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Inflammation

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  • 1. INFLAMMATION Introduction One of the characteristic of living tissue is its ability to react to injury so the survival of an individual depends on the ability of normal cells to respond to damage. In fact without inflammation none of us would be alive to day. The process of inflammation occurs as a part of our day to day lives. Acute inflammation • Acute inflammation is the immediate and early response to injury. This process is usually described by the “Suffix-itis” proceeded by the name of the organ or is involved. Eg. Pulp – puptis Causes of acute inflammation 1. Physical injury a. Chemical injury 2. Microbial infections 3. Immuno logical mechanism induced injury 4. Necrosis induced Physical 1. Mechanical trauma cutting/crushing 2. U.V. rays Eg. Sunburn 3. Ionising radiation 1
  • 2. 4. Injury due to cold and heat. Eg. Burns, frost bite 5. Clinical corrosive acids, alkali etc. which may be protoplasmic poisons. In these are included certain body fluids which when stray from their respiratory organs cause damage to the ts 6. Microbial infection – commonest cause viruses  multiply intracellular and destroy the cell. Bacteria release specific exotoxins or endotoxins. Parasites may cause some hyper sensitivity reactions. 7. Immunologic mechanism These include diseases mediated by antigen antibody interaction as well as those classified as type I and IV which cause an inappropriate reaction which damages the tissues. 8. Necrosis: either due to hormonal changes or around an infarct. Microscopic features The essential physical characteristics of acute inflammation were formulated by celsus 38 AD using the latin words. Rubor, calor, tumour, dolor. Rubor or redness is seen due to the dilatation of small blood vessels within the damaged area. 2
  • 3. Heat or Calor Increase in temperature is seen only in peripheral parts of the body e.g. skin. This is due to increased blood flow or hyperaemia which causes vascular dilatation and the delivery of warm blood to the area. Systemic fever which results from some of the chemical mediator may also contribute. Tumor or swelling which results for acidic mainly, and sometimes due to physical mass of inflammatory cells migrating into the area. Pain – dolor is the common feature for the patient it results partly from the stretching and distortion of tissues due to inflammatory oedema and partly from pus under pressure in an abscess cavity. Some of the chemical mediators of inflmmation e.g. prostaglandins induce pain. Loss of function or function laesa was added to these signs in 1900 by Virchow: According to Under wood movement of an inflamed part is consciously and reflexly inhibited by pain while severe swelling may physically immobilize the tissues. Some special macroscopic features Although the cardinal signs are same for all the organs there may be some descriptive terms pertaining to certain organs. 3
  • 4. Serous inflammation Catarrhal Fibrinous Haemorhagic Suppurative Membraneous Pseudomembraneous Necrotizing Serous inflammation Here there is abundant protein rich fluid exudates with a relatively low cellular content. Vascular dilatation may be apparent to the naked eye due to the serous surfaces having blood laden vessels on the surface e.g. blood shot eyes in conjunctivitis. Catarrhal Inflammation When mucous hyper secretion accompanies acute inflammation e.g. common cold. Fibrinous If the exudates contains fibrinogen which polymerizes into a thick fibrin coating. Seen in acute pepiosteitis because the pericardium shows a bread and butter appearance. Haemorrhagic Seen in severe vascular injury or depletion of coagulation factors e.g. acute pancretitis (destruction of vascular walls). 4
  • 5. Suppurative Seen when mucosed cells form pus which gets walled off to form on abscess membraneous. The epithelium becomes coated with fibrin, desquamated epithelial cells and inflammatory cells. E.g. gray membrane seen in pharyngitis and lacyngitis. Pseudomembraneous inflammation - describes superficial mucosal ulceration with an overlying slough of disrupted mucosa fibrin mucous inflammatory cells. This is seen in pseudomonas colitis following broad spectrum antibiotic therapy. Necrotizing inflammation in tissue pressure due to oedema may lead to vascular occlusion and thrombosis which may result in necrosis. This combined with bacterial putrefraction is called gangrene. Microscopic changes These can be studied under the following headings: 1) Vascular response 2) Swelling and exudation Fluid exudates Cellular exudates (Phagocytosis) 3) Changes in other tissue components (The separation is artificial as all these things occur simultaneously in a inflammation). Vascular response Very initial and transient changes. Initially a transient vasoconstriction is seen. These can be demonstrated in the human skin. Light stroking produces 5
