-by Dr Shruthi B S
1. Robbin’s & Cotron Pathological basis of diseases -7th edn. 2. Walter, Hamilton & Israel’s Principles of pathology for dental students – 5th edn 3. Boyd text book of pathology – 9th edn. 4. Text book of Pathology – Rubin, John L.Farber 2nd edn. 5. Text book of oral pathology – Shafer 4th edn. 6. Contemporary oral & maxillofacial surgery – Peterson. 7. Textbook of medical pharmacology - tripathi 8. Google search
• Inflammation L.inflammatio; inflammare = to set on fire
• Inflammation is a protective response intended to eliminate the initial cause of cell injury as well as the necrotic cells and tissues resulting from the original insult.
. cells that consists of vascular responses. migration & activation of leukocytes. & systemic reactions.Definition
• Acc to Robin’s Inflammation is a complex reaction to injurious agents such as microbes & damaged.
Israel Inflammation is the reaction of the vascular and supporting elements of the tissue to injury and results in the formation of a protein rich exudates.• Acc to J.
. S. B. provided the injury has not been so severe as to destroy the area. Walter & M.
loss of function ( functiolaesa )
• Celsus (3000 BC) – Roman writer listed 4 cardinal signs
• Virchow – 5th clinical sign.
• John Hunter(1793) – Salutary effect
• Julius Cohnheim (18391884) -observed inflamed blood vessels under microscope
• Elie Metchnikoff (1880) – Phagocytosis
• Sir Thomas Lewis Chemical mediators
• Acute inflammation is a rapid response to an injurious agent that serves to deliver mediators of host defense— leukocytes and plasma proteins— to the site of injury.
• Acute inflammation has three major components: (1) alterations in vascular caliber that lead to an increase in blood flow (2) structural changes in the microvasculature that permit plasma proteins and leukocytes to leave the circulation (3) emigration of the leukocytes from the microcirculation, their accumulation in the focus of injury, and their activation to eliminate the offending agent
Stimuli for acute inflammation
• • • Infections (bacterial, viral, parasitic) and microbial toxins Trauma (blunt and penetrating) Physical and chemical agents (thermal injury, e.g., burns or frostbite; irradiation; some environmental chemicals) Tissue necrosis (from any cause) Foreign bodies (splinters, dirt, sutures) Immune reactions (also called hypersensitivity reactions)
• • •
Foreign bodies (splinters.Stimuli for acute inflammation
Infection (bacterial. sutures)
. viral. dirt.
VASCULAR CHANGES CELLULAR CHANGES
Vasoconstriction * Vasodilatation * Permeability * Stasis * Transmigration
Exudation of leukocytes * Phagocytosis
Changes in Vascular Flow and Caliber 2. Increased Vascular Permeability (Vascular Leakage)
Alteration in the microvasculature is the earliest response to tissue injury Two changes are 1.
Increased viscosity & stasis of blood
Changes in the vascular flow
Transient vasoconstriction vasodilation
Normal axial blood flow
Permeability of vasculature
viscosity Stasis of blood
Hallmark of acute inflammation
Loss of plasma protein IOP & HP Outflow of fluid
• A critical function of inflammation is to deliver leukocytes to the site of injury and to activate the leukocytes to perform their normal functions in host defense.
Events are 1. Transmigration across the endothelium (diapedesis) 3. Migration in interstitial tissues toward a chemotactic stimulus
• The sequence of events in the journey of leukocytes from the vessel lumen to the interstitial tissue. Margination. called extravasation. and adhesion to Endothelium 2. rolling.
along the hemodynamic endothelium and conditions change adhere (wall shear stress transiently (a decreases). an appearance calledposition along the they adhere pavementing. This (resembling
. rolling. finally assume a coming to rest at The endothelium can be virtually lined peripheral some point where by white cells. and process called more white cells rolling).Margination. endothelial firmly surface. and adhesion
Blood flow slows Rows of early leukocytes in inflammation tumble slowly (stasis).
