily squeezes vessels and deepens the violation of blood circulation. Venous hyperemia, which lasts very long time, creates conditions for the development of prestasis. The movements of blood are similar to the movements of a pendulum: blood moves from arteries to veins during systole of the heart and comes back during diastole of the heart.

The increase of blood viscosity, platelets aggregation cause the development of stasis, which is characterized by the stop of blood movement, swelling and aggregation of erythrocytes and their destruction. Changes of the erythrocytes membrane cause the aggregation of erythrocytes. The erythrocytes during the inflammation becomes swollen; the decrease of the blood albumins amount, as the result of the amplified penetration of blood plasma out the vessel,causes the decrease of negative charge of membrane erythrocytes and their conglutination.

Lymphatic system also participates in mechanisms of the inflammation. In a healthy organism lymphatic system executes the drainage function. Their major functions are the extract of microparticles, macromolecules, detritus of the cells and the exchange of liquid between blood and tissues. The inflammation involves many sites of lymph system. Edematic liquid compress lymph capillaries and changes local lymphatic circulation. The damage of cells membranes breaks the pump function of lymphatic collective vessels. The inflammation is accompanied by the increase of lymphatic capillaries permeability and their overflow. The detritus of the damaged cells and proteins get into lymph. The injurious factors can cause the inflammation of lymphatic vessels and lymphatic nodes. Due to the drainage function of lymphatic system the amplification of lymphcirculation promotes the decrease of swelling and carry antigens to the lymphatic nodes. Besides the amplification of the drainage function of lymphatic vessels can promote the distribution of the infectious agent and the toxic products of proteins disintegration. Spasm of the lymphatic vessels, which usually arises proximately from the area inflammation and inflammation of the lymphatic nodes deepen the swelling in the area inflammation and evidence development of lymphatic circulation insufficiency. The principal value of the alteration and violations of microcirculation is the creation of unfavorable conditions for further penetration of the pathological agent into the organism.

Exudative and proliferative processes

The increase of vascular wall permeability provokes exudation (penetration of a liquid from the blood into the tissue), emigration of leucocytes.

 

The permeability of microvessels increases first of all (especially of venules). The amplification of exudation provokes: of reologic properties blood change and microperfusion as the result of blood condensation; of laminar blood stream violation; of plasma structure change after the output into the tissue proteins; of microvessels compression by the edematic liquid. These processes provide of phagocytosis (protective process); it is sufficient activity and restoring of the injury tissue. In a stage of arterial hyperemia and especially in venous hyperemia stage fluid with the proteins and salts, dissolved in it, penetrates out the vessel. The high hydrodynamic pressure in vessels and the low colloid-osmotic pressure of blood increase of the vessels permeability and penetration of plasma proteins into the tissue.

There are three ways penetration of fluid through the vessel wall (exudation). The 1st way is interendotelial (between nearby endotheliocytes). Histamine promotes contraction of endothelial cells, the slots between nearby endotheliocytes extend, and basal membrane is exposed. The second way of exudation is transendotelial (through the endoteliocytes cytoplasm). Vesicles pinocytosis activity (the catch of fluid) of the endoteliocytes increases. The blood plasma is inside vesicles, which move through the cell and some time form channels. Various substances can pass without any control through channels (microvesicle transport). The third way of the exudation is the vessels wall area, where are injure endoteliocytes.

The development of the inflammation promotes the amplification of the exudation and the output of blood plasma and the mediators outside the vessels. The main cause of the exudation is mediators of inflammation, but amplifying disorder of the metabolism, the injury cells and leucocytes promotes other pathological mechanisms, which increase vascular permeability. They are lysosomes hydrolytic enzymes of various phagocytes and parenchimal cells (collagenase, elastase) and bacterial enzymes (hyaluronidase), lactic acid and piruvate acid, another non-oxidated substances, which are the result of tissues hypoxia, adenosine, + and K+, especially during the decrease of 2+ level. First of all albumins, than globulins and fibrinogen, which promotes the formation of fibrins clots, penetrate outside the vessels.

The serious damage of vessels wall is accompanied with the erythrocytes diapedesis (penetration through the vessel wall) and the bleeding.

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The exudation peculiarity and its structure depend on osmotic, oncotic and hydrodynamical factor of inflammation. Hyperosmia (high osmotic pressure) and hyperoncia (high oncotic pressure) of the tissue in the area inflammation) and osmotic-oncotic pressure of blood are differed, so fluid penetrates out the vessels and amplifies swelling. Hyperosmia is the result of the accumulation osmotic active particles (K+, Na+, salts, light-weight organic substances) of injurious tissue. Hyperoncia is the result of the macromolecules disintegration substances of the injurious tissue accumulation.

INFL031

 

There are three types of microvessels permeability change. The first type is the, second type immediate-continuous, third type deferred-prolonged increase of permeability of walls of vessels during inflammation. The first type is called the immediate-transient and occurs during weak damages. The main cause of it is the release of histamine, serotonine, and bradykinine. The contraction of endothelial cells and extension of interendothelial slots in small and average venue occurs under the influence of histamine. The permeability of walls of capillaries does not change. Endothelial cells of small and average venue have more histaminic receptors, than the similar cells of capillaries and arterioles; therefore only venue are involved in the process of such type.

The second type of vessels permeability violation arises during hard tissue damages (for example, extensive serious burn). The sharp increase of microvessels permeability arises immediately after damage and lasts up to five day, because endothelial cells of microvessels perish and is characterized by plasmorrhea.

The third type of vessel permeability changes is characterized by the lasting latent period after the damage. After that the permeability of vessels sharply increases and last for some hours or days. This type of vessels response is the most frequently with the human being (thermal damages, tissues injury by ionizing and ultra-violet rays, operation of bacterial toxines, delayed type of the allergy). In these cases endothelial cells dont round, but juncture between endotheliocytes of the capillaries and venules is broken. The combination of several mechanisms in dynamics the inflammation is possible.

