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INFLAMMATION
Hemodynamic Changes in Inflammation

Contents
‡ Definition ‡ Signs of inflammation ‡ Acute inflammation Vascular events Cellular events ‡ Chemical mediators of inflammation Cell derived mediators Plasma derived mediators ‡ Morphology of acute inflammation ‡ Systemic effects of acute inflammation ‡ Fate of acute inflammation ‡ Chronic inflammation ‡ General features of chronic inflamation ‡ Systemic effects of chronic inflamation ‡Pulpal inflammation ‡Conclusion ‡References

" (Slauson and Cooper.‡ "Inflammation is one of the most important and most useful of our host defense mechanisms. Ironically it is also one of the most common means whereby our own tissues are injured. and without an adequate inflammatory response none of us or our patients would be living. 2002) .

in blood and in connective tissues to eliminate the offending irritant and repair the damaged tissue.Definition ‡ Literally. and to destroy invading organisms and inactive toxins . inflammation is the reaction of vascularized living tissues to local injury.Protection: To contain and isolate the injury. More specifically.Achieve healing and repair . inflammation means ³burning´. Roles of Inflammation: . ‡ Inflammation comprises a series of changes in the terminal vascular bed.

radiation. Immunological agents like cell-mediated and antigen-antibody reactions. Physical agents like heat. Infective agents like bacteria. 4. mechanical trauma. 2. viruses and their toxins. cold.The agents causing inflammation are: 1. . Chemical agents like organic and inorganic poisons. 3.

‡ functio laesa was later added by Virchow. and ‡ Dolor .D. ‡ Tumor .SIGNS OF INFLAMMATION ‡ The Roman writer Celsus in 1st century A. ‡ Calor . . 4 cardinal signs of inflammation as: ‡ Rubor .

. Acute inflammation ‡ short and severe course ‡ It begins within 4-6 hours can last for 3-5 days It represents the early body reaction and is followed by repair.classified I. polymorphonuclear neutrophils as inflammatory cells. The main features of acute inflammation are: 1. intravascular activation of platelets. and 3.TYPES OF INFLAMMATION Depending upon duration of response . 2. accumulation of fluid and plasma at the affected site.

or the stimulus is such that it induces chronic inflammation from the beginning. Chronic inflammation is of longer duration and occurs either after the causative agent of acute inflammation persists for a long time. plasma cells and macrophages . The characteristic feature of chronic inflammation is presence of chronic inflammatory cells such as lymphocytes.II.

ACUTE INFLAMMATION VASCULAR CHANGES Hemodynamic changes Vasoconstriction Vasodilatation Local hydrostatic pressure Stasis Leucocytic margination Vascular permeability Contraction of endothelial cells Retraction of endothelial cells Direct injury to endothelial cells Endothelial injury mediated by leucocytes Neovascularisation CELLULAR CHANGES Exudation of leukocytes Phagocytosis .

Haemodynamic Changes ‡ Vasoconstriction time ‡ Vasodilatation redness & warmth ‡ Local hydrostatic pressure transudation of fluid ‡ Stasis ‡ Leucocytic margination emmigration .

Lewis experiment --.Triple response .

Altered Vascular Permeability PATHOGENESIS. In and around the inflamed tissue.transudate in nature Subsequently . exudate .inflammatory oedema. there accumulation of oedema fluid In the initial stage .

and venules is regulated by the balance between intravascular hydrostatic pressure and opposing effects of osmotic pressure exerted by the plasma proteins.Starling¶s law ‡ The movement of fluid in and out of arterioles. capillaries. .

