Inflammation Seminar by Dr Pratik

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Inflammation Seminar by Dr Pratik

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  • Seminar on Inflammation
  • The term inflammation is well renowned.As we all know it serves to destroy, dilute and wall off any injurious agent, by setting in a series of events that ultimately lead to the healing of damaged tissues and its reconstitution by repair.Even though inflammation is a commonly dealt topic ,it is been continuously reviewed.What makes inflammation so important to be extensively studied?Without inflammation, infections would go unchecked, wounds would never heal, and injured organs may remain as permanent festering sores. In our day to day lives we come across many cases starting from gingivitis to oral cancer wherein inflammation exerts a direct or an indirect effect. So understanding inflammation helps us to know the various vascular and cellular changes, mediators involved and therefore help us to evaluate the significance of various anti-inflammatory drugs that we do prescribe, for controlling the same.
  • CORNELIUS Celsus, a Roman writer of the first century AD, first listed the four cardinal signs of inflammation: rubor, calor, dolor and tumor (redness, heat, pain & swelling)fifth clinical sign, loss of function (function laesa), was later added by Rudolf Virchow.In 1793, the Scottish surgeon John Hunter Quoted inflammation as a non specific body response
  • Julius CO HI NUM(1889) providedfirst microscopic description of inflammationIn the 1880s, the Russian biologist ELI MET NI KOFF discovered the process of phagocytosisPAUL ER LICH and MET NI KOFF developed theory of immunity, for that, they were honoured with Nobel Prize in 1908Lewis established the concept that “chemical substances, such as histamine, locally induced by injury, mediate the vascular changes of inflammation.”
  • PREACUTE - It has very short course and the animal die soon (few hours) after exposure to the causative agent. ACUTE - It is an inflammation that has rapid onset and short duration, with prominent circulatory and cellular changes (mainly neutrophils, eosinophils, and lymphocytes). SUBACUTE - caused by mild irritant with less prominent circulatory and cellular changes (neutrophils decrease and macrophages increase). CHRONIC - occurs within months of exposure to the causative agent and lasts for a long time. The circulatory and cellular changes are difficult to be seen in the area, neutrophils are very few in number, macrophages are numerous, and granuloma usually formed by proliferating fibroblasts and mature fibrocytes.
  • Broadly inflammation can be classified in to acute inflammation and chronic inflammation
  • Acute inflammation may be of Serous type - producing a serous exudate.Fibrinous  marked by an exudate of coagulated fibrin.Catarrhal - affecting mainly a mucous surface, marked by a copious discharge of mucus and epithelial debris.Haemorrhagic - Characterized by large numbers or RBC's that leave by DAYA PIDI SUS . Suppurative  marked by pus formation.
  • Bacterial- Streptococci, staphylococci, C diphtheriae, M tuberculosisProtozoa,helminths ,etc
  • cardinal signs of inflammation: calor, rubor, tumor,dolor & functiolaesa (redness, swelling, heat, and pain)
  • components of acute and chronic inflammatory responses: circulating cells and proteins i.e. PMNs, Eosinophils, basophils, monocyte, lymphocyte, clotting factors, kininogens, complement components etc,cells of blood vessels – endothelial cellsand cells and proteins of the extracellular matrix. i.e. mast cells, fibroblast & macrophages
  • Acute inflammation can be explained under following headings
  • Which I have explained in Cause of inflammationInfections (bacterial, viral, parasitic) and microbial toxinsTrauma (blunt and penetrating)Physical and chemical agents (thermal injury, e.g., burns or frostbite; irradiation; some environmental chemicals)Tissue necrosisForeign bodies (splinters, dirt, sutures)Immune reactions (also called hypersensitivity reactions
  • Vascular events can be summarized under following headings
  • Normally, plasma proteins and circulating cells are sequestered inside the vessels and move in the direction of flow.
  • In inflammation, blood vessels undergo a series of changes that are designed to maximize the movement of plasma proteins and circulating cells out of the circulation and into the site of injury or infection.
  • irrespective of type of injury or insult, the immediate response is Transcient vasoconstriction .. Which lasts for 3-5 sec to 5 mins
  • Next follows persistent progressive vasodilation.. Whichresults in increased blood volume in microvasculature bed of area, WHICH IS RESPONSIBLE FOR REDNESS AND WARMTH AT THE SITE OF ACUTE INFLAMMATION
  • progressive vasodilation may increase local hydrostatic pressure resulting in transduction of the fluid in extracellular space… causes swelling of the area
  • To understand How there is increased vascular permeability, we have to understand the normal vascular permeability first
  • The normal vascular permeability is guarded by
  • The NORMAL MICROCIRCULATORY CONTROL is mediated either by
  • Moving on the normal
  • Starlings hypothesis states that, in normal circumstances, the fluid balance is maintained by two opposite sets of force
  • forces causes outward movements- intravascular hydrostatic pressure,osmotic pressure of interstitial fluidinward movements – intravascular osmotic pressure and hydrostatic pressure of interstitial fluid
  • When ever little fluid is left in interstitial compartment , it is drained by lymphatics and thus no oedemareults normallyBut in inflammation microvasculature becomes leaky leadingleading to oedema
  • There are various concept that accounts for leakiness of the microvasulature..like
  • It is mainly mediated by histemin, bradykinin and othe chemical mediators lasts for 15-30 mins
  • Causesnecrosis and apperence of physical gap at the site of damage
  • Adhesion of leucocyte to endothelium may lead to activation of leukocyte The activated leucocyte releases proteolytic enzymes and toxic oxygen species which causes endothelial injury and ultimately increased vascular leakiness
  • Increased transcytosisacross the endothelial cytoplasm also found to be one of the mech of increased leakiness … Transcytosis is the process by which various macromolecules are transported across the interior of a cellIt occurs under the influence of certain factors like vascular endothelial growth factor (VEGF)Family of peptides that includes VEGF-A, VEGF-B, VEGF-C, VEGF-D, and placental growth factor. Potent inducer of blood vessel formation in early development (vasculogenesis) It has Central role in the growth of new blood vessels (angiogenesis) in adults .
  • New vessel sprouts (SPRA U T s) remain leaky until the endothelial cells mature and form intercellular junctions.
  • The sequence of events, in the journey of leukocytes, from the vessel lumen, to the interstitial tissue, called extravasation, can be divided, into the following steps
  • The normal axial blood flow is consist of central stream of cells comprised by leucocytes and peripheral cell-free layer of plasma
  • But due to slowing and stasis , central stream widens and peripheral plasma zone becomes narrower because loss of plasma by exudation. It is called as marginationIn this stage leucocyte slowly rolls over the endothelial surface because of transient bond between leucocyte and endothelial cells, called rolling phase
  • As the transient bond becomes firmer, the leucocyte stops rolling and adhere to endothelial cell – called adhesion Stage.
  • After sticking to the endothelium, neutrophil moves along the endothelial surface, till a suitable site is found, where neutrophil THROWS OUT cytoplasmic pseudopods.
  • Adhesion is facilited by
  • The first events are the induction of adhesion molecules on endothelial cells, by a number of mechanisms.Within 1 to 2 hours, the endothelial cells begin to express E-selectin.Leukocytes express, ligands for the selectins, which bind to the endothelial selectins. These are low-affinity interactions with a fast off-rate, and they are easily disrupted by the flowing blood.As a result, the bound leukocytes detach and bind again, and thus begin to roll along the endothelial surface. That is rolling phasefollowed by, bond become firmer under the influence of cytokines – called adhesion phaseAfter sticking to the endothelium, THROWS OUT cytoplasmic pseudopods. Subsequently it lodges, between endothelial cells and basement membrane, and crosses the basement membrane, by damaging it locally with secreted collagenase…. And escape out in extravascular space.
  • Mediators such as histamine, thrombin, and platelet activating factor (PAF) stimulate the redistribution of P-selectin from its normal intracellular stores in granules (Weibel-Palade bodies) to the cell surface.
  • Resident tissue macrophages, mast cells, and endothelial cells, respond to injurious agents, by secreting the cytokines TNF, IL-1, and chemokines (chemoattractant cytokines).
  • Normally, integrin expressed by leucocyte Is of low affinity, but under the action of chemokines, it is converted to a high affinity state. So The leukocytes stop rolling, and their cytoskeleton is reorganized, and they spread out on the endothelial surface.
  • Here I would like to summerise the leucocyt rolling, adhesion and transmigration events
  • After that it comes the adhesion phaseWhich triggers the cascade of protein activation… which in turn activation and clustering … a dramatic conformational change occurs… this will allows the interaction with the rolling leucocyte to be immobilized.. Additional signalling causes profound reorganization.. Then it is inserted between endothelial cell and basement membrane
  • After extravasation, leukocytes emigrate in tissues toward the site of injury by a process called chemotaxis, due to the chemical stimulation , called as chemotactic stimuli.All granulocytes, monocytes and, to a lesser extent, lymphocytes respond to chemotactic stimuli
  • Leukocytes express a number of surface receptors, that are involved in their activationMicrobes, products of necrotic cells, antigen-antibody complexes, and cytokines, including chemotactic factors, induce a number of responses which ultimately lead to leukocyte activation
  • This term, first used over a century ago by Elie Metchnikoff,
  • Phagocytosis comprises of following processes
  • The process of coating a particle, such as a microbe, to target it for phagocytosis is called opsonization,and substances that do this are opsonins. These substances include antibodies, complement proteins, and lectins
  • The process of coating a particle, such as a microbe, to target it for phagocytosis is called opsonization,and substances that do this are opsonins. These substances include antibodies, complement proteins, This opsonisation greatly increases the efficiency of phagocytosis
  • Although neutrophils and macrophages, can engulf bacteria or extraneous matter, without attachment to specific receptors, but typically, for the phagocytosis of microbes and dead cells, they has to be recognised first, by receptors, expressed on the leukocyte surface. Mannose receptors and scavenger receptors are two important receptors that function to bind and ingest microbes.During engulfment, extensions of the cytoplasm (pseudopods) flow around the particle to be engulfed, eventually resulting in complete enclosure of the particle within a phagosome created by the plasma membrane of the cell this phagocytic vacuole then fuses with a lysosomal granule, resulting in discharge of the granule's contents into the phagolysosomeDuring this process, the neutrophil and the monocyte become progressively degranulated.
  • The ultimate step, in the elimination of infectious agents and necrotic cells is their killing and degradation Microbial killing is accomplished largely by oxygen-dependent mechanisms
  • Phagocytosis stimulates a burst in oxygen consumption, and producesreactive oxygen intermediates by various bio chemical process, mainlydue to the rapidactivation of an NADPH oxidaseIn this process, it reduces oxygen to superoxide anion (O2 ). Superoxide is then converted into hydrogen peroxide (H202 ), mostly by spontaneous dismutationthe azurophilic granules of neutrophils contain the enzyme myeloperoxidase(MPO), which, in the presence of a halide such as Cl- , converts superoxide to hypochlorite (HOCI). This HOCl is a potent antimicrobial agent that destroys microbes by halogenationThis MPO-halide system is the most efficient bactericidal system in neutrophils.
  • I will be covering the rest of the events of inflammation, chemical mediators, chronic inflammation, applied aspect in next class
  • Plasma-derived - precursor forms - must be activated – by a series of proteolytic cleavages,(e.g., complement proteins, kinins) Cell-derived - sequestered - intracellular granules - need to be secreted (e.g., histamine in mast cell granules) orsynthesized de novo (e.g., prostaglandins, cytokines) in response to a stimulus.