Amplified exudation promotes the development of edema, pain and the function violation. The pain is the result of the nervous ending compression caused by exudates. The violation of the organ or tissue function is the result of the increase of diffuse distance between the capillary and parenchymal cells, and also their compression. The exudation deepens negative effects of the inflammation: the disorder of metabolism and microcirculation of the injurious tissue, hemoconcentration, derivation of thrombus. But at the same time the pathological factor operation weakens due to injuries area.

Vascular changes and the blood stream deceleration promote the reallocation of blood cells: leucocytes move to the vessel wall and begin to attach to it. Then, leucocytes adhere on the endotheliocytes and form the cover along the vessels walls.

 

 

The process of the edge standing of leucocytes is necessary two following conditions: the increase of endothelial cells adhesive properties and the activation of leucocytes.

 

 

The increase of adhesive properties of endotheliocytes is promoted by the lowering of their negative membrane charge (its the result of the accumulation in the area of inflammation +, Ca2+, g2+, Mn2+, cationic proteins, excreted by activated leucocytes). These ions reduce the leucocytes negative charge too, and also activate leucocytes enzymes, which increase adhesive properties of these cells.

Complement, fibronectine, immunoglobulins, histamine, interleukines, leucotriens are the most important initiators of the activation of leucocytes adhesive properties. C5, IgG (Fc-fragment) and IL-8 (chemotactic factors) promote the activation of these cells and their movement to endotheliocytes. Gradually leucocytes begin to pass through the vascular wall and to emigrate into the tissues (positive chemotaxis).

The penetration of leukocytes through the vessels wall is promoted by the alteration of leukocytes, endotheliocytes, interendothelial contacts basal membrane and perivascular tissue states.

 

 

After the adhesion of the leukocyte to the endotheliocytes membrane it moves on its surface and goes to the interendothelial slot. The leukocyte forms a pseudopodium, which moves through the interendothelial slot into the underendothelial space.

 

 

All contents of leukocyte move into the pseudopodium, and the leukocyte places in between the endothelial cells and the basal membrane of the microvessel. Then the leukocyte excretes collagenase and elastase, partly alters basal membrane and passes through the vessel wall and gets out the vessel.

In most cases of acute inflammation neutrophyles emigrate the first (that process lasts 6-24 hours). In 24-48 hours monocytes emigrate most actively. Lymphocytes emigrate a little bit later. Lymphocytes can immigrate the first during virus infection and tuberculosis, and eosinophiles during allergic reactions. Leukocytes regulate of the cells cooperation and delete the alien agents or the detritus of defective tissues. The neutrophiles (microphages) destroy pathological agents due to the following properties: the absorption of the foreign agent (phagocytosis), the microbicydity and cytotoxicity (these are the mechanisms of the foreign agent destroy by such biooxidants as superoxide anions, hydroxyl- radicals, singlet oxygen, peroxide), the intra- and extracellular lysis.

The neutrophiles excrete the proteolytic enzymes and oxidants into the phagosoma and destroy pathological agent. The excretion of proteolytic enzymes, biooxidants, thromboxans, prostaglandines, leucotriens out the neutrophiles promotes a self-regulation of the inflammation.

The main functions of the monocytes (macrophages) are the phagocytosis of foreign agent or damaged tissue and the immune reactions stimulation. The high-specifically phagocytosis of the foreign object is carried out due to the electrostatic interaction forces, and especially due to the membranes receptors for F-fragment of immunoglobuline G and component of the complement system, which taking part in a destruction of foreign agent too. The fastening and phagocytosis of the microorganisms promotes stimulation of macrophage, its oxidizing processes and secretion of the bactericide products (lysosomal enzymes, cationic non-enzyme proteins). But some of the particles, especially the inorganic ones, can be stable against such effect and even can cause damage of macrophage. So, the condition of the impossibility of pathological agent elimination is created. In such situation the macrophages execute their protective function in another way: they surround the hard-phagocytible particles and form a cellular conglomerationnode or a granuloma. The macrophages also excrete the factors, which stimulate or inhibit the cellular prolipheration and regulate the regeneration processes (tissues structure restoring).

The lymphocytes play the main role during virus infections. The mowing of lymphocyte out the vessel is promoted by substances (monokines), which are secreted by blood and tissues macrophages. The cooperation of T- and B-lymphocytes with phagocytes is necessary for immune reaction stimulation and phagocytosis activation with the involvement of complement system. All inflammation effectors cells have F-receptors of immunoglobuline G and C- receptors of complement.

 

Types of exudates

 

The inflammation is named the exudative if this component is expressed stronger than others. The exudate type determines type of an inflammation. There are serous, fibrinous, purulent, decaying, hemorrhagic and combination types of the exudates and inflammation. The serous inflammation develops in mucous and serous coats, interstitial tissue, skin, and kidneys glomes capsules. The amount of cells in the serous exudate is not large.

The serous exudate promotes washing off of microorganisms and their toxines from the damaged surfaces. But the serous exudate in brain coats can squeeze the brain and violate its function. The serous infiltration of lungs alveolar septs can cause the development of acute respiratory insufficiency syndrome.

 

 

The fibrinous exudate contains a plenty of fibrinogen, which forms clots of fibrin in tissues. Such inflammation occurs when an organism is affected by corinebacterium diphtheriae, pneumococcus, Fridlander's bacillus, Frencel's diplococcus, streptococcus, and mycobacterium of tuberculosis. Such type of an inflammation occurs on mucous or serous coats more often.