  • 6. a white line this may be due to a mechanical stimulation of the blood vessels or when irritating chemicals are applied. Persistent vasodiltion • This vasoconstriction is followed by vasodilatation which persists for the duration of the inflammation. Arteriolar dilation causes Blood to flow thru the thorough fare cannels to resins. Also per capillary sphineters open up so, blood passes into the capillary bed. Therefore vessels which were closed open up + caliber. Thus the inflamed part seems to contain caliber also increase. Lewis in 1924 noted that for stroking of the skin to results in a triple response and his analysis of these events lead to the hypo thesis that lies lamine liberated from damaged cells was an important factor in the vascular response. What is the triple response, it consists of red line place and weal. As soon as the human skin is stroked firmly with a sharp object. After a short latent period a red line develops. First – bright red, later – cyanosed. This is sharply demarcated and is due to capillary dilatation. Flare 15-30 secs later a blotchy flare with crenated outline appears surrounding the red line. This is due to arteriolar dilation. If the nerve supply is cut off and the skin is pierced the reaction can be seen but if the test is performed ten days later there is no reaction seen. This shows that this is mediated via a local axor reflex. 6
  • 7. Weal A weal may subsequently appear due to exudation of fluid through the vessel wall. As oedema decreases the weal becomes paler due to pressure on capillaries. Note: On role of nerves in vasodilatation. Inflammation can occur in completely denervated tissues but nerves do play a role e.g. axon reflex. Conheim showed that if the nerve supply of rabbit ear is removed vessels become constricted and un responsive. Injection of a test dose of bacteria produces slow inflammatory reaction and relatively more tissue destruction and damage. Under normal conditions the autonomic nervous system plays a little role in inflammation response. Changes in Vessel Wall Normal flow Blood cells occupy central part of stream. The plasmatic stream has a lower viscosity than whole blood. Therefore peripheral resistance is low. Changes 1. Increased in blood velocity due to arteriolar dilatation (short lived phase). This is followed by slowing of the stream. 7
  • 8. 2. Simultaneously WBC’s and Platelets stick to vessels wall. 3. Endothelial cells become thickened and appeared to be covered by a gelatinous layer. These 3 features are • Stasis. • Leucocyte adherence. • Endothelial thickening. Stasis As the rate of flow into the thorough force channels increases, the capillaries that are normally closed begin to open decreased, thus volume of capillary bed increases greatly, so much so that blood flow slows and may stop inspite of the increased amount of blood. The more severe the injury the sooner the slowing develops may be from few minutes – ½ hr / more As the blood slows the red cells sometimes appear to merge forming a homogenous yellow column filling the center. Electron microscopy shows that they are closely packed into a rouleux with eventual loss of their hemoglobin. This column may remain still for min/hrs a days depending on the injury. This curious form of circulatory arrest is called stasis which means standing still. 8
  • 9. CHANGES IN ENDOTHELIAL LAYER 1. In inflammation the endothelial layer becomes swollen and thickened. 2. Swelling may reduce the lumen of a capillary. 3. In the initial stages of inflammation a transudate is seen which is an ultra filtrate of plasma and contains little protein. Later on the vascular permeability increases and exudation of a protein rich fluid is seen which seeps out and leads to oedema. The mechanisms behind the increased vascular permeability are as follows: 1. Endothelial cell contraction inter cellular gaps widen. Mediators - Histamine - Brady kinin - Leukotreines - Seen mostly in venules 20-60µm in diameter 2. Junctional retraction some cytokine mediators induce structural reorganisation of the cytoskeleton. This is a reversible change and may occur 4-6 after injury. 3. Direct endothelial injury – this is seen in several injury this may result in immediate sustained response or delayed prolonged leakage. 4. leukocyte dependant cellular injury may be a result of leukocyte adherence to endothelium, releasing toxic oxygen and enzymes leading to endothelial injury. 5. Increased transcytosis via an intra cellular vesiculovacular pathway. 9
  • 10. Due to all these factors the permeability is increased and leukocytes and erythrocytes escape. First the neutrophils then monocytes, macrophages and R.B.C.s The leukocytes cellular events are: 1. Margination and rolling. 2. Adhesion and transmigration. 3. Migration in interstitial tissue towards chemotactic stimulus. The cellular exudates consists of leukocytes and may be some RBC’s. How the cells escape or the Leucocyte cellular events. Exudation and swelling This is the most characterized feature of acute inflammation in the higher animals. This exudates has a fluid and cellular compartment. The formation of inflammatory exudates depends on several reasons. Normally 32 mm Hg – arteriolar 12 mm Hg – Venous end. Mean colloid osmatic pressure pr-25 mm Hg which is equal to the mean capillary pressure. Although fluid leaves through the pre capillary areteriole. It is returned in equal amounts by the post capillary venule. So the net flow is maintained at zero. 10