  • production of active mediators is triggered by microbialproducts or by host proteinsmediators perform their biologic activity by initiallybinding to specific receptors on target cellsOne mediator can stimulate the release of other mediators or also have opposing activitiesThey quickly decay (e.g., arachidonicacid metabolites) or are inactivated by enzymes (e.g.,kininase inactivates bradykinin), or they are otherwise scavenged(e.g., antioxidants scavenge toxic oxygen metabolites)or inhibited (e.g., complement regulatory proteins break upand degrade activated complement components).
  • Released by mast cell degranulation by variety of stimuliPhysical, heat cold, Immune reactionsanaphylatoxins such as C3a, C5aIncreases venular permeability by increasing venular gaps
  • Present in mast cells of rodent not in humans
  • To maniopulate this ., we have one bloke here 5 HETE hydroxyl ecosatertaeconic acidZileutonazelastine
  • at extremely low concentrations it induces vasodilation and increased venular permeability with apotency 100 to 10,000 times greater than that of histamine.
  • Both type of granules empty into phagocytic vacuoles that form around engulfedmaterial, or the granule contents can be released into theextracellular space. The specific granules are secreted extracellularlymore readily and by lower concentrations of agonists,whereas the potentially more destructive azurophilgranules release their contents primarily within the phagosonmeand require high levels of agonists to be releasedextracellularly.
  • Because of the destructive effects of lysosomal enzymes, theinitial leukocytic infiltration, if unchecked, can potentiate furtherincreases in vascular permeability and tissue damage. Theseharmful proteases, however, are held in check by a system ofantiproteasesin the serum and tissue fluids. Foremost amongthese is a1-antitrypsin, which is the major inhibitor of neutrophilelastase. A deficiency of these inhibitors may lead tosustained action of leukocyte proteases, as is the case inpatients with a1-antitrypsin deficiency (Chapter 15). a,-Macroglobulin is another
  • The first events are the induction of adhesion molecules on endothelial cells, by a number of mechanisms (Fig. 2-7). TNF and IL-1 also induce endothelial expression of ligandsfor integrins, mainly VCAM-1 (the ligand for the VLA-4integrin) and ICAM-1 (the ligand for the LFA-1 and Mac-1integrins). Leukocytes normally express these integrins in alow-affinity state. Meanwhile, chemokines that were producedat the site of injury enter the blood vessel, bind to endothelialcell heparan sulfate glycosaminoglycans (labeled "proteoglycan"in Figure 2-6), and are displayed at high concentrationson the endothelial surface." These chemokines act on therolling leukocytes and activate the leukocytes. One of theconsequences of activation is the conversion of VLA-4 andLFA-1 integrins on the leukocytes to a high-affinity state. Thecombination of induced expression of integrinligands on theendothelium and activation of integrins on the leukocytesresults in firm integrin-mediated binding of the leukocytes tothe endothelium at the site of infection. The leukocytes stoprolling, their cytoskeleton is reorganized, and they spread outon the endothelial surface.
  • In leukocyte adhesiondeficiency type 1 (LAD 1), patients have a defect in thebiosynthesis of the B2 chain part of integrins. Leukocyte adhesion deficiency type 2 (LAD2) is caused by the absence of e selectin
  • Hemodialysis: Profound neutropenia occurs within few minutes; will lead to complement system activation by alternate pathway and generation of c3a and c3b anaphylatoxins [They are called anaphylatoxinsbecause theyhave effects similar to those of mast cell mediators that areinvolved in the reaction called anaphylaxis] C5a induace decreased expression of selectin on all neutrophils so decreased rollingdefects of neutrophil chemotactic, phagocyticand microbicidal activities.defects of neutrophil chemotactic, phagocyticand microbicidal activities.
  • NO, a pleiotropic mediator of inflammation, was discoveredas a factor released from endothelial cells that causedvasodilation by relaxing vascular smooth muscle and wastherefore called endothelium-derived relaxing factor." NO isa soluble gas that is produced not only by endothelial cells, butalso by macrophages and some neurons in the brain. NO actsin a paracrine manner on target cells through induction ofcyclic guanosinemonophosphate (GMP), which, in turn, initiatesa series of intracellular events leading to a response, suchas the relaxation of vascular smooth muscle cells. Since the invivo half-life of NO is only seconds, the gas acts only on cellsin close proximity to where it is produced.NO is synthesized from L-arginine by the enzyme nitric oxidesynthase (NOS)." There are three different types of NOS—endothelial (eNOS), neuronal (nNOS), and inducible (iNOS)(Fig. 2-19)—which exhibit two patterns of expression. eNOSand nNOS are constitutively expressed at low levels and can beactivated rapidly by an increase in cytoplasmic calcium ions.Influx of calcium into cells leads to a rapid production of NO.iNOS, in contrast, is induced when macrophages and othercells are activated by cytokines (e.g., TNF, IFN-y) or otheragents.NO plays an important role in the vascular and cellular componentsof inflammatory responses. NO is a potent vasodilatorby virtue of its actions on vascular smooth muscle. Inaddition, NO reduces platelet aggregation and adhesion(Chapter 4), inhibits several features of mast cell-induced
  • NO, a pleiotropic mediator of inflammation, was discoveredas a factor released from endothelial cells that causedvasodilation by relaxing vascular smooth muscle and wastherefore called endothelium-derived relaxing factor." NO isa soluble gas that is produced not only by endothelial cells, butalso by macrophages and some neurons in the brain. NO actsin a paracrine manner on target cells through induction ofcyclic guanosinemonophosphate (GMP), which, in turn, initiatesa series of intracellular events leading to a response, suchas the relaxation of vascular smooth muscle cells. Since the invivo half-life of NO is only seconds, the gas acts only on cellsin close proximity to where it is produced.NO is synthesized from L-arginine by the enzyme nitric oxidesynthase (NOS)." There are three different types of NOS—endothelial (eNOS), neuronal (nNOS), and inducible (iNOS)(Fig. 2-19)—which exhibit two patterns of expression. eNOSand nNOS are constitutively expressed at low levels and can beactivated rapidly by an increase in cytoplasmic calcium ions.Influx of calcium into cells leads to a rapid production of NO.iNOS, in contrast, is induced when macrophages and othercells are activated by cytokines (e.g., TNF, IFN-y) or otheragents.NO plays an important role in the vascular and cellular componentsof inflammatory responses. NO is a potent vasodilatorby virtue of its actions on vascular smooth muscle. Inaddition, NO reduces platelet aggregation and adhesion(Chapter 4), inhibits several features of mast cell-induced
  • Abnormalities in endothelial production ofNO occur in atherosclerosis, diabetes, and hypertension
  • the physiologicfunction of these reactive oxygen intermediates is todestroy phagocytosed microbeExtracellular release of low levelsof these potent mediators can increase the expression ofchemokines (e.g., IL-8), cytokines, and endothelial leukocyteadhesion molecules, amplifying the cascade that elicits theinflammatory response.'
  • these potent mediators can be damaging to the host. They areimplicated in the following responses:■ Endothelial cell damage, with resultant increased vascularpermeability. Adherent neutrophils, when activated, notonly produce their own toxic species, but also stimulatexanthine oxidation in endothelial cells themselves, thuselaborating more superoxide.■ Inactivation of antiproteases, such as a,-antitrypsin. Thisleads to unopposed protease activity, with increaseddestruction of extracellular matrix.■ Injury to other cell types (parenchymal cells, red bloodcells).Serum, tissue fluids, and host cells possess antioxidantmechanisms that protect against these potentially harmfuloxygen-derived radicals. These antioxidants were discussed inChapter 1; they include: (1) the copper-containing serumprotein ceruloplasmin; (2) the iron-free fraction of serum,transferrin; (3) the enzyme superoxide dismutase, which isfound or can be activated in a variety of cell types; (4) theenzyme catalase, which detoxifies H202 ; and (5) glutathioneperoxidase, another powerful H 2O2 detoxifier.Thus, the influence of oxygen-derived free radicals in anygiven inflammatory reaction depends on the balance betweenthe production and the inactivation of these metabolites bycells and tissues.
  • Play a role in the initiation and propagation of an inflammatory response produced in the central and peripheral nervous systems.Substance P has many biologic functions, including the transmission of pain signals, regulation of blood pressure, and increasingvascular permeability.
  • also an inducer of the inflammatory response. This response is mediated largely by a protein called hypoxia induced factor la, which is produced by cells deprived of OxygenAlthough it has been known for many years that necrotic cells elicit inflammatory reactionsthat serve to eliminate these cells, the molecular basis of thisreaction has been largely unknownUric acid crystals stimulate inflammationand subsequent immune response.'
  • Sugar binding proteins (not glycoproteins)Play role in biological recognition phenomenonPlay imp role in the immune system by recognizing carbohydrate that are found exclusively on the pathogense.g.Manose binding lectin [MBL]Synthesized in liver, binds to carbohydrate patterns on the bacterial cell wall and lead to activation of the complement system pathways
  • Endogenous substance by mast cells, basophils, neurons in cns, pnsRelease, receptors.Betahistine – vertigoprimary vasodilator, enhance blood flow. deliver more nutrients and oxygen to muscle while removing more metabolic waste.Bodybuilders -part of a complete nutritional regimenThe nitric oxide boosters -precursors like arginine, citrulline and L-norvaline.
  • NSAIDs induced gastric ulcer , miscarriagePGI2 vasodialator – raynoud’s phenomenon, ischemia of limb
  • NSAIDs induced gastric ulcer , miscarriagePGI2 vasodialator – raynoud’s phenomenon, ischemia of limb
  • NSAIDs induced gastric ulcer , miscarriagePGI2 vasodialator – raynoud’s phenomenon, ischemia of limb
  • Variety of phenomena in the inflammatory response aremediated by plasma proteins that belong to three interrelatedsystems, the complement, kinin, and clotting systems
  • Thrombin is the connecting link between inflammation and clotting system…It bonds to protease activator receptors (which are GPCR) present on the endothelial cells, leucocytes, plactelets. And intensify the inflammatory response
  • Dipthericmembrance is fibrinous inflammation
  • Phlemon:Exudate mainly serous –occasional pus Insufficient Antibody content of the exudate
  • Special form of inflammation
  • having greater risk of developing in the immunocompromised due to conditions like diabetes, cancer, etc. It is a severe disease of sudden onset and is usually treated immediately with high doses of intravenous antibiotics.
  • longer-term inflammation process may be identifiedby distinctive histologic findings that occur in thesechronic forms of inflammation:— Chronic nonsuppurative inflammation;— Chronic suppurative inflammation;— Granulomatous inflammation
  • In the absence of spontaneous oriatrogenic emptying, the abscess forms an abscessmembrane ( D; chronic liver abscess)of granulation tissue around the necroticarea.
  • Abnormal communicationbetween the necrotic focus of inflammationand an outer or inner surface of thebody. Especially in the case of abscess-forminginflammations, the contents of the abscess canspontaneously empty outside the body througha cutaneous fistula or into a hollow organthrough an internal fistula.
  • This refers to an epithelial or tissuedefect on an outer or inner surface of thebody that fails to heal or whose healing is delayed( E) and which is demarcated by granulationtissue with the three typical layers. Theresorption zone includes the area of fibrinoidconnective-tissue necrosis on the floor of theulcer.