 

 

The causes of purulent inflammation are staphylococcus, streptococcus, gonococcus, meningococcus, and Frenkels diplococcus. Purulent exudate consists of many viable leukocytes and purulent bodies (perishing leukocytes), cells detritus, microorganisms, plenty of proteins (especially globulines).

 

 

1

2

 

Pural bodies (destroing of neutrophyle 1, destroing of monocyte - 2)

 

The decaying inflammation develops after the invasion of decaying microflora into the purulent inflammation site. During this type of inflammation necrosis of injurious tissues progresses, the inflammation area doesnt localize, and this provokes the arrival of alien and toxic products into vessels and the development of intoxication due to which the patients usually dies.

1

 

The hemorrhagic inflammation, as the form of the serous, the fibrinous or the purulent inflammation, is characterized by erythrocytes impurity to the exudate (Siberian ulcer, natural smallpox, influenza).

The combination forms of inflammation are characterized by connection of one type of exudate to another. Any combinations are possible. Such forms usually develop as the result of connection of a new infection to the lasting process. The tissues damage and the process of inflammation cause the restoring of broken structure and function (reparative regeneration).

 

 

INFLAMMATION. PHENOMENON EXUDATIVE. THE SORTS OF EXUDATES

 

The inflammation proliferative phase is simultaneously a phase of the reparatory regeneration. The restoring of the damaged tissues structure depends on the interaction of connective tissues cells among themselves (fibroblasts, macrophages, labrocytes, lymphocytes, endotheliocytes), on the interaction of connective tissues cells with the intercellular matrix (collagen, proteoglicans, fibronectine), on the interaction of connective tissue cells with blood cells and parenchymal ones.

An exudate is any fluid that filters from the circulatory system into lesions or areas of inflammation. It can apply to plants as well as animals. Its composition varies but generally includes water and the dissolved solutes of the main circulatory fluid such as sap or blood. In the case of blood it will contain some or all plasma proteins, white blood cells, platelets, and in the case of local vascular damage: red blood cells. In plants, it can be a healing and defensive response to repel insect attack, or it can be an offensive habit to repel other incompatible or competitive plants. Organisms that feed on exudate are known as exudativores; for example, the Vampire Bat exhibits hematophagy, and the Pygmy marmoset is an obligate gummivore (primarily eats tree gum).

In humans, exudate can be a pus-like or clear fluid. When an injury occurs, leaving skin exposed, it leaks out of the blood vessels and into nearby tissues. The fluid is composed of serum, fibrin, and white blood cells. Exudate may ooze from cuts or from areas of infection or inflammation.

Types

Purulent or suppurative exudate consists of plasma with both active and dead neutrophils, fibrinogen, and necrotic parenchymal cells. This kind of exudate is consistent with more severe infections, and is commonly referred to as pus.

Fibrinous exudate is composed mainly of fibrinogen and fibrin. It is characteristic of rheumatic carditis, but is seen in all severe injuries such as strep throat and bacterial pneumonia. Fibrinous inflammation is often difficult to resolve due to blood vessels growing into the exudate and filling space that was occupied by fibrin. Often, large amounts of antibiotics are necessary for resolution.

Catarrhal exudate is seen in the nose and throat and is characterized by a high content of mucus.

Serous exudate (sometimes classified as serous transudate) is usually seen in mild inflammation, with relatively low protein. Its consistency resembles that of serum, and can usually be seen in certain disease states like tuberculosis. (See below for difference between transudate and exudate)

Malignant (or cancerous) pleural effusion is effusion where cancer cells are present. It is usually classified as exudate.

There is an important distinction between transudates and exudates. Transudates are caused by disturbances of hydrostatic or colloid osmotic pressure, not by inflammation. They have a low protein content in comparison to exudates. Medical distinction between transudates and exudates is through the measurement of the specific gravity of extracted fluid. Specific gravity is used to measure the protein content of the fluid. The higher the specific gravity, the greater the likelihood of capillary permeability changes in relation to body cavities. For example, the specific gravity of the transudate is usually less than 1.012 and a protein content of less than 2 gm/100mL (2 gm%). Rivalta test may be used to differentiate an exudate from a transudate. It is not clear if there is a distinction in the difference of transudates and exudates.

Transudate is extravascular fluid with low protein content and a low specific gravity (< 1.012). It has low nucleated cell counts (less than 500 to 1000 /microlit) and the primary cell types are mononuclear cells: macrophages, lymphocytes and mesothelial cells. For instance, an ultrafiltrate of blood plasma is transudate. It results from increased fluid pressures or diminished colloid oncotic forces in the plasma.

The most common causes of pathologic transudate include: conditions that increase hydrostatic pressure in vessels, left ventricular heart failure, decrease in colloid oncotic pressure in blood vessels, cirrhosis (Cirrhosis leads to hypooalbunism and decreasing of colloid oncotic pressure in plasma that causes edema.), and Nephrotic syndrome (also due to hypoalbuminaemia caused by proteinuria)

Transudate vs. exudate 

 

Transudate

Exudate

Main causes

Increased hydrostatic
pressure
,
Decreased
 colloid
osmotic pressure

Inflammation

Appearance

Clear[10]

Cloudy[10]

Specific gravity

< 1.012

> 1.020

Protein content

< 25 g/L

> 29 g/L[11]

fluid protein
serum protein

< 0.5

> 0.5[12]

Difference of
albumin content
with blood albumin

> 1.2 g/dL

< 1.2 g/dL[13]

fluid LDH
upper limit for serum

< 0.6 or < ⅔

> 0.6[11] or > ⅔[12]

Cholesterol content

< 45 mg/dL

> 45 mg/dL[11]

 

 

 

The process of cells proliferation is regulated by substances, which can stimulate (mitogens) or oppress (keilones) the reproduction of cells. Cambial cells are the tissues source of regeneratory material. The damage of tissues causes intensive proliferation trunk cells. The reparative stage of inflammation begins when phagocytes actively swallow the microorganisms or the tissues detritus. At that time labrocytes activate interaction with macrophages, fibroblasts, and intercellular matrix, clotting blood system and promote the excretion and the synthesis of substances, which stimulate proliferative processes.