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mainly albumin. readily coagulates due to more fibrinogen & other coagulating factors Glucose content low Many cells. does not coagulate ‡ Glucose content same as plasma ‡ Few cells & cellular debris ‡ Eg : oedema in congestive heart failure ‡ Exudate Oedema of inflamed tissue associated with increased vascular permeability Inflammatory oedema High protein content. inflamatory & parenchymal Eg : purulent exudate such as pus ‡ ‡ ‡ ‡ ‡ .Difference Between Transudate And Exudate Transudate ‡ Filtrate of blood plasma without changes in endothelial permeability ‡ Non inflammatory oedema ‡ Low protein content . low fibrinogen.

normally non-permeable endothelial layer of microvasculature becomes leaky. . 15-30 minutes Example . bradykinin and other chemical mediators.MECHANISMS OF INCREASED VASCULAR PERMEABILITY In acute inflammation. Contraction of endothelial cells affects the venules temporary gaps It is mediated by the release of histamine.mild thermal injury of skin of forearm.

Retraction of endothelial cells reversible retraction at the intercellular junctions affects venules mediated by cytokines such as interleukin-1(IL-1) and tumour necrosis factor (TNF). Example . 4-6 hours after injury and lasts for 24 hours or more ( delayed and prolonged leakage).exists in vitro experimental work only .

delayed prolonged leakage examples severe bacterial infections moderate thermal injury and radiation injury.Direct injury to endothelial cells cell necrosis and physical gaps thrombosis All microvasculature immediate sustained leakage. .

affects mostly venules and is a late response.Endothelial injury mediated by leucocytes activation of leucocytes proteolytic enzymes and toxic oxygen species which may cause endothelial injury and increased vascular leakiness. Examples .in pulmonary venules and capillaries. .

excessively leaky Eg : occurring in tumours . During the process of repair there is formation of new capillaries under the influence of vascular endothelial growth factor (VEGF).Neovascularisation.

Cellular Events EXUDATION OF LEUKOCYTES ‡ Changes in the formed elements blood ‡Rolling &Adhesion ‡Emigration ‡Chemotaxis ‡Leukocyte activation PHAGOCYTOSIS ‡Recognition & attachment ‡Engulfment ‡Degranulation ‡Killing &degradation .

Exudation of Leucocytes The escape of leucocytes from the lumen of microvasculature to the interstitial tissue is the most important feature of inflammatory response. In acute inflammation. followed later by monocytes and macrophages. poly morphonuclear neutrophils (PMNs) comprise the first line of body defense. .

CHANGES IN THE FORMED ELEMENTS OF BLOOD Vasodilatation stasis of bloodstream normal axial flow Margination Pavementing .

ROLLING AND ADHESION adhesion molecules are : i) Selectins P-sclectin E-selcctin (synthesised by cytokine activated endodothelial cells) L-selectin ii) Integrins receptors for integrins on the neutrophils are also stimulated. .2) help in localising leucocytes to the site of tissue injury and thus help in transmigration of PMNs. iii) Immunoglobulin superfamily adhesion molecule such as intercellular adhesion molecule (ICAM-1. .

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. Diapedesis .is a passive phenomenon Diapedesis gives haemorrhagic appearance to the inflammatory exudate.EMIGRATION neutrophils throw out cytoplasmic pseudopods emigration 24 hours. and monocyte-macrophages appear in the next 24-48 hours.

peri-vascular myofibroblasts and matrix) to reach the interstitial tissues is called chemotaxis. . basement membrane. The concept of chemotaxis is illustrated by Boy den's chamber experiment. a millipore filter (3 µm pore size) the test solution contains chemotactic agent.CHEMOTAXIS The transmigration of leucocytes after crossing several barriers (endothelium.

The agents acting as potent chemotactic substances for different leucocytes called chemokines are as follows: i) Leukotriene B4 ii) Platelet factor 4 iii) Components of complement system iv) Cytokines (Interleukins 1L-1. IL-6) v) Soluble bacterial products (such as formylated peptides) vi) Monocyte chemoattractant protein (MCP-1) vii) Chemotactic factor for CD4+T cells viii) Eotaxin chemotactic for eosinophils. . IL-5.