  • The epithelium is oedematousand intra- and sub-epithelial vesicles are present. An infiltration oflymphocytes and macrophages is seen in the lamina propria and withinthe epithelium
  • Scully C, Carrozzo M. British Journal of Oral and Maxillofacial Surgery 46 (2008) 15–21
  • Porter SR, Kirby A,Olsen I, Barrett W.OOOOE 1997;83:358-66
  • Regezi, Scuibba, Jordan. Oral Pathology .clinicopathologic correlation 5th ed,2009
  • Regezi, Scuibba, Jordan. Oral Pathology .clinicopathologic correlation 5th ed,2009
  • Suresh L, Kumar V, OOOOE 2007;104:359-62)
  • Suresh L, Kumar V, OOOOE 2007;104:359-62)
  • DCNA, Oral Soft tissue lesions. Jan 2005: 49(1);67-76
  • Mignogna MD et al, Oral Oncology 2004:40;120–130
  • Mignogna MD et al, Oral Oncology 2004:40;120–130
  • Mignogna MD et al, Oral Oncology 2004:40;120–130
  • ColoRectal Cancer
  • Destroy, dilute and wall off any injurious agent & constitutes the repair. Without inflammation, infections would go unchecked, wounds would never heal, and injured organs may remain as permanent festering sores. In our day to day lives we come across many cases starting from gingivitis to oral cancer wherein inflammation exerts a direct or an indirect effect. So understanding inflammation helps us to know the various vascular and cellular changes, mediators involved and therefore help us to evaluate the significance of various anti-inflammatory drugs that we do prescribe, for controlling the same.
  • Inflammation Seminar by Dr Pratik

    1. 1. Good Morning…. Presented by - Dr Pratik Pipalia, CODS, DVG
    2. 2. Available @ http://www.4shared.com/file/0qV66d9k/inflamma tion_by_dr_pratik.html
    3. 3. PPT Available @ http://www.4shared.com/file/0qV66d9k/inflammati on_by_dr_pratik.html
    4. 4. INTRODUCTION HISTORY DEFINITION CAUSES CARDINAL SIGNS OF INFLAMMATION TYPES OF INFLAMMATORY REACTIONS
    5. 5. ACUTE INFLAMMATION VASCULAR EVENTS CELLULAR EVENTS CHEMICAL MEDIATORS OF INFLAMMATION
    6. 6. CHEMICAL MEDIATORS OF INFLAMMATION VASOACTIVE AMINES ARACHIDONIC ACID METABOLITES CYOKINES AND CHEMOKINES LYSOSOMAL CONSTITUENTS OF LEUKOCYTES OTHER MEDIATORS PLASMA PROTEINS PLATELET ACTIVATING FACTORS NITRIC OXIDE OXYGEN DERIVED FREE RADICALS NEUROPEPTIDES
    7. 7. SUMMARY OF MEDIATORS OF INFLAMMATION INFLAMMATORY CELLS OUTCOMES IN INFLAMMATION EVENTS IN THE RESOLUTION OF INFLAMMATION CHRONIC INFLAMMATION APPLIED ASPECTS
    8. 8. LYMPHATICS IN INFLAMMATION
    9. 9. LYMPHATIC SYSTEM Lymphatic system consists of a fluid called lymph, vessels called lymphatic vessels that transports the lymph, a no. of structures and organs containing lymphatic tissue, and red bone marrow, where stem cells develop into various types of blood cells, including lymphocytes Tortora GJ, Derickson BH, Principles of anatomy and physiology,12th ed, Vol 2,2009
    10. 10. Drain excess interstitial fluid Transports dietary fluids Carries out immune responses Tortora GJ, Derickson BH, Principles of anatomy and physiology,12th ed, Vol 2,2009
    11. 11. LYMPHATIC CAPPILLARIES LYMPHATIC VESSELS LYMPH NODES LYMPH TRUNKS Tortora GJ, Derickson BH, Principles of anatomy and physiology,12th ed, Vol 2,2009
    12. 12. Tortora GJ, Derickson BH, Principles of anatomy and physiology,12th ed, Vol 2,2009
    13. 13. LEFT JUGULAR TRUNK RIGHT JUGULAR TRUNK LEFT SUBCLAVIAN TRUNK RIGHT SUBCLAVIAN TRUNK THORACIC (left lymphatic) DUCT LYMPHATIC DUCT SUPERIOR VENECAVA Tortora GJ, Derickson BH, Principles of anatomy and physiology,12th ed, Vol 2,2009
    14. 14. Tortora GJ, Derickson BH, Principles of anatomy and physiology,12th ed, Vol 2,2009
    15. 15. AGEING AND INFLAMMATION Ageing Inflammation Chronic diseases Chronic diseases .eg Cancer Inflammation Ageing Ahmad A, Banerjee S, Wang Z, Curr Aging Sci. 2009; 2(3): 174–186.
    16. 16. worn-out cellular machinery spontaneous mutations accumulation of damaged nucleic acids & proteins + generation of toxic substances Approximately 20% of all human cancers in adults result either from chronic inflammatory state or have inflammatory etiology Ahmad A, Banerjee S, Wang Z, Curr Aging Sci. 2009; 2(3): 174–186.
    17. 17. END-RESULT --susceptibility to oncogene activation --suppression of suppressor gene function development and progression of cancer. Ahmad A, Banerjee S, Wang Z, Curr Aging Sci. 2009; 2(3): 174–186.
    18. 18. Non-cancer chronic diseases such as diabetes, Alzheimer's disease, Parkinson's disease, atherosclerosis, sarcopenia, and osteoporosis are also intimately connected with aging initiated or worsened by systemic inflammation suggests biochemical relevance of inflammation in cancer and other chronic diseases Ageing ---- free radical-induced/mediated generation/activation of signaling molecules & transcription factors generation of pro-inflammatory molecules induction of a chronic inflammatory state Ahmad A, Banerjee S, Wang Z, Curr Aging Sci. 2009; 2(3): 174–186.
    19. 19. Aged residential phagocytes :macrophages & PMN’s within host ↓ inappropriate respiratory burst ↓ release of reactive nitrogen and oxygen intermediates ↓ decrease the ability to destroy pathogens Ahmad A, Banerjee S, Wang Z, Curr Aging Sci. 2009; 2(3): 174–186.
    20. 20. Aged dendritic cells (DCs) ↓ less efficient in activating T and B cells aged ↓ natural killer (NK) cells ↓ ability and efficiency in killing tumor cells Ahmad A, Banerjee S, Wang Z, Curr Aging Sci. 2009; 2(3): 174–186.
    21. 21. ↑ production of pro-inflammatory cytokines, IL-1, IL-6 and TNF-α, compared to young people Ahmad A, Banerjee S, Wang Z, Curr Aging Sci. 2009; 2(3): 174–186. Up-regulated COX-2 and resulting ↑ production of PGE2
    22. 22. INTRODUCTION
    23. 23. HISTORY The earliest reference to inflammation in ancient medical literature is of the Smith Papyrus from around 3000 B.C. Egypt The use of a symbol of a flame, as the determinant, shows that the ancient Egyptians, associated inflammation with heat. Robbins And Cotran, Pathologic basics of diseases,2005, 7th ed
    24. 24. HISTORY Ancient Greeks used the term “flegmonh” to mean the inflammation, - „to burn‟ Inflammation - Latin, „īnflammō‟ - "ignite, set alight" Rubin’s Pathology,2012, 6th edi
    25. 25. HISTORY CORNELIUS CELSUS  Rubor  Calor  Dolor  Tumor Rudolf Virchow  Functio laesa John Hunter (surgeon in 1793) “inflammation as a non-specific body response” Robbins And Cotran, Pathologic basics of diseases,2005, 7th ed
    26. 26. Julius Cohnheim(1889) provided first microscopic description of inflammation Elie Metchnikoff(1880S) discovered the process of phagocytosis Paul Ehrlich and Metchinikoff theory of immunity Thomas Lewis demonstrated that inflammation - chemical mediators, most of them act locally Robbins And Cotran, Pathologic basics of diseases,2005, 7th ed
    27. 27. Inflammation is defined as the reaction of vascularized living tissue to local injury [Robbins and Contran , 7th edi. ] Inflammation is a reaction, both systemic and local, of tissues and microcirculation to a pathogenic insult [Rubin’s Path. 6th edi.] A localized protective response elicited by injury or destruction of tissues, which serves to destroy, dilute or wall off both injurious agent and the injured tissue [Dorland's Med Dict. 32nd edi] DEFINITION
    28. 28. According to duration:- 1 Per-acute inflammation 2 Acute inflammation 3 Sub-acute inflammation 4 Chronic inflammation CLASSIFICATION University of Babylon: www.uobabylon.edu.iq/uobColeges/ad_downloads/6_17350_197.pdf
    29. 29. According to the cause: - 1-Mechanical inflammation trauma, blow, kick, or sprain 2-Physical inflammation: heat, cold, electricity, or radiation 3-Chemical inflammation: alkali, acid 4-Biological inflammation bacteria (it has direct effect on affected tissue and indirect effect by circulating toxin), viruses, or parasites. classification University of Babylon: www.uobabylon.edu.iq/uobColeges/ad_downloads/6_17350_197.pdf
    30. 30. ACUTE INFLAMMATION CHRONIC INFLAMMATION CLASSIFICATION OF INFLAMMATION Robbins And Cotran, Pathologic basics of diseases,2005, 7th ed
    31. 31. SEROUS FIBRINOUS CATARRHAL HAEMORRAGIC PURULENT ACUTE INFLAMMATION Reide & Werner, Color Atlas of Pathology,, 2005
    32. 32. CHRONIC INFLAMMATION DIFFUSE SUPPURATIVE GRANULOMATOUS FIBRINOID Robbins And Cotran, Pathologic basics of diseases,2005, 7th ed
    33. 33. Rubbin R, Strayer D; Rubbin’s Pathology, clinicopathologic foundation of medicine,2005, 5th ed DIFFERENCE BETWEEN EXUDATE AND TRANSUDATE