Thrombocytes produce substances, which strengthen the proliferation and the chemotaxis of fibroblasts to the injurious area: the thrombocytal factor growth of fibroblasts, the factor of epidermis and fibroblasts growth, the peptide, which activates connective tissue etc.

The labrocytes excrete histamine and leucutrien 4, which activate fibroblasts proliferation. The neutrophiles excrete peptide, which activates the growth of fibroblasts and leucotrien, which cause the migration of fibroblasts into the injurious tissue.

The macrophages are the main cells, which regulate the reparative processes. Macrophages enclose (segregate) of the injurious tissue, form neutrophile-macrophagal, macrophagal and macrophagal-fibroblasts barriers the granulating tissue.

The macrophagal-fibroblastic interaction conduces migration, proliferation, and differentiation of fibroblasts, synthesis and secretion of collagen and other components of tissues matrix. The accumulation of fibroblasts in the inflammation site inhibits their growth and stimulates the biosynthesis of collagen. Fibroblasts contact interaction stimulates the production of keilons.

The macrophages, lymphocytes, neutrophiles produce the intercellular matrix (collagen, fibronectine). The further stage of connective tissue growth autoregulation is characterized by the collagen synthesis inhibition, the destruction of the majority cells, the transformation of the fibroblasts in fibrocytes (inactive cells). The fibroblasts destroy unnecessary collagen fibres by means of their phagocytosis, or the secretion of collagenase. All of these promote the stop of connective tissue growth.

GRANULOUS TISSUE

2

Young connective tissue with lot of vessels

This tissue covers of wound and ulcer skin defects, it is formed during the damage of mucous membranes and internal organs, during bones fractures, hematoma organization, at necrosis (infarction), and during chronic inflammation.

FUNCTIONS:

covering of defect

trophy (microcirculation regulation, oxygen and metabolites transport, filtering of substances)

morphogenetic (influence on epithelium and muscular tissue differentiation).

incapsulation (closing) of necrosis area and alien bodies

reconstruction of anatomic and functional structure of injurious tissues

GRANULOUS TISSUE - one of the very important products of inflammatory-reparative process is, this is a young connective tissue with a plenty of vessels. This tissue fills wound and ulcer skin defects, it is formed during the damage of mucous coats and internal organs, during bones fractures, hematomes organization, at necrosis and infarctions sites, and during chronic inflammation. The functions of granulation tissue are as follows: mechanical (filling of defect), trophic (microcirculation regulation, oxygen and metabolites transport, filtering of substances), morphogenetic (influence on epithelium and muscular tissue differentiation). But the main function of the granulation tissue is the protection against unfavorable influences of the external environment, against infection and intoxication, incapsulation (closing) of necrosis area and alien bodies, and also reconstruction of anatomic and functional structure of injurious tissues. During the proliferative processes activation, the cells, which are constantly stimulated by mitogens, become very sensitive to carcinogenic substances. Abnormal mitosis can lead to tumour formation.

The course of inflammatory reaction depends on the organism reactivity, on the nervous, endocrine and immune systems condition. The meaning of the nervous system in the dynamics of the inflammation proves to be true by numerous cases of inflammation sings development in the patients under the influence of suggestion during hypnosis. The occurrences of hyperergic inflammation during the local action of the damaging factor at maniac excitement are often in psychiatric clinic, and at serious depressions the inflammatory reaction proceeds very languidly. The change of nervous impulse and nervous trophic influences on the damaged tissue promotes the amplification of exudative processes and the violation of microcirculation.

Neuromediators and trophogens, activate the phagocytosis and the free-radical processes. The violation of afferent innervation strengthens alteration processes and decelerates the reparation of parenchymal cells. Proliferative processes pass most actively on the periphery of the inflammation area, because just there nervous fibres regenerate first and anabolic processes on the periphery proceed more actively.

Neuropeptides take active part in the regulation of proliferative-regeneratory processes in tissues of organs, especially the opiod peptides. The stimulation of C-fibres opioid receptors by these peptides weakens the pain, reduces the release of noradrenalin from sympathetic nervous endings, the activation of labrocytes and trombocytes stops, the disorders of microcirculation and violation of hemostasis are eliminated.

The influence of endocrine system on the inflammation is proved by numerous clinical observations. Hyperthyroidism amplifies manifestations of the inflammation and hypothyroidism is characterized by the insignificant sings. Mineralocorticoids promote the development of inflammatory reaction and glucocorticoids weaken it. The ability of glucocorticoids to weaken the inflammation is constantly used in clinics because they reduce the amount of tissues basophiles, increase the activity of histaminase (enzyme, which destroys histamine), reduce serotonine formation, stabilize lysosome membranes and inactivate their enzymes. Glucocorticoids induce synthesis of proteins, which block prostaglandines and leucotriens synthesis. Mineralocorticoids are capable to strengthen the exudation, to accelerate the reproduction of cells, the derivation of new capillaries, and synthesis of the connective tissue.

The inflammatory reaction in the process of phylogenesis has arisen as a protective response of the organism of hot-blood biological individuals. The organism protects itself from the influence of the pathological factor due to limitation of the inflammatory area from the whole organism. The barrier is formed around the inflammation area; it allows various substances to flow in one direction (to the centre of the inflammation site) due to blockade of lymphatic and blood vessels. The unfavorable conditions for microorganisms are created in the centre of the inflammation. But in the conditions of significant tissues damage or microcirculation violations, the hard metabolism disorder in the damaged tissue or organ, hypoxia and the common intoxication strengthening patients sufferings can be provoked. The inflammation is the example, which connects both the elements of injury and the elements of organism protective forces.