  • 11. INFLAMMATION A pressure – 50mm Hg Venous pressure – 30mm this is (due to arteriolar dilatation). At the same time osmotic pressure is reduced to 20mm Hg because of protein leakage across the venule. This leads to extravasation of fluid. The crucial factor in the formation of an exudate is an increased permeability of the vessel wall to plasma proteins. Experiment If trypan blue is injected intravenously into an animal the dye becomes bound to plasma albumin and does not readily leave the circulation. When inflammation is seen the albumin can be seen to pass the inflamed area as the exudates forms. Function of the fluid exudates All the constituents of plasma are poured into the area of inflammation. 1. The clinical importance of this fluid is that along with fluid even drugs present in plasma will be seen here. So drugs in inflammation should be given early as it is obvious that they are merely carried to the inflamed area via the exudates and are in no way concentrated. 2. The fluid dissolves local irritants if any. 11
  • 12. 3. It has high fibrinogen content which results in a fibrin clot this has 3 main functions: i. It forms a union between severed tissues as in a cut. ii. May form a barrier against bacterial invasion. iii. It aids phagocytosis. 4. The cellular component As the vasoconstriction permeability increases the leukocytes erythrocytes escape out of these the 1st to appear are the neutrophils which are seen in 2-9 minutes followed by monocytes macrophages and erythrocytes. The leukocytes cellular events are as follows: 1. Margination and rolling. 2. Adhesion and transmigration. 3. Chemotaxis and activation. 4. Phagocytosis and degranulation. Margination and Rolling As vasoconstriction permeability increases fluid exists the vascular lumen, blood flow slows. So, leukocytes settle out of the central column. Marginate to the vessel periphery, also they tumble on the endothelial surface transiently sticking along the way. This is called Rolling. These 2 processes are mediated by the binding of complementary adhesion molecules on the leukocytes and endothelial surfaces similar lock and key mechanism. 12
  • 13. Adhesion and Transmigration Eventually the leukocytes firmly adhere to the endothelial surface (adhesion) before crawling between the cells and through the membrane into the extravascular (diapedesis) space. The leukocytes vary 6-24 hrs – Neutrophils 24-47 – monocytes but neutrophils are short lived. Chemotaxis and Activation After extravasation, the leukocytes emigrate towards the site of injury along a chemical gradient in a process called chemotaxis. Both exogenous and endogenous factors may act for chemotaxis. 1. Soluble bacterial products. 2. Components of the complementary system. 3. Products of the lipoxygenase pathway of arachidonic acid metabolism. 4. Cytokines especially those from the chemokine family. Besides stimulating slow motion these factors also induce other leukocyte responses called leukocyte activation. Phagorytosis & degranulation Phagocytoses and the release of lysosomal enzymes are 2 of the major benefits of leukocyte. Accumulation at the site of inflammation. It has 3 steps: i) Recognition and attachment of the particle to the leukocytes. ii) Engulfment with formation of a phagocytic vacuole. iii) Killing on degradation of the injected material 13
  • 14. Chemical mediators of inflammation Although the chemical mediators may be vital to the process it is neither possible nor desirable to remember every mediator in detail. *Mediators derive from plasma or by local production from cells. Plasma derived ones are present as circulating precursors that must be activated to achieve their biologic properties. Cell derived ones are sequestered in intra cellular granules and are secreted or synthesized in response to a stimuli. *Most mediators may bind to specific receptors on target cells. *They may also have direct enzymatic and or toxic activities. Some mediators may stimulate target cells to release secondary effector molecules. These may have activities similar to the initial molecules so, they may amplify a particular response or they may also have opposing activities thus they regulate the initial response. Mediators may be short lived i.e. once released they may quickly decay or are inactivated by enzymes. The major reason for this check is that most of the mediators have harmful effects. 14
  • 15. Effects of Acute inflammation Acute inflammation has local and systemic effects both of which may be beneficial or harmful. The local effects are clearly beneficial but they may also cause harm. Beneficial effects Dilution of toxins such as those produced by bacteria these are then carried via lymphatics. Entry of antibodies this is because of increased vascular permeability into the extravascular space. Where they may lead to lysis or phagocytosis of microorganism. They also neutralize the toxins. Transport of drugs to the place where bacteria are multiplying. Fibrin formation from exuded fibrinogen, impedes movement of microorganism traps them facilitates phagocytosis. Harmful effects 1. Digestion of normal tissue by enzymes this may cause vascular damage. 2. Swelling in some tissue may be very harmful e.g. in children the swelling of epiglottis in haemophilus influenza may result in death. 3. Inappropriate response some times the responses may be in appropriate e.g. a reaction to an antigen which is not harmful to the individual as is seen in hypersensitivity reactions. Such reactions may be life threatening e.g. extrinsic asthma. 15