    34. 34. FEATURES EXUDATE TRANSUDATE ORIGIN ACUTE INFLAMMATION CIRCULATORY STASIS DUE TO CARDIAC / RENAL FAILURE CHARACTER INFLAMMATORY NON-INFLAMMATORY MECHANISM INCREASED VASCULAR PERMEABILITY INCREASED INTRCAPILLARY PRESSURE (filtrate of blood plasma without changes in endothelial permeability) APPEARANCE MAY CONTAIN FIBRIN FLAKES. -TURBID : due to leukocytes -HAEMORRAHGIC : due to blood CLEAR,TRANSPARENT- MAY BE PALE YELLOW IN COLOUR DIFFERENCE BETWEEN EXUDATE AND TRANSUDATE Robbins And Cotran, Pathologic basics of diseases,2005, 7th ed
    35. 35. FEATURES EXUDATE TRANSUDATE PROTEIN CONTENT HIGH(2.5-3.5g/dl) [HIGH FIBRINOGEN] LOW(<1g/dl), [LOW FIBRINOGEN] COAGULABILITY -SPONTANEOUS COAGULABILITY DUE TO FIBRINOGEN CONTENT, -CLOTS ON STANDING -NO SPONTANEOUS COAGULATION SPECIFIC GRAVITY HIGH[>1.018] LOW[<1.015] GLUCOSE CONTENT LOW[<60mg/dl] SAME AS IN PLASMA Ph <7.3 >7.3 CYTOLOGY INFLAMMATORY CELLS & PARENCHYMAL CELLS MESOTHELIAL CELLS & CELLULAR DEBRI Harsh Mohan, Essentials of pathology ,2005,3rd ed
    36. 36. FEATURES EXUDATE TRANSUDATE DISTRIBUTION OF CELLS LARGE IN NUMBER SCANTY IN NUMBER TOTAL LEUKOCYTE COUNT HIGH: POLYMORPHS (in acute) & LYMPHOCYTES (in chronic inflammation) USUALLY BELOW 100/mm3 DISTRIBUTION OF CELLS LARGE IN NUMBER SCANTY IN NUMBER EXAMPLES PURULENT EXUDATE SUCH AS PUS OEDMA IN CONGESTIVE HEART FAILURE Harsh Mohan, Essentials of pathology ,2005,3rd ed
    37. 37. DIFFERENCE BETWEEN ACUTE & CHRONIC INFLAMMATION ACUTE CHRONIC Duration Days-weeks Months –Years Cardinal signs Present Doubtful/ not perceptible Vascular phenomenon Present Doubtful/ not perceptible Exudation of plasma Present Doubtful/ not perceptible Cellular exudate Present, PMN - >macrophages & fibroblasts (later stages) Histiocytes, lymphocytes & plasma cells Type of inflammation Exudative Proliferative Repair Follows  debris removed Goes side by side along with vascular+ cellular proliferation Dey N C, A Textbook of pathology,1985,9th edition
    38. 38. CAUSES Mechanical • Injury like trauma, presence of foreign body, ligature, dead tissue, sequestrum, etc. Physical • Thermic ( heat & cold), electricity like electric burn, x-ray etc Chemical • Strong acids, alkalies or poisons Non living
    39. 39. CAUSES Bacteria Viruses & their toxins Fungi Animal parasites Necrosis of tissue Allergy Living
    40. 40. CARDINAL SIGNS OF INFLAMMATION Riede & Werner, Color Atlas of Pathology , 2004
    41. 41. COMPONENTS OF INFLAMMATION Robbins And Cotran, Pathologic basics of diseases,2005, 7th ed
    42. 42. ACUTE INFLAMMATION Acute inflammation is a rapid response to an injurious agent that serves to deliver mediators of host defence—leukocytes and plasma proteins—to the site of injury. Robbins And Cotran, Pathologic basics of diseases,2005, 7th ed
    43. 43. Robbins And Cotran, Pathologic basics of diseases,2005, 7th edition
    44. 44. Robbins And Cotran, Pathologic basics of diseases,2005, 7th edition
    45. 45. CHANGES IN VASCULAR FLOW AND CALIBER
    46. 46. VASOCONSTRICTION RAPID BLOOD FLOW (VASODIALATION) SLOWING OF THE CIRCULATION STASIS Rubin E, Farber J L, Essential pathology, 1990, 1st edition
    47. 47. Robbins And Cotran, Pathologic basics of diseases,2005, 7th ed
    48. 48. Robbins And Cotran, Pathologic basics of diseases,2005, 7th ed
    49. 49. Riede & Werner, Color Atlas of Pathology , 2004 VASOCONSTRICTION
    50. 50. Riede & Werner, Color Atlas of Pathology , 2004 VASODIALATION
    51. 51. Riede & Werner, Color Atlas of Pathology , 2004 SLOWING DOWN OF CIRCULATION AND INCREASED PERMEABILITY OF MICROVASCULATURE
    52. 52. CHANGES IN VASCULAR PERMEABILITY INCREASED NORMAL
    53. 53. NORMAL MICROCIRCULATORY CONTROL NORMAL PERMEABILITY & STRUCTURE OF MICROCIRCULATION
    54. 54. NORMAL MICROCIRCULATORY CONTROL SYSTEMIC FACTORS LOCAL FACTORS
    55. 55. NORMAL PERMEABILITY & STRUCTURE OF MICROCIRCULATION
    56. 56. OUTWARD MOVEMENT OF FLUID INWARD MOVEMENT OF FLUID STARLING’S HYPOTHESIS Rubin E, Farber J L, Essential Pathology, 1990, 1st Edition
    57. 57. OSMOTIC PRESSURE OF INTERSTITIAL FLUID TISSUE HYDROSTATIC PRESSURE INTRAVASCULAR HYROSTATIC PRESSUE OSMOTIC PRESSURE OF PLASMA PROTEINS OUTWARD MOVEMENT OF FLUID INWARD MOVEMENT OF FLUID Rubin E, Farber JL, Essential Pathology, 1990, 1st Edition
    58. 58. NORMAL FLUID EXCHANGE ACUTE INFLAMMATION Harsh Mohan, Essentials Of Pathology For Dental Students,2005,3rd Edition
    59. 59. MECHANISMS OF VASCULAR PERMEABILITY FORMATION OF ENDOTHELIAL GAPS IN VENULES. DIRECT INJURY : ENDOTHELIAL CELL NECROSIS DELAYED PROLONGED LEAKAGE. LEUKOCYTE-MEDIATED ENDOTHELIAL INJURY. INCREASED TRANSCYTOSIS LEAKAGE FROM NEW BLOOD VESSELS. Robbins And Cotran, Pathologic Basics Of Diseases,7th ed,2005
    60. 60. GAPS DUE TO ENDOTHELIAL CONTRACTION Robbins And Cotran, Pathologic Basics Of Diseases,7th ed,2005
    61. 61. DIRECT INJURY Robbins And Cotran, Pathologic Basics Of Diseases,7th ed,2005
    62. 62. LEUKOCYTE DEPENDENT INJURY Robbins And Cotran, Pathologic Basics Of Diseases,7th ed,2005
    63. 63. INCREASED TRANSCYTOSIS Robbins And Cotran, Pathologic Basics Of Diseases,7th ed,2005
    64. 64. ANGIOGENESIS Robbins And Cotran, Pathologic Basics Of Diseases,7th ed,2005
    65. 65. LEUKOCYTE ADHESION AND TRANSMIGRATION CHEMOTAXIS LEUKOCYTE ACTIVATION PHAGOCYTOSIS CELLULAR EVENTS Robbins And Cotran, Pathologic Basics Of Diseases,7th ed,2005
    66. 66. MARGINATION , ROLLING & ADHESION EMIGRATION & DIAPEDESIS CHEMOTAXIS Robbins And Cotran, Pathologic Basics Of Diseases,7th ed,2005
    67. 67. NORMAL AXIAL FLOW Harsh Mohan, Essentials Of Pathology For Dental Students,2005,3rd Edition
    68. 68. MARGINATION & PAVEMENTING Harsh mohan, essentials of pathology for dental students,2005,3rd edition Riede & Werner, Color Atlas of Pathology , 2004 Thieme
    69. 69. ADHESION Harsh Mohan, Essentials Of Pathology For Dental Students,2005,3rd Edition Riede & Werner, Color Atlas of Pathology , 2004
    70. 70. EMIGRATION AND DIAPEDESIS Harsh Mohan, Essentials Of Pathology For Dental Students,2005,3rd Edition Riede & Werner, Color Atlas of Pathology , 2004
    71. 71. LEUKOCYTIC ADHESION AND TRANSMIGRATION • COMPLIMENTARY ADHESION MOLECULES ADHESION • CHEMOATTRACTANTS • CYTOKINES TRANS- MIGRATION Kumar, Abbas, Fausto ; Robbins And Cotran, Pathologic Basics Of Diseases, 2005, 7th Edition
    72. 72. COMPLIMENTARY ADHESION MOLECULES SELECTINS INTEGRINS Ig SUPERFAMILY MUCIN like glycoproteins Harsh Mohan, Essentials Of Pathology,2005, 3rd ed
    73. 73. Robbins And Cotran, Pathologic Basics Of Diseases,2005,7thed
    74. 74. Robbins And Cotran, Pathologic Basics Of Diseases,2005,7thed
    75. 75. Robbins And Cotran, Pathologic Basics Of Diseases,2005,7thed
    76. 76. Robbins And Cotran, Pathologic Basics Of Diseases,2005,7thed
    77. 77. CHEMO ATTRACTANT EXOGENOUS ENDOGENOUS Robbins And Cotran, Pathologic Basics Of Diseases,2005,7thed
    78. 78.  Exogenous Agents – Bacterial Products  Endogenous Agents Robbins And Cotran, Pathologic Basics Of Diseases,2005,7thed
    79. 79. PRODUCTION OF AA METABOLITES LYSOSOMAL DEGRANULATION & SECRETION SECRETION OF CYTOKINES MODULATION OF LEUKOCYTE ADHESION MOLECULES LEUKOCYTIC ACTIVATION  Toll – like receptors (tlrs)  7 – transmembrane G- protein coupled receptor (gpcrs)  Receptors for cytokines  Receptors for opsonins Expression of surface receptors Robbins And Cotran, Pathologic Basics Of Diseases,2005,7thed
    80. 80. LEUKOCYTIC ACTIVATION production of cytokines LPS Robbins And Cotran, Pathologic Basics Of Diseases,2005,7thed
    81. 81. PHAGOCYTOSIS Robbins And Cotran, Pathologic Basics Of Diseases, 2005, 7th Edition Phagocytosis : is the process of Uptake of extracellular particulate matter by cells
    82. 82. PHAGOCYTOSIS RECOGNITION & ATTACHMENT KILLING OR DEGRADATION ENGULFMENT Kumar, Abbas, Fausto ; Robbins And Cotran, Pathologic Basics Of Diseases, 2005, 7th Edition
    83. 83. PHAGOCYTOSIS RECOGNITION AND ATTACHMENT Opsonins - C3b, IgG, lectins ENGULFMENT STAGE Cytoskeletal mechanisms Degranulation KILLING / DEGRADATION O2-Dependent - H2O2 HOCl O2-Independent - lysozyme, cationic proteins, defensins, lactoferrin NO -Dependent Kumar, Abbas, Fausto ; Robbins And Cotran, Pathologic Basics Of Diseases, 2005, 7th Edition
    84. 84. OPSONIZATION Harsh Mohan, Essentials Of Pathology,2005, 3rd ed
    85. 85. OPSONISATION
    86. 86. RECOGNITION & ATTACHMENT ENGULFMENT KILLING / DEGRADATION Robbins And Cotran, Pathologic Basics Of Diseases,2005,7thed
    87. 87. RECEPTORS FOR OPSONINS Robbins And Cotran, Pathologic Basics Of Diseases,2005,7thed Promotes phagocytosis Opsonization Opsonins Antibodies, Complement Proteins , Lectins.