Adhesio n molecul es
• The selectins are a family of three closely related proteins that differ in their cellular distribution • Selectins bind, through their lectin domain, to sialylated forms of oligosaccharides (e.g., sialylated Lewis X), which • E-selectin- bound to various themselves are covalentlyendothelium mucin like glycoproteins • P-selectin- endothelium • various mucin-like glycoproteinsbinding of selectins to their & fast on rate ligands has a platelets but also has a fast off rate and is of low affinity; this property allows selectins to mediate • L-selectin- leukocyte initial attachment and subsequent rolling of leukocytes on endothelium in the face of flowing blood
• Integrins are transmembrane heterodimeric glycoproteins, made up of α and β chains, that are expressed on many cell types and bind to ligands on endothelial cells, other leukocytes, and the extracellular matrix . • The integrins LFA-1 and Mac-1 (CD11a/CD18 and CD11b/CD18) bind to ICAM-1, and the integrins (such as VLA-4) bind VCAM-1.
Ig family molecules
• The immunoglobulin family molecules include two endothelial adhesion molecules: ICAM-1 (intercellular adhesion molecule 1) VCAM-1 (vascular cell adhesion molecule 1) • Both these molecules serve as ligands for integrins found on leukocytes
Mucin like glycoproteins
• Mucin-like glycoproteins. serve as • ligands for the leukocyte adhesion molecule called CD44. • These glycoproteins are found in the extracellular matrix and on cell
. such as heparan sulfate.
•Chemokines stimulate the cells to migrate through interendothelial spaces toward the chemical concentration gradient.
.e. i.•Process of migration of the leukocytes through the endothelium. towards the site of injury or infection. called transmigration or diapedesis.
. • In most forms of acute inflammation. neutrophils predominate in the inflammatory infiltrate during the first 6 to 24 hours. then are replaced by monocytes in 24 to 48 hours.• The type of emigrating leukocyte varies with the age of the inflammatory response and with the type of stimulus.
• Neutrophils are more numerous in the blood • They respond more rapidly to chemokines • They may attach more firmly to the adhesion molecules that are rapidly induced on endothelial cells. such as P. they undergo apoptosis and disappear after 24 to 48 hours.and Eselectins • In addition. after entering tissues. neutrophils are short-lived. whereas monocytes survive longer
Schematic & histologic sequence of events following acute injury
Early (neutrophilic) Infiltration
Later (mononuclear) cellular Infiltrates
It is the locomotion of leukocytes oriented along a chemical gradient towards the site of injury All granulocytes. lymphocytes respond to chemotactic stimuli with varying rates of speed. monocytes and. Exogenous. 1. to a lesser extent.bacterial products 2.
particularly those of the chemokine family (e.Endogenous substances
(1)Components of the complement system. mainly leukotriene B4 (LTB4).g. and (3)Cytokines.. IL-8).
. (2)Products of the lipoxygenase pathway. particularly C5a.
Chemotactic agents Leukocyte receptors Increase in cytosolic Ca Polymerization & reorganization of actin
Linear assembly of actin polymers along filopod Leukocyte moves by pulling back of the
The functional responses that are induced on leukocyte activation include the following:
• Production of arachidonic acid metabolites • Degranulation and secretion of lysosomal enzymes • Secretion of cytokines • Modulation of leukocyte adhesion molecules
• It is defined as the process of engulfment of solid particulate material by the cells( cell eating) • Phagocytosis and the release of enzymes by neutrophils and macrophages are responsible for eliminating the injurious agents
scavenger receptors are two neutrophils and macrophages •The limiting important receptors membrane of this phagocytic vacuole •microbes are opsonized by then fuses with the specific proteins (opsonins) limiting membrane of a lysosomal •major opsonins are IgG granule. and certain phagolysosome •Phagocytosis is plasma lectins
.of infectious agents and necrotic and cells is their killing and degradation within forms phagosome.•Extensions of the 1. the C3b discharge of the granule's contents breakdown product of into the complement. resulting in antibodies.RECOGNITION AND ATTACHMENT cytoplasm (pseudopods) flow around the particle Elimination •Mannose receptors to be engulfed.