  • 16. Sequelae of Acute inflammation Sequelae depends on • Type of tissue involved. • Amount of ts destruction which depend on nature of injurious agent. Resolution Means complete restoration of tissue after an episode of acute inflammation. Conditions which favour resolution are: 1. Minimal cell death and its damage. 2. Regenerative capacity of the organism. 3. Rapid destruction of causative agent. 4. Rapid removal of fluid and debris by good local vascular drainage. Sequence Of Events Leading To Resolution May Be: Phagocytosis of bacteria  Intracellular killing  Fibrinolysis  Phagocytosis of debris  Disappearance of vascular dilatation 16
  • 17. Suppuration Is the formation of pus – Pus is a mixture of - Living and dying neutrophils and bacteria. - Cellular debris. - Globules of liquid. Factors : Causative agent must be persistent e.g. pyogenic bacteria. Once pus accumulates it gets surrounded by a “PYOGENIC MEMBRANE” consisting of: - Sprouting capillaries. - Neutrophils. - Occassional fibroblasts. Such a collection is called an abscess, the special feature of this abscess is that bacteria within it are inaccessible to antibodies and antibiotic drugs, thus e.g. acute osteomyelitis is very difficult to treat. Abscess This abscess usually points and bursts, abscess cavity collapses and is obliterated by organization and fibrosis leaving a small scar. If it forms in a hollow viscus, the mucosal layers of the outflow tract may become fused and lead to empyema such deep seated abscess sometimes discharge their pus along on abnormal connection between the abscess and skin lined by granulation tissue called sinus. If this results in an abnormal tract connecting 2 mucosal surfaces it is called a fistula. 17
  • 18. The fibrous walls of long standing abscess may become complicated by dystrophic calcification. Organisation Organisation is the replacement of tissues by granulation tissue. This happens when: 1. Large amounts of fibrin are formed which cannot be removed by fibrinolytic enzymes. 2. Large volumes of tissue become necrotic and the dead tissue is not digested. 3. Exudate and debris cannot be removed or discharged. During organization new capillaries grow into the inflammatory exudates macrophages migrate into the zone fibroblasts proliferate resulting in fibrosis. Sometimes the fibrin is not easily removed and capillaries grow into the fibrin accompanied by macrophages and fibroblasts. Eventually fibrous adhesion occurs between the parietal and visceral plasma. If the agent causing inflammation is not removed the inflammation may progress to the chronic phase. In addition to the organization the character of the cellular exudates changes with lymphocytes plasma cells and macrophages. 18
  • 19. CHRONIC INFLAMMATION The word chronic applied to any process implies that the process has extended over a long period of time. But in the case of the word chronic inflammation the word chronic takes on a specific meaning i.e. the type of cellular reaction differs from acute inflammation. Chronic inflammation may be defined as an inflammatory process in which lymphocytes, plasma cells and macrophages predominate and which is usually accompanied by formation of granulation tissue resulting in fibrosis. Chronic inflammation may follow acute or may start primarily in the chronic form. P.C.I. is the response in which there are all the histologic features of C.I. and no initial stage of acute inflammation is seen. Chronic inflammation is characterized by: 1. Infiltration with mononuclear cells. Macrophages Lymphocytes Plasma cells. 2. Tissue destruction 3. Repair involving new vessel proliferation (angiogenesis) and fibrosis. 19
  • 20. Causes I. Primary chronic inflammation. a. Resistance of infective agent to phagocytosis and intra cellular killing. b. Foreign body reaction. c. Some autoimmune diseases e.g. rheumatoid arthritis contact hypersensitivity. d. Specific disease of unknown aetiology – ulcerative colitis. e. Primary granulomatous disease – sarcoidiosis. f. Transplant reflection involves chronic inflammation response. II. Progression from acute inflammation If there is suppuration  Deep seated access cavity  Delayed / inadequate drainage  Scarring due to granulation tissue in growth Another feature is the presence of indigestible material e.g. keratin from a ruptured cyst, fragments of necrotic bone and inert foreign body materials. 20