    88. 88. ENGULFMENT STAGE
    89. 89. KILLING / DEGRADATION Robbins And Cotran, Pathologic Basics Of Diseases,2005,7thed KILLING / DEGRADATION O2-Dependent - H2O2 HOCl O2-Independent - lysozyme, cationic proteins, defensins, lactoferrin NO -Dependent
    90. 90. KILLING / DEGRADATION Robbins And Cotran, Pathologic Basics Of Diseases,2005,7thed
    91. 91. Other mechanisms responsible for killing bacteria: BACTERICIDAL PERMEABILITY- INCREASING PROTEIN Causing phospholipase activation and membrane phospholipid degradation LYSOZYME Causing degradation of bacterial coat oligosaccharides MAJOR BASIC PROTEIN An important eosinophil granule constituent DEFENSINS Peptides that kill microbes by forming holes in their membranes Robbins And Cotran, Pathologic Basics Of Diseases,2005,7thed
    92. 92. PROCESS OF PHAGOCYTOSIS
    93. 93. Thank You …
    94. 94. Good Morning…
    95. 95. ACUTE INFLAMMATION VASCULAR EVENTS CELLULAR EVENTS CHEMICAL MEDIATORS OF INFLAMMATION
    96. 96. CHEMICAL MEDIATORS OF INFLAMMATION VASOACTIVE AMINES ARACHIDONIC ACID METABOLITES CYOKINES AND CHEMOKINES LYSOSOMAL CONSTITUENTS OF LEUKOCYTES OTHER MEDIATORS PLASMA PROTEINS PLATELET ACTIVATING FACTORS NITRIC OXIDE OXYGEN DERIVED FREE RADICALS NEUROPEPTIDES
    97. 97. SUMMARY OF MEDIATORS OF INFLAMMATION OUTCOMES IN INFLAMMATION EVENTS IN THE RESOLUTION OF INFLAMMATION CHRONIC INFLAMMATION INFLAMMATION OF ORAL TISSUES
    98. 98. LEUKOCYTES & ITS CONSTITUENTS 60-70% of WBC Cytoplasm-fine pale granules 10-12μm in diameter, nucleus has 2-5 lobes connected with - chromatin Phagocytosis Destruction of bacteria with lysosomes, defensins & strong oxidants NEUTROPHIL Tortora GJ, Derickson BH, Principles of anatomy and physiology,12th ed, Vol 2,2009
    99. 99. 2-4% of WBC Coarse red-orange granules 10-12μm in diameter, nucleus- usually 2 lobed Combats in allergic reactions Destroys certain parasitic worms EOSINOPHIL Tortora GJ, Derickson BH, Principles of anatomy and physiology,12th ed, Vol 2,2009
    100. 100. 0.5-1% of WBC 10-12μm in diameter nucleus bi-lobed Coarse cytoplasmic granules- deep blue purple in colour Liberate heparin, histamine & serotonin Intensify the inflammatory response BASOPHIL Tortora GJ, Derickson BH, Principles of anatomy and physiology,12th ed, Vol 2,2009
    101. 101. 20-25% of WBC Includes T-cells, B-cells & NK cells Small: 6-9μm & Large: 10-14μm in diameter resp. Nucleus-round or slightly intended LYMPHOCYTE Tortora GJ, Derickson BH, Principles of anatomy and physiology,12th ed, Vol 2,2009
    102. 102. Mediates immune response incl. Anti- Antib reactions B-cells →plasma cells → ANTIBODIES T- cells attack invading viruses, cancer cells & transplanted tissue cells NK cells attack wide variety of infectious microbes & tumour cells Tortora GJ, Derickson BH, Principles of anatomy and physiology,12th ed, Vol 2,2009
    103. 103. MONOCYTE 3-8% of WBC 12-20μm in diameter , nucleus kidney/horseshoe shaped Cytoplasm-blue gray & has foamy appearance Phagocytosis- after transforming into fixed /wandering macrophages Tortora GJ, Derickson BH, Principles of anatomy and physiology,12th ed, Vol 2,2009
    104. 104. CHEMICAL MEDIATORS CELL DERIVED PLASMA DERIVED CHEMICAL MEDIATORS
    105. 105. Robbins And Cotran, Pathologic Basics Of Diseases,2005,7thed
    106. 106. PROPERTIES OF MEDIATORS Triggered by microbial products / host proteins. Specific mechanism of action Amplify/antagonize each other Short lived Potentially harmful
    107. 107. present in preformed stores in cells among the 1st mediators of inflammation mainly comprise of histamines & serotonin Robbins and Cotran, Pathologic Basics Of Diseases,2005,7thed Vasoactive Amines
    108. 108. Principal mediator of immediate transient response ↑ vascular permeability- venular gaps Richest source - mast cells Granules Also found in basophils & platelets HISTAMINE Rubin E, Farber JL, Essential Pathology, 1990, 1st Edition
    109. 109. SEROTONIN mediator of inflammation ↑ vascular permeability source –platelets and enterochromaffin cells Release stimulated when platelets aggregate after contact with collagen, plasmin, & Anti-Antib complexes Dey N C, A Text Book Of Pathology,9thed,1985
    110. 110. Robbins And Cotran, Pathologic Basics Of Diseases,2005,7thed P R O S T A G L A D I N S L E U K O T R I E N E S ARACHIDONIC ACID METABOLITES
    111. 111. Arachidonic Acid Leukotrienes LTC4, D4, E4 Cyclooxygenase5-Lipoxygenase Prostaglandins Prostacyclins Cell Damage Cell Membrane Phospholipids
    112. 112. Rubin E and Farber JL , Essential Pathology,1st ed
    113. 113. Antibody Response Produced by platelets, basophils, mast cells, PMN, monocytes / macrophages, & endothelial cells low concentrations -vasodilation & ↑ venular permeability PAF causes vasoconstriction PLATELET ACTIVATING FACTORS(PAF) Robbins And Cotran, Pathologic Basics Of Diseases,2005,7thed
    114. 114. Robbins And Cotran, Pathologic Basics Of Diseases,2005,7thed Also - increased leukocyte adhesion to endothelium, chemotaxis, degranulation, and the oxidative burst. Boost synthesis of other mediators- eicosanoids, by leukocytes and other cells
    115. 115. LYSOSOMAL CONSTITUENTS OF LEUKOCYTES
    116. 116. NEUTROPHIL Tortora GJ, Derickson BH, Principles of anatomy and physiology,12th ed, Vol 2,2009 Myeloperoxidase Lysozymes Defensins Bactericidal permeability increasing proteins Elastase Cathepsin protease3 Glucoronidase Mannosidase Phospolipase
    117. 117. NEUTROPHIL Lysozymes Collagenase Lactoferrin Histaminase Plasminogen activator FMLP receptors C3b proteins Tortora GJ, Derickson BH, Principles of anatomy and physiology,12th ed, Vol 2,2009
    118. 118. GRANULES EXTRA CELLULAR SPACE VACUOLES more readily by lower concentrations of agonists require high levels of agonists to be released extracellularly Robbins And Cotran, Pathologic Basics Of Diseases,2005,7thed
    119. 119. ACID PROTEASES degrade bacteria and debris within the phagolysosomes NEUTRAL PROTEASES are capable of degrading various extracellular components-can attack collagen, basement membrane, fibrin, elastin, & cartilage, resulting in the tissue destruction. NEUTRAL PROTEASES can also cleave C3 and C5 directly, releasing anaphylatoxins. NEUTROPHIL ELASTASE has been shown to degrade virulence factors of bacteria and thus combat bacterial infections. Robbins And Cotran, Pathologic Basics Of Diseases,2005,7thed FUNCTIONS
    120. 120. PROTEASES ANTIPROTEASES (a1-antitrypsin Macroglobulin) Robbins And Cotran, Pathologic Basics Of Diseases,2005,7thed
    121. 121. • GENETIC DEFECIENCIES • DEFECTS IN LEUKOCYTE FUNCTION LEUKOCYTES APPLIED ASPECTS Robbins And Cotran, Pathologic Basics Of Diseases,2005,7thed
    122. 122. Robbins And Cotran, Pathologic Basics Of Diseases,2005,7thed
    123. 123. LEUCOCYTE ADHESION PROTEINS (LAD) LAD-1 – Defective Biosynthesis of β 2 chain LAD -2 – absence of E- selectin Antibodies to Adhesion Molecules GENETIC DEFICIENCIES of leukocytes Robbins And Cotran, Pathologic Basics Of Diseases,2005,7thed
    124. 124. DEFECTS IN LEUKOCYTE FUNCTION DISEASE DEFECT GENETIC Leukocyte adhesion deficiency 1 Β chain of CD11/CD18 integrins Leukocyte adhesion deficiency 2 Fucosyl transferase – synthesis – Sialylated oligosaccharide ( receptor for selectin) Chronic granulomatous disease Decreased oxidative burst X- linked NADPH oxidase ( membrane component) Autosomal recessive NADPH oxidase (cytoplasmic component) Myeloperoxidase deficiency Absent MPO-H₂O₂ system Chediak- Higashi syndrome Protein involved in organelle membrane docking and fusion Robbins And Cotran, Pathologic Basics Of Diseases,2005,7thed
    125. 125. DEFECTS IN LEUKOCYTE FUNCTION DISEASE DEFECT ACQUIRED Thremal injury, diabetes, malignancy, sepsis, immunodeficiencies Chemotaxis Hemodialysis, Diabetes mellitus Adhesion Leukemia, anemia, sepsis, diabetes, Phagocytosis and microbicidal activity Robbins And Cotran, Pathologic Basics Of Diseases,2005,7thed
    126. 126. CYTOKINES & CHEMOKINES
    127. 127. All are proteins-modulate the functions of other cell types Mainly synthesised by immune cells. Regulate differentiation and activation of immune cells. Partly responsible for coordination of the inflammatory response. Act through high affinity receptors on target cells. Cytokines. Robbins And Cotran, Pathologic Basics Of Diseases,2005,7thed
    128. 128. Compliment Protein Cascade Antibody Response Robbins And Cotran, Pathologic Basics Of Diseases,2005,7thed
    129. 129. INTERLEUKINS Molecularly defined cytokines are called interleukins, implying that they mediate communications between leukocytes
    130. 130. Name Major Cellular Source Selected Biologic Effects IFN α,β Macrophages (IFN-), fibroblasts (IFN-) Antiviral IFN γ (interferon) T cells, NK cells Activates macrophages, TH1 differentiation TNF α Macrophages, T cells Cell activation, fever, cachexia, antitumor TNF β, LT (lymphotoxin) T cells Activates PMNs IL-1 (interleukin-1) Macrophages Cell activation, fever IL-2 (interleukin-2) T cells T cell growth and activation IL-3 (interleukin-3) T cells Hematopoiesis IL-4 (interleukin-4) T cells, mast cells B cell proliferation and switching to IgE, TH2 differentiation Jawetz, Melnick, & Adelberg's Medical Microbiology, 24th ed
    131. 131. Name Major Cellular Source Selected Biologic Effects IL-5 (interleukin -5) T Cells Differentiation of Eosinophils, activates B cells IL-7 (interleukin-7) Bone marrow stroma cells T cell progenitor differentiation IL-8 (interleukin-8) Macrophages, T cells Chemotactic for neutrophils IL-10 (interleukin-10) Macrophages, T cells Inhibits activated macrophages and dendritic cells IL-12 (interleukin-12) Macrophages Differentiation of T cells, activation of NK cells Jawetz, Melnick, & Adelberg's Medical Microbiology, 24th ed
    132. 132. Name Major Cellular Source Selected Biologic Effects GM-CSF (granulocyte- macrophage colony- stimulating factor) T cells, macrophages, monocytes Differentiation of myeloid progenitor cells M-CSF (monocyte- macrophage colony- stimulating factor) Macrophages, monocytes, fibroblasts Differentiation of monocytes and macrophages G-CSF (granulocyte colony- stimulating factor) Fibroblasts, monocytes, macrophages Stimulates neutrophil production in bone marrow Jawetz, Melnick, & Adelberg's Medical Microbiology, 24th ed
    133. 133. CHEMOKINES Robbins And Cotran, Pathologic Basics Of Diseases,2005,7thed Family of small proteins that act primarily as chemoattractants for specific type of leukocytes. Stimulate leukocyte recruitment in: inflammation constitutively control normal migration of cells through various tissues during organogenesis.