– Increased glucose oxidation via the hexosemonophosphate shunt. and – Production of reactive oxygen intermediates (ROIs.• Phagocytosis stimulates:
– A burst in oxygen consumption. – Glycogenolysis.
. also called reactive oxygen species).
Oxygen-Dependent Antimicrobial Activity
Bactericidal permeability increasing protein
. defensins.Oxygen-Independent Antimicrobial Activity
• Increased production of lactate & action of carbonic anhydrase • Lactoferrin • Lysozyme • Phagocytin. Major basic protein.
Nitric oxide mechanism
• NO is released from endothelial cells & macrophages • Fungicidal & antiparasitic action
Why is the host cell not affected by the ROI?
Defects in leukocyte function
Disease Genetic Leukocyte adhesion deficiency 1 Leukocyte adhesion deficiency 2
Defect β chain of CD11/CD18 integrins Fucosyl transferase required for synthesis of sialylated oligosaccharide (receptor for selectin) Decreased oxidative burst NADPH oxidase (membrane component) NADPH oxidase (cytoplasmic components)
Chronic granulomatous disease X-linked Autosomal recessive
Myeloperoxidase deficiency Chédiak-Higashi syndrome
Absent MPO-H2O2 system Protein involved in organelle membrane docking and fusion Acquired
from macrophages and other cells – Neural impulses (cholinergic discharge) that inhibit the production of TNF in macrophages
• mediators of inflammation have short half-lives • a variety of stop signals that serve to actively terminate the reaction • These active mechanisms include – A switch in the production of pro-inflammatory leukotrienes to anti-inflammatory lipoxins from arachidonic acid – The liberation of an anti-inflammatory cytokine. transforming growth factor-β (TGF-β).
Chemical mediators of inflammation
• Mediators originate either from plasma or from cells • production of active mediators is triggered by microbial products or by host proteins • perform their biologic activity by initially binding to specific receptors on target cells • One mediator can stimulate the release of other mediators by target cells themselves
most of these mediators are short-lived • Most mediators have the potential to cause harmful effects.• Mediators can act on one or few target cell types • Once activated and released from the cell.
basophils and platelets Stimuli (1)Physical injury such as trauma. (3)Fragments of complement called anaphylatoxins (C3a and C5a).g. or heat.. IL-8). cold. and (6) cytokines (IL-1. (2)Immune reactions involving binding of antibodies to mast cells.
. Histamine Released from mast cells . (4)Histamine-releasing proteins derived from leukocytes.Vasoactive Amines
1. and (5)Neuropeptides (e. substance P).
• It is considered to be the principal mediator of the immediate transient phase of increased vascular permeability. histamine causes dilation of the arterioles and increases the permeability of venules.Actions
• In humans. causing venular gaps. • Itching & pain mediator
adenosine diphosphate (ADP). and antigen-antibody complexes • Increases the vascular permeability
• Released by platelets and enterochromaffin cells • Released when platelets aggregate after contact with collagen. thrombin.
Plasma proteins that belong to three interrelated systems: • The complement. and • Clotting systems
. • Kinin.
• C3 and C5 are the most important inflammatory mediators.
• 20 component proteins (and their cleavage products) • found in greatest concentration in plasma • This system functions in both innate and adaptive immunity for defense against microbial agents.
as aC3bBb complex is a C3 convertase functions the C3 convertase. and cobra venom. and proteolysis of C2 by C4.The Early Steps
The alternative pathway can be triggered by microbial surface molecules (e. and factorsis triggered by fixation of The classical pathway B and D). endotoxin. and of C3b and aformation of product of Factor B subsequent breakdown a C4b2b complex that called Bb. mannose-binding lectin. or LPS). a plasma collectin.g. theto antibody (IgM or IgG) of C3has combined Cl spontaneous cleavage that that occurs normally is enhanced and stabilizedanda complex with antigen. complex polysaccharides. binds to carbohydratecontaining proteins on bacteria and viruses and directly activates Cl
. In the lectin pathway. In this pathway.. It involves a distinct set of plasma components (properdin.