 

 

 

FEVER

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The temperature within the deep tissues of the body (core temperature) is normally maintained within a range of 36.0C to 37.0C. Within this range, there are individual differences and variations; internal core temperatures reach their highest point in late afternoon and evening and their lowest point in the early morning hours. Virtually all biochemical processes in the body are affected by changes in temperature. Metabolic processes speed up or slow down, depending on whether body temperature is rising or falling.

One of the most important examples of homeostasis is the regulation of body temperature. Not all animals can do this. Animals that maintain a fairly constant body temperature are called homeotherms, while those that have a variable body temperature are called poikilotherms. The homeotherms maintain their body temperatures at around 37C, so are sometimes called warm-blooded animals, but in fact poikilothermic animals can also have very warm blood during the day by basking in the sun.

Human organs and the organs of warm-blooded animals also can be divided into two groups:

) organs with permanent and high temperature;

b) organs with changeable and more lower temperature.

So, our organism consists of two parts: warm-blooded and cold-blooded. To the first part one belong the inner organs. The highest temperature has a liver. Then blood comes in aorta, after that the organs of pectoral and abdominal cavity, brain and spinal cord. These organs and tissues aresituated in deep areas of the body. They have permanent temperature and are called by coore, kernel. Other organs have a more low temperature. It depends on temperature of envirenment and easely changes. These organs are situated on periphery, they are called as envelope. To these organs one belong, first of all a skeletal muscles and skin. Conditional middle temperature of the skin in axillary domain is 37 C. It is taken as a norm.

Regulation of body temperature realizes by the centre of thermoregulation. It is situated in arterior part of the hypothalamus in bottom of its third ventricle. A centre coordinates thermogenesis and delivery of the heat. It provides maintenance of temperature of inner organs (kernel) in necessary limits.

 

A centre of thermoregulation consists of a few anatomic and functional units. The main of them are

sensative area (thermostat),

thermoestablishing area (adjusting point)

and two effector areas (centres of thermogenesis and delivery of the heat).

 

Mechanisms of fever.

(1) Release of endogenous pyrogen from inflammatory cells, (2) resetting of hypothalamus thermostatic set point to a higher level (prodrome), (3) generation of hypothalamicmediated responses that raise body temperature (chill), (4) development of fever with elevation of body to new thermostatic set point, and (5) production of temperaturelowering responses (flush and defervescence) and return of body temperature to a lower level.

 

Body temperatures under different conditions.

 

Thermostat is a part of brain, which takes temperature of the body with very high exactness (0,01 ). The neurons of this area register the temperature of arterial blood, which flows over brain straightly. Besides, they receive signals from receptors of skin and from thermoreceptors of inner organs. The neurons of thermostat analyse and integrate all this temperature signalling. They determine a middle temperature of inner organs (kernel) continously and pass this information on adjusting point.

 

http://www.mfi.ku.dk/ppaulev/chapter21/images/21-12.jpg

 

Adjusting point is a group of neurons, which determine a necessary temperature of the body at this moment. It reconstructs the center of thermogenesis and delivery of the heat. If a temperature of the body is low, a centre of thermogenesis becomes excited. If temperature of the body is high, centre of delivery of the heat become excited.

A centre of thermogenesis regulates a temperature by rising of general metabolic activity. The most quantity of heat is maked in skeletal muscles. At the lowering of body temperature in cold regions at first rises muscules tone, not always can give sufficient amount of supplementary heat. In these cases starts muscular trembling. This is spontaneous rhythmic abbreviations is skeletal muscules. They can raise a metabolism speed in five times (retractive thermogenesis). Forming energy partially comes on mechanical work, but more part of it disengages in the form of the heat. Body temperature rises. Essential significance in maintenance of body temperature has a liver. In usual conditions in liver about 30 % of heat are maked.

A heat emission centre regulates a heat exchange by following ways:

separate of sweat and evaporation of water over skin and respiratory organs;

radiation is lossing of heat in form of electromagnetic waves without contact with surrounding objects;

conduction is loss of warm at straight contact with objects;

convection is heat transfer by air molecules or liquid.

Centre of thermoregulation receives input from two sets of thermoreceptors: receptors in the hypothalamus itself monitor the temperature of the blood as it passes through the brain (the core temperature), and receptors in the skin monitor the external temperature. Both pieces of information are needed so that the body can make appropriate adjustments. The thermoregulatory centre sends impulses to several different effectors to adjust body temperature:

The thermoregulatory centre is part of the autonomic nervous system, so the various responses are all involuntary. The exact responses to high and low temperatures are described in the table below. Note that some of the responses to low temperature actually generate heat (thermogenesis), while others just conserve heat. Similarly some of the responses to heat actively cool the body down, while others just reduce heat production or transfer heat to the surface. The body thus has a range of responses available, depending on the internal and external temperatures.

http://www.mrothery.co.uk/module4/webnotes/Image12.gif

 

 

Effector

Response to low temperature

Response to high temperature

Smooth muscles in peripheral arterioles in the skin.

Muscles contract causing vasoconstriction. Less heat is carried from the core to the surface of the body, maintaining core temperature. Extremities can turn blue and feel cold and can even be damaged (frostbite).

Muscles relax causing vasodilation. More heat is carried from the core to the surface, where it is lost by radiation. Skin turns red.

Sweat glands

No sweat produced.

Glands secrete sweat onto surface of skin, where it evaporates. Water has a high latent heat of evaporation, so it takes heat from the body.

Erector pili muscles in skin (attached to skin hairs)

Muscles contract, raising skin hairs and trapping an insulating layer of still, warm air next to the skin. Not very effective in humans, just causing "goosebumps".