    134. 134. At least 3 families Relative position of Cys residue determines nomenclature e.g. CXC, CC or C. Act through 7 Transmembrane GPCR ; which also function as co-receptors for HIV entry into immune cells. CHEMOKINES Robbins And Cotran, Pathologic Basics Of Diseases,2005,7thed
    135. 135. synthesized from L-arginine by enzyme NOS Potent vasodilation by relaxing vascular smooth muscle Produced by endothelial cells, macrophages & some neurons in the brain Acts in a paracrine manner through induction of cyclic GMP relaxation of vascular smooth muscle NITRIC OXIDE H2N-CH.COOH (CH2)3 NH C HN NH2 Robbins And Cotran, Pathologic Basics Of Diseases,2005,7thed
    136. 136. Robbins And Cotran, Pathologic Basics Of Diseases,2005,7thed
    137. 137. endogenous regulator of leukocyte recruitment- ↓ inflammatory responses reduces platelet aggregation and adhesion Plays a role during the process of angiogenesis (antiangiogenic effect) In vivo half-life of NO is only seconds acts on- cells in close proximity Abnormalities in endothelial production of NO- atherosclerosis, diabetes, &hypertension Robbins And Cotran, Pathologic Basics Of Diseases,2005,7thed
    138. 138. released extracellularly from WBC production dependent-activation of the NADPH oxidative system. Extracellular release -↑chemokines (e.g., IL-8), cytokines  amplifies inflammatory response Robbins And Cotran, Pathologic Basics Of Diseases,2005,7thed OXYGEN-DERIVED FREE RADICALS
    139. 139. Endothelial cell damage, with resultant increased vascular permeability Inactivation of antiproteases, such as a,-antitrypsin Injury to other cell types (parenchymal cells, red blood (cells). the copper-containing serum protein ceruloplasmin the iron-free fraction of serum, transferrin the enzyme superoxide dismutase, which is found or can be activated in a variety of cell types The enzyme catalase, which detoxifies H202 glutathione peroxidase, another powerful H2O2 detoxifier
    140. 140. NEUROPEPTIDES - substance P - neurokinin
    141. 141. OTHER MEDIATORS HYPOXIA INDUCED FACTOR la URIC ACID
    142. 142. Good Morning…
    143. 143. Lectins  immune system by recognizing carbohydrate that are found exclusively on the pathogens  Synthesized in liver, binds to carbohydrate patterns on the bacterial cell wall and lead to activation of the complement system pathways Sugar binding proteins (not glycoproteins) Play role in biological recognition phenomenon e.g.Manose binding lectin [MBL] http://en.wikipedia.org/wiki/Lectin
    144. 144. Histamine Nitric oxide
    145. 145. PGE2 Misoprostole PGI2 iloprost, cisaprost
    146. 146. Recombinant –human Erythropoietin • Anaemia of chronic renal Recombinant – human M- CSF • Acceleration of myeloid recovery in patients with Lymphoma Interferon -α • Chronic Myeloid Leukaemia • Chronic Hepatitis C International Journal of Pathology; 2004; 2(1):47-58
    147. 147. Thrombopoietin • thrombocytopen ia due to myelosuppressiv e therapy Recombinant Interleukin –11 • severe thrombocytopen ia due to myelosuppresive therapy IL- 3 • Chemotherapy induced myelosuppresion International Journal of Pathology; 2004; 2(1):47-58
    148. 148. SUMMARY OF MEDIATORS OF INFLAMMATION OUTCOMES IN INFLAMMATION EVENTS IN THE RESOLUTION OF INFLAMMATION CHRONIC INFLAMMATION INFLAMMATION OF ORAL TISSUES
    149. 149. COMPLIMENT CLOTTINGKININ Robbins And Cotran, Pathologic Basics Of Diseases,2005,7thed
    150. 150. Robbins And Cotran, Pathologic Basics Of Diseases,2005,7thed COMPLEMENT ACTIVATION begins with the formation of Ag-Ab complex is initiated by cell-surface constituents that are foreign to the host – Ab-independent is activated by binding of MBL to mannose residues on glycoproteins or carbohydrates on the surface of microorganisms – Ab-independent CLASSICAL PATHWAY ALTERNATIVE PATHWAY LECTIN PATHWAY
    151. 151. Robbins And Cotran, Pathologic Basics Of Diseases,2005,7thed COMPLEMENT ACTIVATION
    152. 152. COMPLEMENT ACTIVATION
    153. 153. Robbins And Cotran, Pathologic Basics Of Diseases,2005,7thed COMPLEMENT ACTIVATION CLEAVAGE OF C3
    154. 154. Robbins And Cotran, Pathologic Basics Of Diseases,2005,7thed COMPLEMENT ACTIVATION MEMBRANE ATTACK COMPLEX
    155. 155. Robbins And Cotran, Pathologic Basics Of Diseases,2005,7thed COMPLEMENT ACTIVATION MEMBRANE ATTACK COMPLEX
    156. 156. RESULTS OF COMPLEMENT ACTIVATION Tortora GJ, Derickson BH, Principles of anatomy and physiology, 12th ed, Vol 2,2009
    157. 157. Factor XII Factor XIIa Prekallikrein Kallikrein Plasminogen Plasmin Fibrin Tissue plasminogen activator HMWK BRADYKININ Fibrin degradation products KININ & FIRINOLYTIC SYSTEM Burkets oral medicine,10th ed,2003
    158. 158. CLOTTING SYSTEM EXTRINSIC PATHWAY INTRINSIC PATHWAY Tortora GJ, Derickson BH, Principles of anatomy and physiology,12th ed, Vol 2,2009
    159. 159. Robbins And Cotran, Pathologic Basics Of Diseases,2005,7thed
    160. 160. MOST LIKELY MEDIATORS OF INFLAMMATION
    161. 161. MOST LIKELY MEDIATORS OF INFLAMMATION • PROSTAGLANDINS VASODIALATION • VASOACTIVE AMINES • C3a & C5a (through liberating amines) • BRADYKININ • LEUKOTRIENE C4,D4,E4,PAF INCREASED VASCULAR PERMEABILITY • C5a • LEUKOTRIENE B4 • OTHER CHEMOTACTIC LIPIDS • BACTERIAL PRODUCTS CHEMOKINES Rubin E and Farber JL , Essential Pathology,1st ed
    162. 162. • INF-1, TNF • PROSTAGLANDINS FEVER • PROSTAGLANDINS • BRADYKININ PAIN • NEUTROPHIL & MACROPHAGE LYSOSOMAL ENZYME • OXYGEN METABOLITES TISSUE DAMAGE Rubin E and Farber JL , Essential Pathology,1st ed
    163. 163. Robbins And Cotran, Pathologic Basics Of Diseases,2005,7thed
    164. 164. MORPHOLOGIC PATTERNS OF ACUTE INFLAMMATION
    165. 165. ACCORDING TO THE TYPE OF EXUDATE Serous Inflammation Catarrhal inflammation Fibrinous inflammation Suppurative inflammation Hemorrhagic inflammation Allergic inflammation
    166. 166. necrotizing inflammation lymphocytic inflammation fetal inflammation Riede & Werner, Color Atlas of Pathology,1st ed,2001 SPECIAL FORMS OF ACUTE INFLAMMATION
    167. 167. SEROUS INFLAMMATION : Riede & Werner, Color Atlas of Pathology CATARRHAL INFLAMMATION DEFINITION: a form affecting mainly a mucous surface, marked by a copious discharge of mucus and epithelial debris. (in mucous membrane of GIT or respiratory tract) . FIBRINOUS INFLAMMATION DEFINITION: Acute inflammation with exudation of fibrinogen- containing serum that polymerizes to fibrin outside the blood vessels.
    168. 168. SUPPURATIVE INFLAMMATION DEFINITION: Inflammation with exudate consisting primarily of neutrophils and cellular debris. Riede & Werner, Color Atlas of Pathology  ABSCESS[ localised]  PHLEGMON[ diffuse] DEFINITION : It is characterized by the diffuse spread of the exudate through tissue spaces caused by virulent bacteria like streptococci without either localization or marked pus formation
    169. 169. DEFINITION: Acute inflammation involving microvascular injury with massive microvascular bleeding, producing an exudate with a high erythrocyte content HEMORRHAGIC INFLAMMATION ALLERGIC INFLAMMATION DEFINITION: This is an inflammation of the mucous membrane caused by powerful necrotizing toxin which produce coagulation necrosis and cause pseudomembrane formation.
    170. 170. NECROTIZING INFLAMMATION DEFINITION: Acute inflammation in which tissue necrosis predominates. Ulcerous necrotizing. Diffuse necrotizing. Gangrenous T Y P E S Riede & Werner, Color Atlas of Pathology
    171. 171. DEFINITION: Acute inflammation with focal necrosis extending into the submucosa or deeper and covered with fibrinous exudate. eg. ANUG, peptic ulcer ULCEROUS NECROTIZING INFLAMMATION Riede & Werner, Color Atlas of Pathology
    172. 172. DIFFUSE NECROTIZING INFLAMMATION DEFINITION: Acute inflammation with rapidly spreading necrosis & an ineffective or absent leukocyte reaction. eg. Necrotizing fascitis Riede & Werner, Color Atlas of Pathology GANGRENOUS INFLAMMATION DEFINITION: Putrid disintegration of necrotizing inflammation due to infestation with anaerobic putrefactive bacteria.
    173. 173. CHRONIC INFLAMMATION
    174. 174. DEFINITION : chronic inflammation is inflammation of prolonged duration (weeks or months) in which active inflammation, tissue destruction, and attempts at repair are proceeding simultaneously.
    175. 175. Chronic nonsuppurative inflammation; — Chronic suppurative inflammation; — Granulomatous inflammation
    176. 176. CAUSE S Persistent infections Prolonged exposure to potentially toxic agents Autoimmunity
    177. 177. MORPHOLOGIC FEATURES Mononuclear Cell Infiltration Macrophages, Lymphocytes & Plasma Cells . Tissue Destruction Persistent stimuli or Inflammatory Cells. Healing By Connective Tissue Replacement Angiogenesis & Fibrosis. Rubin E and Farber JL , Essential Pathology,1st ed
    178. 178. CHRONIC INFLAMMATORY CELLS
    179. 179. LYMPHOCYTE EOSINOPHILS TISSUE MACROPHAGES MAST CELLS
    180. 180. ORIGIN MONOCYTES & MACROPHAGES HALF-LIFE STRUCTURE CONTENTS FUNCTION TYPES
    181. 181. PROPERTIES MONOCYTES MACROPHAGES Site Blood Tissues Size Small Large Half-Life 1 day Months to years Characteristic of Acute inflammation Chronic inflammation Secretory granules Less in quantity More in quantity Rubin E and Farber JL , Essential Pathology,1st ed
    182. 182. Harsh Mohan, Essentials Of Pathology,2005, 3rd ed
    183. 183. ROLES OF ACTIVATED MACROPHAGES Rubin E and Farber JL , Essential Pathology,1st ed
    184. 184. OTHER CELLS IN CHRONIC INFLAMMATION Rubin E and Farber JL , Essential Pathology,1st ed
    185. 185. Chronic Nonsuppurative Inflammation DEFINITION: Chronic inflammation without suppurative tissue liquefaction. Riede & Werner, Color Atlas of Pathology Chronic Suppurative Inflammation DEFINITION: This may occur as a chronic mucopurulent inflammation or a chronic granulomatous inflammation (a special form of suppurative inflammation).