Phagocytosis ‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ Phagocytosis phagocytes. 2 main types of phagocytic cells: PMNs also called as microphages. . The process of phagocytosis involves 4 steps: recognition and attachment stage (opsonisation) Engulfment stage Secretion (degranulation) stage Digession or degradation stage. circulating monocytes and fixed tissue mononuclear phagocytes called as macrophages.

‡ ii) C3b opsonin is the fragment of complement. ‡ micro-organisms get coated with opsonins which occur in serum. ‡ The opsonins and their corresponding receptors are : ‡ i) IgG opsonin is the Fc fragment of immunoglobulin G. ‡ iii) Lectins are carbohydrate-binding proteins in the plasma which bind to bacterial cell wall.RECOGNITION AND ATTACHMENT STAGE. ‡ The phagocytic cells are recognised and attracted to a by chemotatic factors released by bacterial products as well as by tissue proteins. .

ENGULFMENT STAGE ‡ ‡ ‡ ‡ ‡ The opsonised particle is engulfed. cytoplasmic pseudopods Cytoplasmic processes meet. . and fuse membrane lined phagocytic vacuole lies free in the cell cytoplasm The lysosomes of the cell fuse with the phagocytic vacuole and form phagolysosome or phagosome .

. ‡ In particular. the preformed granule stored products of PMNs are discharged or secreted into the phagosome and the extracellular environment. the specific or secondary granules of PMNs are discharged (e. . lysosomes) while the azurophilic granules are fused with phagosomes.DEGRANULATION STAGE ‡ During this process.g.

KILLING OR DEGRADATION STAGE ‡ scavenger cells ‡ degraded by hydrolytic enzymes ‡ fails to kill and degrade some bacteria like tubercle bacilli. ‡ Oxygen independent bactericidal mechanism . ‡ The antimicrobial agents act by either of the following mechanisms: ‡ Oxygen-dependent bactericidal mechanism.

OH'. HOCl. ‡ A phase of increased oxygen consumption ('respiratory burst') by activated phagocytic leucocytes requires the essential presence of NADPH oxidase. HOBr). .‡ Oxygen-dependent bactericidal mechanism ‡ Microbicidal killing occurs by the production of reactive oxygen metabolites (O'2 H20. HOI.

Mature macrophages lack the enzyme MPO and they carry out bactericidal activity by producing OHions .‡ bactericidal activity occurs with or without enzyme myeloperoxidase (MPO) present in neutrophils and monocytes : ‡ MPO-dependent killing (H202-MPO-halide system). ‡ MPO-independent killing.

‡ ii) Oxygen-independent bactericidal mechanism. These include lysosomal hydrolases. Some agents released from the granules of phagocytic cells do not require oxygen for bactericidal activity. . permeability increasing factors. defensins and cationic proteins.

the plasma. or damaged tissue itself.CHEMICAL MEDIATORS OF INFLAMMATION ‡ permeability factors or endogenous mediators ‡ enhance vascular permeability ‡ The substances acting as chemical mediators of inflammation may be released from the cells. .

heat cold. Interleukins. trauma. VASOACTIVE AMINES. histamine releasing proteins from leukocytes.g. neuropeptides ( subs.early inflammatory response (first one hour) are histamine and 5-hydroxytryptamine (5-HT) or serotonin i) Histamine. Stimuli e. basophils and platelets. It is stored in the granules of mast cells. irradiation. immunologic reactions etc Anaphylatoxins like fragments of complement C3a and C5awhich increase vascular permeability and cause oedema in tissues.‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ 1. P ) & cytokines ( IL-1. . IL-8 ). irritant chemicals.

‡ itching and pain. ‡ ii) 5-Hydroxytryptamine (5-HT or serotonin).‡ actions of histamine are: ‡ vasodilatation. spleen. ‡ increased vascular (venular) permeability. mast cells and platelets. ‡ actions . carcinoid tumour is a serotonin-secreting tumour.nervous tissue. ‡ It is present in tissues like chromaffin cells of GIT.increased vascular permeability and vasodilatation ‡ Eg . .