  • 21. III. Recurrent bouts of inflammation and repair - Will usually result in the clinicopathological cavity of chronic inflammation. Macroscopic features These are: 1. Chronic ulcer: with a base lined by granulation tissue and fibrous tissue extending through the muscle layers of the wall. 2. Chronic abscess: e.g. in osteomyelitis 3. Thickening of the wall of a hollow viscous e.g. Cohn’s disease. Macroscopic features • Granuloma formation. • Fibrosis – this is the most prominent feature. Microscopic features The cellular infiltrate consists characteristically of lymphocytes plasma cells and macrophages. A few eosinophils may be present but neutrophils are scarce. Macrophages are one component of the mononuclear phagocytic system consisting of closely related cells of bone marrow origin. When monocytes reach the site of inflammation. They activated into macrophages. After activation the macrophages help in mediating tissue 21
  • 22. destruction angiogenesis and fibrosis which is characteristic of chronic inflammation. Unlike acute inflammation in which the macrophage eventually die or go into the lymphatics. In chronic inflammation they persist. They may also fuse to form giant multi-nucleated cells. Under appropriate conditions they also have a capacity to proliferate. Other cells seen in chronic inflammation are: T - Lymphocytes B - Plasma cells - Eosinophils • Eosinophils are characteristics found in inflammatory sites around parasitic infections or as part of immune reactions mediated by immunoglobulins associated with allergies. • T and B lymphocytes are brought into the inflammatory site by the same adhesions and chemokines that bring monocytes. • Plasma cells produce antibodies against antigens in the inflammatory site, or against altered tissue components. Granulomatous Inflammation Granulomatous inflammation is a distinctive pattern of chronic inflammation characterized by aggregation of activated macrophages that have acquired an enlarged squamous cell like or epitheloid appearance. 22
  • 23. Granulomas are seen in the following conditions: Bacterial – e.g. tuberculosis (most common). Parasitic – Schistosomiasis. Fungal – Blastomycosis. Inorganic metals / dusts – Silicosis Foreign body – Sutures / vascular grafts. Unknown – Sarcoidiosis Agranuloma can be basically called as an aggregation of epitheloid histiocytes. These cells are: - Large vesicular nuclei. - Plenty of cytoplasm - Elongated. Some times they may be conveled into multinucleate giant cells. These giant cells form when indigestible matter accumulates for e.g. – Silica, Bacteria which have indigestible walls containing mycolic acids and waxes. Some which contain about 100 nuclei are thought to develop by accident when 2 more macrophages attempt to engulf the same particle simultaneously. Their cell membranes fuse and the become one e.g. Langhans giant cell foreign body 9C Toutons 9C. Role of Lymphatics The lymphatic system helps to drain and sample fluid accumulated in the extravascular matrix. 23
  • 24. It acts as a second line of defense whenever a local inflammatory response fails to contain and neutralize injurious agents. Lymphatics also delivers the antigens and lymphocytes from peripheral sites to more central lymphnodes where T cells, B cell and the appropriate antigen presenting cells can all gather to mount an immune response. Lymph flow is increased in inflammation and is important in the resolution of the inflammatory response. It helps to drain the oedema fluid extravasated leukocytes and cellular debris from the extravascular space. At the same time they may also cause disintegration of the injurious agent so, secondary inflammatory involvement of the lymphatic channel or regional lymphatic lymphnodes may develop these may then drain to larger lymphatics and then into the blood stream where they may cause bacterimia. Systemic factors 1. Fever / Pyrexia 2. Constitutional symptoms 3. Weight loss 4. Reactive hyper plasia of R.E.S. 5. Hematological changes. - E.S.R. - Leukocytosis - Anaemia - Amylodiosis 24
  • 25. Fever This is due to compound known as endogenous pyrogens which act on the hypo thalamus to set the thermoregulation mechanisms at a higher temperature. Constitutional symptoms Includes – Malaise - Anorexia - Slow wave sleep - Nausea Weight loss – Due to negative nitrogen balance is common in chronic inflammation. R.E.S. Local or systemic lymphnode enlargement is seen commonly and spleenomegaly is seen in specific infections. Haematological changes Increased E.S.R. is seen - Neutrophilia pyrogenic infection eosinophilia in allergic disorders lymphocytosis in chronic inflammation monocytosis in bacterial infections. 25
  • 26. Anaemia • Because of blood loss in the inflammatory exudates. • Haemolysis • Bone marrow depression. Amytodiosis May also be seen in long standing chronic infections. CONCLUSION Inflammation is the first response to any harmful stimulus. It is one of the main component of body’s defense mechanism at this point the clinician should intervene and with a thorough knowledge of the process. The clinician can stop the process where the beneficial effects stop and harmful effects begin. 26
  • 27. Contents 1. Introduction 2. Acute Inflammation 3. Chronic Inflammation 4. Sequalae 5. Conclusion 27

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