    186. 186. GRANULATING INFLAMMATIONS DEFINITION: Chronic inflammations characterized by formation of new capillary-rich, absorptive mesenchyma (granulation tissue). ZONES : Resorption zone Granulation zone Mature connective tissue zone Riede & Werner, Color Atlas of Pathology
    187. 187. Riede & Werner, Color Atlas of Pathology
    188. 188. MORPHOLOGIC VARIANTS OF GRANULATING INFLAMMATIONS — Chronic abscess; — Chronic fistula; — Chronic ulcer. Riede & Werner, Color Atlas of Pathology
    189. 189. CHRONIC PERIAPICAL ABSCESS
    190. 190. CHRONIC FISTULA
    191. 191. CHRONIC ORAL ULCER
    192. 192. GRANULOMATOUS INFLAMMATION Granulomatous inflammation is a distinctive pattern of chronic inflammatory reaction characterized by focal accumulations of activated macrophages, which often develop an epithelial- like (epithelioid) appearance. Riede & Werner, Color Atlas of Pathology
    193. 193. A granuloma is a focus of chronic inflammation consisting of a microscopic aggregation of macrophages that are transformed into epithelium-like cells surrounded by a collar of mononuclear, leukocytes, principally lymphocytes and occasionally plasma cells. Riede & Werner, Color Atlas of Pathology
    194. 194. Riede & Werner, Color Atlas of Pathology TUBERCULOUS GRANULOMA PSEUDOTUBERCULOUS GRANULOMA SARCOID GRANULOMAS RHEUMATIC GRANULOMA RHEUMATOID GRANULOMA
    195. 195. DEFINITION: Large circumscribed granulomas consisting of epithelioid cells with central caseous necrosis and an outer layer of lymphocytic cells.(referred to as a TUBERCLE ) TUBERCULOUS GRANULOMA Eg:  Tuberculosis  Leprosy  Syphilis Riede & Werner, Color Atlas of Pathology
    196. 196. TUBERCULOUS GRANULOMA Riede & Werner, Color Atlas of Pathology
    197. 197. PSEUDOTUBERCULOUS GRANULOMA DEFINITION: Often ill-defined granulomas consisting of macrophages and epithelioid cells with central necrosis with granulocytes. (Reticocytically absessing granuloma) eg:  Histoplasmosis  Cryptococcosis  Typhoid fever Riede & Werner, Color Atlas of Pathology
    198. 198. PSEUDOTUBERCULOUS GRANULOMA Riede & Werner, Color Atlas of Pathology
    199. 199. DEFINITION: Small granulomas of epithelioid cells (noncaseating epithelioid granulomas) without central necrosis (caseation) and with an outer layer of collagen fibers. SARCOID GRANULOMAS Riede & Werner, Color Atlas of Pathology
    200. 200. DEFINITION: Histiocytic granuloma around a core of fibrinoid collagen necrosis, occurring primarily in the myocardium and only with rheumatic fever. RHEUMATIC GRANULOMA (Aschoff’s lesion) Riede & Werner, Color Atlas of Pathology
    201. 201. DEFINITION: Histiocytic granuloma around a core of fibrinoid collagen necrosis, often occurring at multiple locations in the subcutaneous tissue and in articular nodules in rheumatoid arthritis RHEUMATOID GRANULOMA Riede & Werner, Color Atlas of Pathology
    202. 202. DEFINITION : Histiocytic granuloma surrounding material that the body can break down only with difficulty or not at all and that has lodged in or been released into tissue. FOREIGN-BODY GRANULOMA Riede & Werner, Color Atlas of Pathology
    203. 203. EFFECTS OF INFLAMMATION
    204. 204. LOCAL EFFECTS SYSTEMIC EFFECTS INFLAMMATION OF ORAL TISSUES
    205. 205. LOCAL EFFECTS
    206. 206. EXUDATE : LOCAL EFFECTS The escape of fluid, proteins and blood cells from the vascular system into interstitial tissue or body cavities. Plasma filtrate without changes in vascular permeability Excess of fluid in the interstitial or serous cavitiesEDEMA : TRANSUDATE :
    207. 207. SYSTEMIC EFFECTS IN INFLAMMATION
    208. 208. The systemic changes associated with inflammation, especially in patients who have infections, are collectively called the acute phase response, or the systemic inflammatory response syndrome (SIRS)." SYSTEMIC INFLAMMATORY RESPONSE SYNDROME (SIRS)
    209. 209. FEVER Reset the TEMPERATURE HIGH-POINT
    210. 210. ACUTE PHASE PROTEINS C-reactive protein (CRP) Fibrinogen Serum amyloid A protein (SAA)
    211. 211. C-reactive protein (CRP) Fibrinogen Serum amyloid A protein (SAA) HEPATOCYTES Up regulated by CYTOKINES
    212. 212. CRP & Fibrinogen + FIBRINOGEN RBC
    213. 213. LEUKOCYTOSIS 15,000 OR 20,000 Cells/pl, LEUKEMOID REACTON CSF Proliferation of precursors in the bone marrow
    214. 214. Chills Rigors Malaise Anorexia Decreased sweating Increased pulse and blood pressure OTHER MANIFESTATIONS OF ‘SIRS / APR’
    215. 215. INFLAMMATION OF ORAL TISSUES SOFT TISSUES HARD TISSUES
    216. 216. ORAL SOFT TISSUE inflammationS PULPITIS PERIODONTITIS RECURRENT APTHOUS ULCERS ORAL LICHEN PLANUS ORAL SUBMUCOUS FIBROSIS ORAL CANCER
    217. 217. ORAL HARD TISSUE inflammationS ALVEOLITIS OSTEITIS OSTEOMYELITIS ARTHRITIS
    218. 218. MISCELLANEOUS inflammation FOLLICULITIS DERMATITIS RHINITIS SINUSITIS. . . .
    219. 219. PULPAL & PERIAPICAL INFLAMMATION
    220. 220. PULPAL INFLAMMATION
    221. 221. PULPAL INFLAMMATION
    222. 222. PULPAL INFLAMMATION
    223. 223. PULPAL & PERIAPICAL INFLAMMATION Focal Pulpitis Acute Chronic Apical Periodontitis Radicular cyst Osteomyelitis Diffuse Periostitis AbscessCellulitis Acute Acute Chronic Chronic Periapical granuloma Periapical abscess
    224. 224. PERIODONTAL INFLAMMATION
    225. 225. Infectious Disease – AA , P. Gingivalis , etc Begins As Gingivitis Bacterial Plaque – Mediators MMP’s – collagenase , proteoglycans , etc PDL Destruction – Immune Response ( Hypersensitivity) PERIODONTAL INFLAMMATION
    226. 226. PERIODONTAL INFLAMMATION
    227. 227. RECURRENT APTHOUS ULCERS
    228. 228. RECURRENT APTHOUS ULCERS  Minor  Major  Herpetiform
    229. 229. RECURRENT APTHOUS ULCERS  Genetic predisposition - genotypes of IL-1B; IL-6,  Positive family history  cell-mediated immune response mechanism, and involves generation of T-cells and TNF α  Elevated levels of interleukin-2 (IL-2) and lower levels of IL-10 have been found.  Natural killer cells activated by IL-2 play a role in the process of this disease
    230. 230. ORAL LICHEN PLANUS Oral lichen planus (OLP) is a common chronic immunologic inflammatory mucocutaneous disorder that varies in appearance from keratotic (reticular or plaquelike) to erythematous and ulcerative. Burket’s Oral Medicine Diagnosis and treatment, 10th ed Reticular Plaque Atrophic Bullous Erosive Ulcerative T Y P E S
    231. 231. ORAL LICHEN PLANUS Reticular lichen planus Papular lichen planus Atrophic lichen planus Scully C, Carrozzo M. British Journal of Oral and Maxillofacial Surgery 46 (2008) 15–21
    232. 232. ORAL LICHEN PLANUS Erosive lichen planus Bullous lichen planus Gingival lichen planus Scully C, Carrozzo M. British Journal of Oral and Maxillofacial Surgery 46 (2008) 15–21
    233. 233. ORAL LICHEN PLANUS Common chronic inflammatory disorder affecting stratified squamous epithelia. It is genetically induced Genetic polymorphism of cytokines - govern whether lesions develop in the mouth alone (interferon-gamma (IFN-) associated) or in the mouth & skin (tumour necrosis factor-alpha (TNF-) associated) Scully C, Carrozzo M. British Journal of Oral and Maxillofacial Surgery 46 (2008) 15–21
    234. 234. ORAL LICHEN PLANUS  Increased production of TH1 cytokines is a key and early event in LP  T-cell-mediated autoimmune disease principally CD4+ and CD8+ lymphocytes  Gradual accumulation of CD8+ T cells with disease progression.  proportion of CD8+ cells -↑ in the superficial lamina propria.  Auto- cytotoxic CD8+ T cells trigger apoptosis of oral epithelial cells. Porter SR, Kirby A,Olsen I, Barrett W.OOOOE 1997;83:358-66
    235. 235. ANTIGENIC STIMULATION (exogenous/endogenous) * LANGERHANS CELLS AND FACTOR XIII A DENDROCYTES INCREASE (associated with antigenic challenge) ENDOTHELIUM UPREGULATES ADHESION MOLECULES (E.G., ICAM AND ELAM) (induced by resident macrophages, langerhans cells, and dendrocytes) LYMPHOCYTES (T CELLS) RECRUITED TO AND RETAINED IN SUBMUCOSA (Through receptors to endothelial adhesion molecules) Regezi, Scuibba, Jordan. Oral Pathology .clinicopathologic correlation 5th ed,2009
    236. 236. Basal keratinocytes neoexpress ICAM and lymphocytes attach (Through lymphocyte receptors to ICAM) Basal keratinocytes undergo apoptosis (Mediated by lymphocyte-derived cytokines) Hyperkeratosis (Reduced keratinocyte desquamation due to enhanced membrane adhesion) Regezi, Scuibba, Jordan. Oral Pathology .clinicopathologic correlation 5th ed,2009
    237. 237. ORAL SUBMUCOUS FIBROSIS
    238. 238. ORAL SUBMUCOUS FIBROSIS Oral submucous fibrosis (OSF) is a slowly progressive chronic fibrotic disease of the oral cavity and oropharynx, characterized by fibroelastic change and inflammation of the mucosa, leading to a progressive inability to open the mouth, swallow,or speak. Burket’s Oral Medicine Diagnosis and treatment, 10th ed
    239. 239. ORAL SUBMUCOUS FIBROSIS ORAL MUCOSA BETEL QUID HABIT CONSTANT IRRITATION ACTIVATED T-CELL & MACROPHAGES ↑ IL-6, TNF, IF-α, TGF-β CHRONIC INFLAMMATION Duration & frequency of the habit ↑ susceptibility due to Fe+ & Vit B12
    240. 240. Arecoline ↓ the MMP-2 secretion (gelatinolytic) ↑ TIMP-1 levels increased deposition of collagen in the extracellular matrix Chang YC et al 2004 Polymorphisms of the genes coding for TNF-α has been reported as a significant risk factor for OSF ↑ levels of fibrogenic cytokines : TGF-β, platelet derived growth factor (PDGF) & basic fibroblast growth factor (bFGF) in OSF tissues . Tilakaratne WM, Klinikowski MF, Saku T, Peters TJ, Warnakulasuriya S Oral Oncology 2006:42;561– 568
    241. 241. collagen-related genes CoL1A2, COL3A1, CoL6A1, COL6A3 and COL7A1 (altered- ingredients in the quid) definite TGF-β targets Induced in fibroblasts at early stages of the disease. may contribute to increased collagen levels in OSF Tilakaratne WM, Klinikowski MF, Saku T, Peters TJ, Warnakulasuriya S Oral Oncology 2006:42;561– 568
    242. 242. Expression of cyclooxygenase enzymes( COX-2) & inflammatory mediators esp prostaglandins Increased in moderate fibrosis disappeared in advanced fibrosis. Finding compatible with - histology of the disease lack of inflammation in the advanced disease. Biopsies from buccal mucosa of OSF cases and from controls stained for COX-2 by immunohistochemistry: Tilakaratne WM, Klinikowski MF, Saku T, Peters TJ, Warnakulasuriya S Oral Oncology 2006:42;561– 568
    243. 243. Why do we prescribe corticosteroids???? OSF shows a gross imbalance in ECM remodeling Fibroblasts from OSF patients and controls were incubated with collagen beads: proportion of phagocytic cells 35% and 75% respectively. After incubation with fibronectin coated beads, normal fibroblasts exhibited 70% internalization OSF fibroblast revealed 22% internalization. Tsai CC, Ma RH, Shieh TY in 1999 Tilakaratne WM, Klinikowski MF, Saku T, Peters TJ, Warnakulasuriya S Oral Oncology 2006:42;561– 568
    244. 244. Increased levels of immune complexes and raised serum levels of IgG, IgA and IgM Tilakaratne WM et al. Oral Oncology 2006:42;561– 568 There was a dose-dependent enhancement of phagocytic cells when the cultures were treated with corticosteroids. reduction of phagocytic cells -strongly related to the levels of arecoline in fibroblast culture Shieh DH, Chiang LC, Lee CH, Yang YH, Shieh TY in 2004
    245. 245. IMMUNE-MEDIATED SUB-EPITHELIAL BLISTERING DISEASES (IMSEBD) PEMPHIGUS VULGARIS Circulating Antibodies Directed Against Desmoglein 3 & HLA class II alleles
    246. 246. Pemphigoid is a heterogeneous group of putative, autoimmune, chronic inflammatory subepithelial vesiculobullous disorders affecting skin (bullous pemphigoid), mucous membranes of the oropharynx (mucous membrane pemphigoid), and eyes (ocular cicatricial pemphigoid). MUCOUS MEMBRANE PEMPHIGOID (MMP) Suresh L, Kumar V, OOOOE 2007;104:359-62)
    247. 247.  autoantibodies—tissue bound or in circulation—  against heterogeneous molecular targets in the epithelial basement membrane zone (BMZ)  Direct IF -- IgG, IgA, &/or complement C3 deposition in a linear band at the BMZ  The synthesis of IgG4 is dependent upon secretion of interleukins (IL-4, IL-8, and IL-10) triggered by lymphocytes in response to a chronic or repeated antigenic exposure. Suresh L, Kumar V, OOOOE 2007;104:359-62)
    248. 248. Hematoxylin-eosin, original magnification x 40. Direct immunofluorescence with salt split, revealing monoclonal IgG4 deposits, under fluorescent microscope, on the epithelial side of separation in A1 A2 Suresh L, Kumar V, OOOOE 2007;104:359-62)
    249. 249. Hematoxylin-eosin, original magnification x 40. Direct immunofluorescence , with salt split, revealing monoclonal IgG4 deposits, under fluorescent microscope, on the epithelial side of separation in B1 B2 Suresh L, Kumar V, OOOOE 2007;104:359-62)
    250. 250. ERYTHEMA MULTIFORME It is an acute muco-cutaneous hypersensitivity reaction characterized by a skin. SJS is usually initiated by drugs, and the tissue damage is mediated by soluble factors .