Muscles relax, lowering the skin hairs and allowing air to circulate over the skin, encouraging convection and evaporation.

Skeletal muscles

Muscles contract and relax repeatedly, generating heat by friction and from metabolic reactions.

No shivering.

Adrenal and thyroid glands

Glands secrete adrenaline and thyroxine respectively, which increase the metabolic rate in different tissues, especially the liver, so generating heat.

Glands stop releasing adrenaline and thyroxine.

Behaviour

Curling up, huddling, finding shelter, putting on more clothes.

Stretching out, finding shade, swimming, removing clothes.

The thermoregulatory centre normally maintains a set point of 37.5 0.5C in most mammals. However the set point can be altered is special circumstances.

 

Body temperature reflects the difference between heat production and heat loss. Body heat is generated in the tissues of the body, transferred to the skin surface by the blood, and then released into the environment surrounding the body. The thermoregulatory center in the hypothalamus functions to modify heat production and heat losses as a means of regulating body temperature.

Mechanisms of Heat Production

Metabolism is the bodys main source of heat production. The sympathetic neurotransmitters, epinephrine and norepinephrine, which are released when an increase in body temperature is needed, act at the cellular level to shift metabolism so energy production is reduced and heat production is increased. This may be one of the reasons fever tends to produce feelings of weakness and fatigue. Thyroid hormone increases cellular metabolism, but this response usually requires several weeks to reach maximal effectiveness. Fine involuntary actions such as shivering and chattering of the teeth can produce a threefold to fivefold increase in body temperature. Shivering is initiated by impulses from the hypothalamus. The first muscle change that occurs with shivering is a general increase in muscle tone, followed by an oscillating rhythmic tremor involving the spinal-level reflex that controls muscle tone. Because no external work is performed, all of the energy liberated by the metabolic processes from shivering is in the form of heat. Physical exertion increases body temperature. With strenuous exercise, more than three quarters of the increased metabolism resulting from muscle activity appears as heat within the body, and the remainder appears as external work.

 

Mechanisms of Heat Loss

Most of the bodys heat is produced by the deeper core tissues (i.e., muscles and viscera), which are insulated from the environment and protected against heat loss by the subcutaneous tissues. Adipose tissue is a particularly good insulator, conducting heat only one third as effectively as other tissues. Heat is lost from the body through radiation and conduction from the skin surface; through the evaporation of sweat and insensible perspiration; through the exhalation of air that has been warmed and humidified; and through heat lost in urine and feces. Contraction of the pilomotor muscles of the skin, which raises the skin hair and produces goose bumps, reduces the surface area available for heat loss. Of these mechanisms, only heat losses that occur at the skin surface are directly under hypothalamic control. Most of the bodys heat losses occur at the skin surface as heat from the blood moves to the skin and from there into the surrounding environment. There are numerous arteriovenous (AV) shunts under the skin surface that allow blood to move directly from the arterial to the venous system (Fig. 9-13). These AV shunts are much like the radiators in a heating system. When the shunts are open, body heat is freely dissipated to the skin and surrounding environment; when the shunts are closed, heat is retained in the body. The blood flow in the AV shunts is controlled almost exclusively by the sympathetic ner-vous system in response to changes in core temperature and environmental temperature. The transfer of heat from the skin to the environment occurs by means of radiation, conduction, convection, and evaporation.

Radiation. Radiation involves the transfer of heat through the air or a vacuum. Heat from the sun is carried by radiation. The human body radiates heat in all directions. The ability to dissipate body heat by radiation depends on the temperature of the environment. Environmental temperature must be less than that of the body for heat loss to occur.

Conduction. Conduction involves the direct transfer of heat from one molecule to another. Blood carries, or conducts, heat from the inner core of the body to the skin surface. Normally, only a small amount of body heat is lost through conduction to a cooler surface. However, loss of heat by conduction to air represents a sizable proportion of the bodys heat loss.

The conduction of heat to the bodys surface is influenced by blood volume. In hot weather, the body compensates by increasing blood volume as a means of dissipating heat. Exposure to cold produces a cold diuresis and a reduction in blood volume as a means of controlling the transfer of heat to the bodys surface.

Convection. Convection refers to heat transfer through the circulation of air currents. Normally, a layer of warm air tends to remain near the bodys surface; convection causes continual removal of the warm layer and replacement with air from the surrounding environment. The wind-chill factor that often is included in the weather report combines the effect of convection

caused by wind with the still-air temperature.

Evaporation. Evaporation involves the use of body heat to convert water on the skin to water vapor. Water that diffuses through the skin independent of sweating is called insensible perspiration. Insensible perspiration losses are greatest in a dry environment. Sweating occurs through the sweat glands and is controlled by the sympathetic nervous system. In contrast to other sympathetically mediated functions, sweating relies on acetylcholine, rather that the catecholamines, as a neurotransmitter. This means that anticholinergic drugs, such as atropine, can interfere with heat loss by interrupting sweating.

Evaporative heat losses involve insensible perspiration and sweating, with 0.58 calories being lost for each gram of water that is evaporated.12 As long as body temperature is greater than the atmospheric temperature, heat is lost through radiation. However, when the temperature of the surrounding environment becomes greater than skin temperature, evaporation is the only way the body can rid itself of heat. Any condition that prevents evaporative heat losses causes the body temperature to rise.

 

Etiology and pathogenesis of the fever

Rise of body temperature is very frequent symptom attached to much diseases. There are two type of rising temperature: a fever and hyperthermy.

Fever is typical pathological process. He describes by change of thermoregulation and rise of body temperature, irrespective of temperature of environment. Attached to fever thermoregulation centre oneself aspires to rise of temperature.