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2. ARACHIDONIC ACID METABOLITES Arachidonic acid is a fatty acid, and its 2 main sources are: from diet directly; and conversion of essential fatty add, linoleic acid to arachidonic acid. Arachidonic acid is activated by stimuli or mediators like C5a to form arachidonic acid metabolites by 2 pathways: ‡ i) Metabolites via cyclo-oxygenase pathway (prostaglandins, thromboxane A2, prostacyclin).

Metabolites via lipo-oxygenase pathway (5-HETE, leukotrienes). The enzyme, lipo-oxygenase, acts on activated arachidonic acid to form hydroperoxy compound, 5-HPETE (hydroperoxy eicosatetraenoic acid)

APPLIED ASPECT
I. Cyclooxygenase inhibitors

1. Nonselective Cox inhibitors
‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ Salicylates -aspirin Pyrazolone derivatives - phenylbutazone Indole derivatives - indomethacin Propionic acid derivatives - ibuprofen Anthronilic acid derivatives ± mephenamic acid Aryl-acid derivatives - diclofenac Oxicam derivatives - piroxicam Pyrrolo-pyrrole derivatives - ketorolac

2. Preferential Cox-2 inhibitors
Nimesulide

Selective Cox-2 inhibitors ‡ II. Zileuton II. Broad spectrum inhibitors I. Rofecoxib. Lipoxygenase inhibitors I. Glococorticoids . Celecoxib. zafirlukost III. Valdecoxib.3.

LYSOSOMAL COMPONENTS ± Neutrophil granules ‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ Lactoferrin Lysozyme Alkaline phosphatese Collagenase Myeloperoxidase Acid hydrolases Acid protease Collagenase Elastase Plasminogen activator ± Monocyte granules .3.

Interferon (IF)-gama 4. PLATELET ACTIVATING FACTOR ‡ ‡ ‡ ‡ 5. Tumour necrosis factor (TNF)-alfa & beta 3.4. PF-4) . Increased vascular permeability Vasodilatation Broncho constriction Chemotaxis CYTOKINES 1. Chemokines (IL-8. Interleukins 1(IL-1) 2.

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6. NITRIC OXIDE & OXYGEN METABOLITES ± ± ± NO-Derived from activated macrophases O2.derived from activated neutrophils & macrophases They include-superoxide oxygen -hydrogen peroxide -hydroxyl ion .

Plasma derived mediators 1) The kinin system 2) The clotting system 3) The fibrinolytic system 4) The complement system .

‡ increased vascular permeability. ‡ Bradykinin acts in the early stage of inflammation and its effects include: ‡ smooth muscle contraction. ‡ vasodilatation.THE KININ SYSTEM. and ‡ pain .

‡ The actions of fibrinopeptides in inflammation are: ‡ increased vascular permeability. . and ‡ anticoagulant activity. ‡ chemotaxis for leucocyte.THE CLOTTING SYSTEM ‡ Factor Xlla initiates the cascade of the clotting system resulting in formation of fibrinogen which is acted upon by thrombin to form fibrin and fibrinopeptides .

‡ This system is activated by plasminogen activator .THE FIBRINOLYTIC SYSTEM.

splits off complement C3 to form C3a which is a permeability factor.‡ The actions of plasmin in inflammation are: activation of factor XII to form prekallikrein activator that stimulates the kinin system to generate bradykinin. . and degrades fibrin to form fibrin split products which increase vascular permeability and are chemotactic to leucocytes.