    251. 251. Erythema Multiforme (EM) is an acute mucocutaneous hypersensitivity reaction characterised by skin eruption, with or without oral or other mucous membrane lesions CLASSIFICATION Mild or minor EM More severe or major form- Stevens-Johnson syndrome Most severe form/ Toxic epidermal necrolysis (TEN) or Lyell’s Syndrome Farthing P, Bagan JV, Scully C. Oral Diseases 2005:11;261-267 DCNA, Oral Soft tissue lesions.Jan 2005: 49(1);67-76
    252. 252. ETIOLOGY 70%-80% : HSV Others include Infectious agents : Hepatitis viruses(A,B,C), EB virus, Mycoplasma pneumoniae, haemolytic streptococci, rickettsia, coccidiodomycosis, histoplasmosis, Trichomonas Immune conditions : Hepatitis B immunisation, IBD,SLE Food additives or : Benzoates, nitrobenzene, perfumes, terpenes Chemicals Drugs : Sulphonamides, Cephalosporins, Aminopenicillins, Oxicam NSAIDs, Anticonvulsants, even corticosteriods Genetic : HLA-B15, HLA-B35, HLA-A33, HLA-DR53, HLA-DQBI*0301 (recurrent) HLA-DQBI*0402 (rare allele associated with extensive mucosal invovement) DCNA, Oral Soft tissue lesions. Jan 2005: 49(1);67-76 Farthing P, Bagan JV, Scully C. Oral Diseases 2005:11;261-267
    253. 253. IFN-γ tissue damage (Kokuba et al,1999) expression correlates with HSV-protein expression Farthing P, Bagan JV, Scully C. Oral Diseases 2005:11;261-267
    254. 254. Drug induced lesions TNF-α-- present in keratinocytes ; --also produced by macrophages and monocytes --mediate keratinocyte apoptosis The mechanisms of tissue damage in EM Virally induced EM----> IFN-γ Drug induces EM ----> TNF-α
    255. 255. HISTOPATHOLOGY OF EM MINOR.
    256. 256. Other inflammatory conditions
    257. 257. RECURRENT APTHOUS ULCERS  Minor  Major  Herpetiform
    258. 258. RECURRENT APTHOUS ULCERS  cell-mediated immune response mechanism, and involves generation of T-cells and TNF α  Elevated levels of interleukin-2 (IL-2) and lower levels of IL-10 have been found.  Natural killer cells activated by IL-2 play a role in the process of this disease
    259. 259. ORAL LICHEN PLANUS Oral lichen planus (OLP) is a common chronic immunologic inflammatory mucocutaneous disorder that varies in appearance from keratotic (reticular or plaquelike) to erythematous and ulcerative. Burket’s Oral Medicine Diagnosis and treatment, 10th ed
    260. 260. ORAL LICHEN PLANUS Common chronic inflammatory disorder affecting stratified squamous epithelia. It is genetically induced Genetic polymorphism of cytokines – interferon-gamma (IFN-) associated or tumour necrosis factor-alpha (TNF-) associated
    261. 261. ORAL LICHEN PLANUS  Increased production of TH1 cytokines is a key and early event in LP  T-cell-mediated autoimmune disease principally CD4+ and CD8+ lymphocytes  Gradual accumulation of CD8+ T cells with disease progression.  proportion of CD8+ cells -↑ in the superficial lamina propria.  Auto- cytotoxic CD8+ T cells trigger apoptosis of oral epithelial cells. (epithelial-mesenchymal junction)
    262. 262. ANTIGENIC STIMULATION (exogenous/endogenous) * LANGERHANS CELLS AND DENDROCYTES INCREASE (associated with antigenic challenge) ENDOTHELIUM UPREGULATES ADHESION MOLECULES (E.G., ICAM ) (induced by resident macrophages, langerhans cells, and dendrocytes) LYMPHOCYTES (T CELLS) RECRUITED TO AND RETAINED IN SUBMUCOSA (Through receptors to endothelial adhesion molecules)
    263. 263. Basal keratinocytes neoexpress ICAM and lymphocytes attach (Through lymphocyte receptors to ICAM) Basal keratinocytes undergo apoptosis (Mediated by lymphocyte-derived cytokines) Hyperkeratosis (Reduced keratinocyte desquamation due to enhanced membrane adhesion)
    264. 264. ORAL SUBMUCOUS FIBROSIS Oral submucous fibrosis (OSF) is a slowly progressive chronic fibrotic disease of the oral cavity and oropharynx, characterized by fibroelastic change and inflammation of the mucosa, leading to a progressive inability to open the mouth, swallow,or speak.
    265. 265. ORAL SUBMUCOUS FIBROSIS ORAL MUCOSA BETEL QUID HABIT CONSTANT IRRITATION ACTIVATED T-CELL & MACROPHAGES ↑ IL-6, TNF, IF-γ, TGF-β CHRONIC INFLAMMATION Duration & frequency of the habit
    266. 266. Arecoline ↓ the MMP-2 secretion (gelatinolytic) increased deposition of collagen in the extracellular matrix ↑ levels of fibrogenic cytokines : TGF-β, platelet derived growth factor (PDGF) & basic fibroblast growth factor (bFGF) in OSF tissues .
    267. 267. IMMUNE-MEDIATED SUB-EPITHELIAL BLISTERING DISEASES (IMSEBD) PEMPHIGUS VULGARIS Circulating Antibodies Directed Against Desmoglein 3
    268. 268. Pemphigoid is a heterogeneous group of autoimmune, chronic inflammatory subepithelial vesiculobullous disorders affecting skin (bullous pemphigoid), mucous membranes of the oropharynx (mucous membrane pemphigoid), and eyes (ocular cicatricial pemphigoid). MUCOUS MEMBRANE PEMPHIGOID (MMP)
    269. 269. Erythema Multiforme (EM) is an acute mucocutaneous hypersensitivity reaction characterised by skin eruption, with or without oral or other mucous membrane lesions CLASSIFICATION Mild or minor EM More severe or major form- Stevens-Johnson syndrome Most severe form/ Toxic epidermal necrolysis (TEN) or Lyell’s Syndrome ERYTHEMA MULTIFORME
    270. 270. ETIOLO GY Others include Infectious agents : Hepatitis viruses(A,B,C), EB virus, Mycoplasma pneumoniae, haemolytic streptococci, rickettsia, coccidiodomycosis, histoplasmosis, Trichomonas Immune conditions : Hepatitis B immunisation, IBD,SLE Food additives or : Benzoates, nitrobenzene, perfumes, terpenes Chemicals Drugs : Sulphonamides, Cephalosporins, Aminopenicillins, Oxicam NSAIDs, Anticonvulsants, even corticosteriods Genetic : HLA-B15, HLA-B35, HLA-A33, HLA-DR53, HLA-DQBI*0301 (recurrent) HLA-DQBI*0402 (rare allele associated with extensive mucosal invovement)
    271. 271. ORAL CANCER
    272. 272. Inflammation is the 7th hallmark of cancer
    273. 273. chronic inflammatory infiltrate ( inflammatory cells +cytokines) characterizing chronic disorders ↓ main cause of Tissue malignancy It has been suggested that :
    274. 274. Pathways connecting inflammation & cancers
    275. 275. • Invasion: Macrophages proteases  breakdown the basement membrane around areas of proliferating tumor cells  prompting their escape into the surrounding stromal tissue. • Angiogenesis: macrophages cooperate with tumor cells  secreats proangiogenic factors  stimulates vascular endothelial cells  induce vascular supply. • Immunosuppression: Macrophages secrete factors that suppress the anti-tumor functions of innate immune system. • Metastasis: Macrophages associated with tumor vessels secretes factors that guide tumor cells toward blood vessels where they then escape into the circulation.. The Roles of Tumor-Associated Macrophages in Tumor Progression
    276. 276. The Roles of Tumor-Associated Macrophages in Tumor Progression
    277. 277. Prostaglandin Promotes Cell Growth
    278. 278. Differing Functions of COX-1 & COX-2 Arachidonic Acid COX-1 (constitutive) Homeostasis • Stomach/GI protection • Platelet aggregation • Renal blood flow COX-2 (inducible) Pathophysiology • Inflammation, Pain • Fever • Cancer • Morbus Alzheimer • Ischemia (CNS)
    279. 279. Evidence of a COX-2 Dependent Role in Neoplasia Epidemiological Studies w Decreased risk of CRC-associated deaths in aspirin users. w The NSAID sulindac decreases the size and number of polyps . w Prostaglandin levels are increased in CR tumors. w Overexpression of COX-2 detected in adenomas and adenocarcinomas. Animal Studies w Sulindac and other NSAIDs attenuate intestinal tumor and xenografted cancer cell growth in mice. Cellular Studies w Overexpression of COX-2 in epithelial cells results in: Decreased apoptosis Angiogenesis (increased VEFG, FGF, PDGF… expression) Metastatic potential (increased adhesion and MMP expression) Genetic Model w Mice defective in COX-2 have a dramatic reduction (86%) in colorectal polyp formation.
    280. 280. COX-2 is Overexpressed in Multiple Components of Cancer
    281. 281.  Destroy, dilute and wall off any injurious agent & constitutes the repair. Without inflammation, infections would go unchecked, wounds would never heal, and injured organs may remain as permanent festering sores.  In our day to day lives we come across many cases starting from gingivitis to oral cancer wherein inflammation exerts a direct or an indirect effect.  So understanding inflammation helps us to know the various vascular and cellular changes, mediators involved and therefore help us to evaluate the significance of various anti- inflammatory drugs that we do prescribe, for controlling the same.
    282. 282. Thank You . . . “I choose a lazy person to do a hard job. Because a lazy person will find an easy way to do it.” ― Bill Gates
    283. 283. PPT Available @ http://www.4shared.com/file/0qV66d9k/inflammati on_by_dr_pratik.html

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