Hypothermy is a fortune, when body temperature rises under dominance of external and inlying factors. Thermoregulation centre tackles body temperature within the pale of normal sizes, however this to him does not turn out well.

On origin distinguish two fevers appearance infectious and uninfectious. Evolutional fever arose as reaction on penetration in microorganisms organism and their toxins, therefore she most typical for infectious illnesses.

Infectious fever. microorganisms contain the pyrogenetic matters (exogenous pyrogens). They go into composition of toxins of mycroorganisms. Most are studied the endotoxins of Gramnegative bacterium. They consist of three parts: lipid, polysacharid and albuminous. Pyrogenetic properties has lipid fraction (lipoid A).

Under influence lipoid in organism forms endogenous pyrogen interleukin 1. It exudes by neutrophils, monocytes, macrophags and with by other cells, that is apportionment of interleukin 1 is function of phagocyting cells. Attached to contact exogenous pyrogens with these cells acceterate the genes, which encode synthesis of interleukin 1. It immediatly influences on thermoregulation centre.

Many microorganisms do not pick out the endotoxins, but are followed with fever (flu exciters, diphtheria, stupor). Here displays general conformity to natural laws: any phagocytosis stimulates apportionment inlying of pyrogen. Bacterium and viruses actively eliminate from blood by system of mononuclear phagocytes cells. These cells initiate production inlying of pyrogen in liver, spleen and other organs.

 

http://www.pediatriconcall.com/fordoctor/pharmaupdates/images/fever.gif

 

The uninfectious fevers divide by two hinds appearance on origin: fever attached to allergy and fever attached to aseptical inflammation. Their pathogeny identical: they call inlying by pyrogen. Attached to aseptical inflammations (myocardium heart attack, illness of connecting tissue) takes place phagocytosis of lost and damaged cells and ferments. Attached to allergies phagocytes eat the complexes of antigen-antibody.

Interleukin 1 acts on thermosensitive neurons of thermoregulation centre, that is on thermostat. These neurons have on its membranes the sensible receptors. After their irritation activates adenilatecyclase thermostat neurons system. In them grows cyclic adenosinemonophosphate. It changes sensitiveness of these neurons to cold and thermal signals. To cold signals sensitiveness grows, and to thermal falls.

In these conditions adjusting of thermoregulation centre point values blood-heat of inlying organs as low. Referenting temperature of adjusting point displaces up starts to fever. Transmission of information from thermostat neurons on neurons of adjusting point performs with the help of prostaglandins.

Fever stages

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Pick out three fever stages:

stage of temperature rising (stadium incrementi),

stage of high temperature standing (stadium fastigii),

stage of temperature lowerings (stadium decrementi) .

 

In the first stage of heat production prevails over heat emission. Mechanisms of heat production and heat emissions reform like so, to retain body temperature on more high level. Foremost, heat emission limits. This mechanism matters decisive. The peripheral vessels narrows, diminishes an influx of warm blood to peripheral tissues, diminishes sweat separate and evaporation. In-parallel with that increases heat production. Grows muscles tone. Appears muscles thremor. Grows heat production in liver. Rising of body temperature is attended with shivering. By this term designate strong of cold feel in combination with intensive thremor.

Body temperature gradually rises. It reaches referenting temperature of adjusting point, that is necessary temperature. On this level it holds on a few hours or days. This is the second stage (stage of high standing). In this stage heat production anew becomes equal as heat emission. However an equilibrium supports on more higher level. Sick feels a heats flow (heat). Rises not only the temperature of inlying organs, but the skins temperature also.

On temperature up degree in second stage distinguish such types of fever:

subfebrile to 38 C,

moderate 38-39 C,

high 39-41 C,

hyperpiretic above 41 C.

 

In third stage the action of interleukin 1 on thermoregulation centre ceases. Referenting temperature of adjusting point anew goes down. The centre of heart production oppresses. Heat emission centre, inside out, activates. Diminishes heart production in muscles and hepar. Heat return grows on all possible ways. Lowering of body temperature is gradual (lytical) or rapid (critical).

 

image006

Rapid (critical) () and gradual (lytical) (HB) lowering of body temperature on third stage of fever reaction

 

 

Types of the temperature curves

Nature of curve depends on two factors illness exciter peculiarities and organism reactivity. Major types of temperature curves:

Febris continua permanent fever. Oscillations between morning and evening temperature do not exceed 1 C. Such temperature curve is observed on the first period of abdominal typhus, attached typhus, crupose pneumonia.

Febris remittens indulgence fever. Oscillations between morning and evening temperature exceeds 1 C. Such type of curve observes attached to viral infections, sepsis, in second half of abdominal typhus.

Febris intermittens. It is alternating fever. Describes ot the rising periods of temperature (paroxysmuses) right alternate with the periods of normal temperature (apirrhexions). Temperature of the body rises to the level of 40 C and higher, holds on a few hours, goes down to the norm and rises again. This fever type is observed to the malaria. The paroxysmuses can arise every fourth day (febris quartana), every third day (febris tertiana) or daily (febris quotidiana). Periodicity of the temperature rise depends on duration of development cycle of malarial plasmodium. Paroxysmuses coincide in course of the time of destruction of erythrocytes (after completion of cycle).

Febris recurrens. It is recurrent fever. Describes by more protracted periods of rising temperature (5-8 days) and lack of clear regularity in beginnings of paroxysmuses. Example is recurrent typhus.

Febris hectica. It is exhausting fever. Daily oscillations of it are equal 2-3 C and more. Sometimes temperature goes down below the norm. Such fever is typical to sepsis, tuberculosis.

Febris undulans. It is undulating fever. It is typical for brucellosis.

 

Later clean types of temperature curves are rare. This related to wide antibiotics application and antipyretics.