complex polysaccharides. which is triggered by fixation of Cl to antibody (IgM or IgG) combined with antigen The classical pathway is triggered by fixation of Cl to antibody (IgM or IgG) that has combined with antigen. binds to carbohydrate-containing proteins on bacteria and viruses and directly activates Cl
. and subsequent formation of a C4b2b complex that functions as a C3 convertase. and proteolysis of C2 and C4. a plasma collectin. endotoxin. in which plasma mannose-binding lectin binds to carbohydrates on microbes and directly activates Cl. It involves a distinct set of plasma components (properdin. In this pathway.In the lectin pathway. and cobra venom.g. the spontaneous cleavage of C3 that occurs normally is enhanced and stabilized by a complex of C3b and a breakdown product of Factor B called Bb.The Early Steps of Complement Activation
• the classical pathway.. The alternative pathway can be triggered by microbial surface molecules (e. the C3bBb complex is a C3 convertase The lectin pathway. and factors B and D). mannose-binding lectin. or LPS).
. which allows fluid and ions to enter and causes cell lysis. called the membrane attack complex. Polymerized C9 forms a channel in lipid membranes. C5b remains attached to the complex and forms a substrate for the subsequent binding of the C6–C9 components.The Late Steps of Complement Activation
The C3b that is generated by any of the pathways binds to the C3 convertase and produces a C5 convertase. which cleaves C5.
C5b forms a substrate for the subsequent binding of the C6–C9
.The Late Steps
Polymerized C9 forms a channel in lipid membranes. called the membrane attack complex. which cleaves . which allows fluid and ions to enter and causes cell
C3b binds to the C3 convertase and produces a C5 convertase.
. eosinophils. monocytes. and activation C5a is a powerful chemotactic agent for neutrophils.Actions
• Vascular phenomena Aphylatoxins (C3a. chemotaxis.increase vascular permeability & vasodilation C5a also activates the lipoxygenase pathway of arachidonic acid (AA) metabolism • Leukocyte adhesion. and basophils • Phagocytosis.
• The kinin system generates vasoactive peptides from plasma proteins. by the action of specific proteases called kallikreins • Activation of the kinin system results in the release of the vasoactive nonapeptide bradykinin.
Plasma prekallikrein XIIa Factor Kallikrei n High-molecular-weight Bradykinin kininogen
. called kininogens.
pain when injected into the skin dilation of blood vessels
• Bradykinin increases vascular permeability causes contraction of smooth muscle.
• Factor XII initiates clotting cascade as it encounters collagen or basement membrane or activated platelets • The protease thrombin formed from its precurses prothrombin provides the main link between the coagulation system and inflammation
• The clotting system and inflammation are intimately connected processes.
• Thrombin binds to receptors that are called protease-activated receptors (PARs) • It causes 1.expression of endothelial adhesion molecules for leukocyte integrins 4.induction of cyclooxygenase-2 5.changes in endothelial shape
. production of PAF and nitric oxide 7.production of chemokines 3. production of Prostaglandins 6.mobilization of P-selectin 2.
Plasminogen activator Plasminog en C3 C3a
Fibrin split products
Actions: 1. 2.Splits off complement C3 to form C3a .Fibrin products : Increases vascular permeability
.Stimulates the kinin system to generate bradykinin.
Arachidonic Acid Metabolites
• Arachidonic acid (AA) is derived from dietary sources or by conversion from the essential fatty acid linoleic acid • It does not occur free in the cell but is normally esterified in membrane phospholipids • It is released from membrane phospholipids through the action of cellular phospholipases
increase in cytoplasmic Ca2+ and activation of various kinases activation of phospholipase A2
. and physical stimuli or by other mediators (e.mechanical.