THE COMPLEMENT SYSTEM. C5a and C4a. and C5a is chemotactic for leucocytes. C3b augments phagocytosis. increased vascular permeability causing oedema in tissues. ‡ The actions of anaphylatoxins in inflammation are: release of histamine from mast cells and basophils. cobra venoms and IgA. ‡ The activation of complement system can occur by antigenantibody complexes or by bacterial toxins. . ‡ Complement system on activation by either of these two pathways yields anaphylatoxins C3a.

and together with necrosed epithelium.MORPHOLOGY OF ACUTE INFLAMMATION ‡ Inflammation of an organ is usually named by adding the suffixitis to its Latin name e. hepatitis. meningitis etc. . appendicitis.g. so plasma exudes on the surface where it coagulates. forms false membrane. respiratory) ‡ denudation of epithelium. ‡ morphologic varieties ‡ PSEUDOMEMBRANOUS INFLAMMATION. ‡ It is inflammatory response of mucous surface (oral.

bacillary and amoebic dysentery. ‡ The bacteria which cause suppuration are called pyogenic. duodenum. ulcers of legs due to varicose veins etc. . ‡ SUPPURATION (ABSCESS FORMATION). ‡ Common sites are the stomach. it results in tissue necrosis. ‡ When acute bacterial infection is accompanied by intense neutrophilic infiltrate in the inflamed tissue. intestinal ulcers in typhoid fever. intestinal tuberculosis. ‡ local defects on the surface of an organ produced by inflammation. ‡ A cavity is formed which is called an abscess and contains purulent exudate or pus and the process of abscess formation is known as suppuration.‡ ULCER.

fragments of tissue debris and fibrin. some red cells. healing occurs by fibrous scarring.‡ pus is creamy or opaque in appearance and is composed of numerous dead as well as living neutrophils. Due to tissue destruction. . ‡ An abscess may be discharged to the surface due to increased pressure inside or may require drainage by the surgeon. ‡ Some of the common examples of abscess formation are as under: ‡ i) Boil or furruncle which is an acute inflammation via hair follicles in the dermal tissues. ‡ ii) Carbuncle is seen in untreated diabetics and occurs as a loculated abscess in the dermis and soft tissues of the neck.

. Bacteraemia is defined as presence of small number of bacteria in the blood which do not multiply significantly. ‡ 5. ‡ They are commonly not detected by direct microscopy. BACTERIAL INFECTION OF THE BLOOD. Blood culture is done for their detection e. ‡ This includes the following 3 conditions: ‡ i. Streptococcus viridans. Escherichia coli. ‡ It is a diffuse inflammation of soft tissues resulting from spreading effects of substances like hyaluronidase released by some bacteria. infection with Salmonella typhi.g.‡ CELLULITIS.

bacilli of plague etc. pyogenic cocci. highly pathogenic bacteria in the blood e. ‡ iii) Pyaemia is the dissemination of small septic thrombi in the blood which cause their effects at the site where they are lodged. ‡ This can result in pyaemic abscesses or septic infarcts.g.‡ ii) Septicaemia means presence of rapidly multiplying. .

. ‡ b) Septic infarcts result from lodgement of larger fragments of septic thrombi in the arteries.‡ a) Pyaemic abscesses are multiple small abscesses in various organs resulting from very small emboli fragmented from septic thrombus.

2.SYSTEMIC EFFECTS OF ACUTE INFLAMMATION 1.000-20. and in parasitic infestations. interleukin-1 and tumour necrosis factor in response to infection. Fever occurs due to bacteraemia. It is thought to be mediated through release of factors like prostaglandins. ‡ ‡ ‡ ‡ ‡ Leucocytosis 15. . eosinophilia. in viral infections lymphocytosis.000/ µl A leukocyte count above is termed a leukemoid reaction in bacterial infections there is neutrophilia.

increased vascular permeability and intravascular volume loss.3. ‡ These changes causes hypotension and shock. in response to severe tissue injury or infection results in systemic vasodilatation. . Lymphangitis-lymphadenitis ‡ This response represents either a nonspecific reaction to mediators released from inflamed tissue or is an immunologic response to a foreign antigen. Shock ‡ Massive release of cytokine TNF . a mediator of inflammation. 4.

OUTCOME OF ACUTE INFLAMMATION RESOLUTION Acute inflmn INJURY ABSCESS FORMATION HEALING Chronic inflmn .