 

image040

Types of the temperature curves: a - Febris continua, b - Febris remittens, c - Febris intermittens, d - Febris recurrens

 

Biological role of the fever

Fever, as regulations, renders positive influence on sick organism. It is instrumental in convalescence. In the same time fever is followed with undesirable changes in the organism. At first we will bring arguments to the fever benefit as protective, adaptated reaction.

Fever is negatively for the growing and reproduction of some microorganisms. For example, gonococcuses and treponems perish at the temperature of 40-40,1 C. Fever creates inauspicious sfere for development of some types of the pneumococcuses, prevents to reproduction of some pathogenic viruses. Typical example is oppression of the reproduction of poliomyelitis virus

Fever decrease resistibility of microorganisms to medical preparations, stimulates immunological answer of the organism on encroachment of infectious agent. The fever activates phagocytosis, antibodies synthesis rises, T-lymfocytes increase the multiply synthesis and secretion of interferon, which makes antiviruses action.

Fever is a strong stressor. Attached to fever rises activity of hypothalamic kernels, fter takes place an activation of front pituitary gland part and of suprarenal glands cortices. These phenomena is typical for general adaptation syndrome. In-parallel rises activity of sympathetic-adrenal system.

Becomes stronger disintegration of glycogen, appears hyperglycemia. In conditions of raised metabolism and raised thermogeneration it provides to the tissues energy.

Fever is followed with much effects positive for organism. They served by foundation for elaboration and inculcation in practice of special cure appearance pyrotherapy.

Fever is absolutely adaptation reaction. But it is not always useful. In dependence on illness nature, age, to individual reactivity she can begin undesirable, even harmful.

Fever makes worse sick state of hereth, followed with discomfort. It is attended with shivering, general indisposition, headache, heat sense, sometimes delirium.

 

http://www.colorado.edu/kines/Class/IPHY3430-200/image/figure19a.jpg

 

Fever inauspiciously affects metabolic processes. It sharply raises the basic metabolism. Such rules is established conformity to natural laws: increases of body temperature on 1 C conforms to rise of basic metabolism exemplarily on 10 %.

Diverse types of cargo exchangevariously react on fever. Not single conformity to natural laws in interchange changes of carbohydrates, fats, proteines. These changes depend on fever causes, stage of feverish reaction, power reserves of organism, reliability of regulation systems, nourishment character and other factors.

Attached to some infectious illnesses disorder of carbohydrates and fatty metabolism are very big. Carbohydrates backlogs are exhausted fully. By energy sources begin fat acids. Surplus receipt of fat acids in lever brings about surplus generation of ketone bodies. Develops metabolic acidosis.

The violations of albuminous exchange attached to fever are more various. Attached to infectious diseases smart few protein disintegration in organism reinforced. It does not compensate by protein receipt with food. Arises the negative nitrous balance. Heightened albuminous exchange attached to fever interconnect with action of microbic toxins and tissues disintegration products. Toxic protein disintegration in experiment is observed, for example, attached to introduction of dysenteric toxin, fresh pus, streptococci culture, blue pus bacillus. It typical, foremost, for sharp infectious diseases.

Fever inauspiciously affects cardio-vascular system. As a regulations, frequency of cardiac abbreviations increases (tachycardia). It conditioned by much factors:

a) rise of activity of sympatical nervous system;

b) straight hormones dominance of thyroid on heart;

c) dominance of warm blood on sinus knot;

d) lowering of peripheral vessels resistance.

By Libermayster, rise of body temperature on 1 C is attended with speed up of pulse on ten beat in one min. Except of tachycardia, rises a shock heart volume. Cardiac output increases on 25-30 %.

Change of arterial pressure depends on fever stage. In first stage it rises, in second stage will normalize or will bit lowers. Lowering of arterial pressure in third stage depends on temperature degradation speed. Attached to slow temperature (lysis) degradation pressure lowers gradually and moderately. Attached to rapid temperature (crisis) degradation pressure lowers rapidly and sharply. In this case is possible collapse development.

Changes blood circulation. On periphery of the body it limits. But in inlying organs (buds, liver, spleen) resistance of vessels lowers, and circulation of the blood becomes stronger.

Breathing attached to rise of temperature becomes more frequent (tachypnoe). High frequency of breathing are accounted for by straight dominance of high temperature on respiratory centre.

Permanent fever satellite violation of function of digestive organs. Function of alimentary canal strongly disturbs attached to abdominal typhus, diphtheria, measles, less - attached to flu, recurrent typhus, tuberculosis. Nature of these similar violations attached to fever of any origin. The very frequent displays: appetite loss, lowering of saliva secretion, bowels atony (constipation, flatulency), lowering of pancreas excretory function, lowering of motored and secretory function of stomach.

Disorders of digestion unconnected immediately with fever. They related to water loss and chlorids. Therefore antipyretics do not give medical effect. For removal of digestion disorders it is need a special diet.

Heavy fever oppresses the central nervous system. In sick appear such symptoms, as leading pain, weariness, insomnia. Attached to expressed intoxication are the hallucinations, delirium, consciousness loss, in children the cramp. In pathogenesis of these symptoms an essential significance has brain anoxaemia.

If disease flows with high temperature, always stands up a question of medical tactics: as will make away fever or not? Absolute testimonies for symptomatic cure fevers following: body temperature sick above 39 C, cramps presence in anamnesis, concomitant heart diseases and vessels, sharp neurulogic diseases, sepsis, shock.

For wrestling with fever adapt antipyretics. Mechanism of their action is very various: braking of synthesis leukocytes pyrogen interleukin 1, oppression of synthesis of fever mediator prostaglandins, oppression of thermoregulation centre excitability, lowering of intensity of oxydizing processes and diminution of heat making, augmentation of blood flow in peripheral vessels, reinforcement of sweat separate processes.