D4. leukocyte adhesion Metabolite Thromboxane A2. leukotrienes C4. E4 PGI2. PGD2 Leukotrienes C4.Inflammatory actions of eicosanoids
Action Vasoconstriction Vasodilation Increased vascular permeability Chemotaxis. HETE. D4. PGE1. lipoxins
. PGE2. E4 Leukotriene B4.
and endothelial cells. • PAF mediates its effects via a single G-proteincoupled receptor. and its effects are regulated by a family of inactivating PAF acetylhydrolases
. neutrophils. can elaborate PAF. including platelets. monocytes/macrophages. • A variety of cell types. basophils (and mast cells).Platelet activating factor
• PAF is another bioactive phospholipid-derived mediator.
and – induces vasodilation and increased venular permeability at extremely low concentrations – increased leukocyte adhesion to endothelium (by enhancing integrin-mediated leukocyte binding).
. particularly eicosanoids. by leukocytes and other cells. and the oxidative burst
.• In addition to platelet stimulation. degranulation.boosts the synthesis of other mediators. chemotaxis. PAF causes – Vasoconstriction and bronchoconstriction.
and connective tissue cells) that modulate the functions of other cell types • TNF and IL-I are two of the major cytokines that mediate inflammation. but also endothelium. epithelium.Cytokines
• Cytokines are proteins produced by many cell types (principally activated lymphocytes and macrophages. They are produced mainly by activated macrophages
• Chemokines are a family of small (8 to 10 kD) proteins that act primarily as chemoattractants for specific types of leukocytes. • Chemokines stimulate leukocyte recruitment in inflammation and control the normal migration of cells through various tissues.
. • About 40 different chemokines and 20 different receptors for chemokines have been identified.
four major groups
• Some chemokines are produced transiently in response to inflammatory stimuli and promote the recruitment of leukocytes to the sites of inflammation.
• Other chemokines are produced constitutively in tissues and function in organogenesis to organize different cell types in different anatomic regions of the tissues.
such as the relaxation of vascular smooth muscle cells. a pleiotropic mediator of inflammation.
. was discovered as a factor released from endothelial cells that caused vasodilation by relaxing vascular smooth muscle and was therefore called endothelium-derived relaxing factor. initiates a series of intracellular events leading to a response. but also by macrophages and some neurons in the brain. • NO acts in a paracrine manner on target cells through induction of cyclic guanosine monophosphate (GMP). in turn. which. • NO is a soluble gas that is produced not only by endothelial cells.Nitric Oxide
• Thus. NO reduces platelet aggregation and adhesion. production of NO is an endogenous compensatory mechanism that reduces inflammatory responses. • In addition. the gas acts only on cells in close proximity to where it is produced. and serves as an endogenous regulator of leukocyte recruitment.• Since the half-life of NO is only seconds. inhibits several features of mast cell-induced inflammation.
and thus NO is also a mediator of host defense against infection • High levels of NO production by a variety of cells appear to limit the replication of bacteria. protozoa. and viruses (as well as tumor cells).• NO and its derivatives are microbicidal.
and these metabolites can combine with NO to form other reactive nitrogen intermediates. amplifying the cascade that elicits the inflammatory response.g.Oxygen-derived Free Radicals • Oxygen-derived free radicals may be released extracellularly
from leukocytes after exposure to microbes. chemokines. hydrogen peroxide (H2O2). and endothelial leukocyte adhesion molecules.. or following a phagocytic challenge.
. and immune complexes. • Superoxide anion. and hydroxyl radical (OH) are the major species produced within the cell. • Extracellular release of low levels of these potent mediators can increase the expression of chemokines (e. cytokines. IL-8).
and host cells possess antioxidant mechanisms that protect against these potentially harmful oxygen-derived radicals. tissue fluids. release of these potent mediators can be damaging to the host. the influence of oxygen-derived free radicals in any given inflammatory reaction depends on the balance between the production and the inactivation of these metabolites by cells and tissues
.• The physiologic function of these reactive oxygen intermediates is to destroy phagocytosed microbes. • Thus. • Serum. At higher levels.
Outcome of acute inflammation
Resolution of acute inflammation