3. . 2. Chronic inflammation following acute inflammation. Chronic inflammation starting de novo. ‡ ‡ ‡ ‡ caused by one of the following 3 ways: 1.CHRONIC INFLAMMATION ‡ Chronic inflammation is defined as prolonged process in which tissue destruction and inflammation occur at the same time. Recurrent attacks of acute inflammation.

plasma cells. MONONUCLEAR CELL INFILTRATION. epithelioid cells and sometimes. ‡ Other chronic inflammatory cells include lymphocytes. . macrophages. ‡ Phagocytes .circulating monocytes. ‡ mononuclear inflammatory cells .GENERAL FEATURES OF CHRONIC INFLAMMATION ‡ 1. ‡ These appear at the site of chronic inflammation from: ‡ chemotactic factors ‡ local proliferation of macrophages and ‡ longer survival of macrophages at the site of inflammation. multinucleated giant cells. eosinophils and mast cells.phagocytes and lymphoid cells.

eollagenase. elastase. PROLIFERATIVE CHANGES.g. TISSUE DESTRUCTION OR NECROSIS. healing by fibrosis and collagen laying takes place. protease. cytokines (TL-1. IL-8. nitric oxide. ‡ Tissue destruction and necrosis are central feature of chronic inflammatory lesions which occurs by activated macrophages which release a variety of biologically active substances e. proliferation of small blood vessels and fibroblasts is stimulated resulting in formation of inflammatory granulation tissue.‡ 2. Eventually. reactive oxygen radicals. TNF). lipase. ‡ 3. angiogenesis growth factor etc. . As a result of necrosis.

Anaemia Leucocytosis ESR Amyloidosis occurs in long-term cases of chronic suppurative inflammation. .SYSTEMIC EFFECTS OF CHRONIC INFLAMMATION ‡ ‡ ‡ ‡ ‡ Fever.

abnormally responsive to cold b. Chronic a. asymptomatic with pulp exposure b. Irreversible pulpitis 1. Reversible 1. hyperplastic pulpitis c. Asymptomatic (chronic) B.Inflamation of the pulp Pulpal inflammation A. Symptomatic (acute) 2. internal resorption Partial Total . Acute a. abnormally responsive to heat 2.

‡ Inflammatory changes caused by severe injury can lead to necrosis of the pulp and subsequent pathologic changes in the periradicular tissues. ‡ ‡ ‡ ‡ metabolic changes waste products spread inflammation total necrosis of the pulp . ‡ portals of entry ‡ The vascular response causes the aggregation of red blood cells in the vessels.

Kim Hypothetical Model .

‡ noxious products produce bone resorption and granulation tissue .Periradicular Manifestations ‡ the root canal will serve as a pathway to the periradicular area for the noxious products of tissue necrosis.

‡ Three requisites are necessary for suppuration: ‡ 1. Necrosis of tissue cells ‡ 2. ‡ Degenerative Changes ‡ Degenerative changes in the pulp may be one of the following: ‡ Fibrous ‡ Resorptive ‡ Calcific ‡ Another form of degeneration is suppuration. A sufficient number of polymorphonuclear leukocytes ‡ 3. Digestion of the dead material by proteolytic enzymes .Tissue Changes Following Inflammation ‡ Tissue changes following inflammation are either degenerative or proliferative.

a substance may be both an irritant and a stimulant. . Within the same area. such as calcium hydroxide and its effect on adjacent tissue.Proliferative Changes ‡ Proliferative changes are produced by irritants mild enough to act as stimulants.

and (iv) zone of stimulation.Endodontic Implications ‡ ‡ ‡ ‡ ‡ ‡ ‡ The reaction of the periradicular tissues was described by Fish. . (ii) zone of contamination. foci of infection in the jaws of guinea pigs 4 well defined zones of reaction were found: (i) zone of infection. (iii) zone of irritation.

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Conclusion ‡ Inflammation has a protective role as well as may harm the body. . Thus proper treatment is to be devised and implemented for optimum health to be achieved.

References ‡ Harsh Mohan ± pathology ‡ Robbins ‡ Internet sources .

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