Inflammation Seminar by Dr Pratik

Good Morning….

Presented by- Dr Pratik Pipalia, CODS, DVG

Available @http://www.4shared.com/file/0qV66d9k/

inflammation_by_dr_pratik.html

PPT Available @http://www.4shared.com/file/0qV66d9k/


INTRODUCTION

HISTORY

DEFINITION

CAUSES

CARDINAL SIGNS OF INFLAMMATION

TYPES OF INFLAMMATORY REACTIONS

CONTENTS

ACUTE INFLAMMATION

VASCULAR EVENTS

CELLULAR EVENTS

CHEMICAL MEDIATORS OF INFLAMMATION

CHEMICAL MEDIATORSOF 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

SUMMARY OF MEDIATORS OF INFLAMMATION

INFLAMMATORY CELLS

OUTCOMES IN INFLAMMATION

EVENTS IN THE RESOLUTION OF INFLAMMATION

CHRONIC INFLAMMATION

APPLIED ASPECTS

LYMPHATICS IN INFLAMMATION

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

Drain excess interstitial fluid

Transports dietary fluids

Carries out immune responses


LYMPHATIC CAPPILLARIES

LYMPHATIC VESSELS

LYMPH NODES

LYMPH TRUNKS


LYMPH

ENDOTHELIUM OF LYMPHATIC CAPILLARY

TISSUE CELL

INTERSTITIAL FLUID ANCHORING FILAMENTS

OPENING

LYMPHATIC CAPPILLARY


LEFT JUGULAR TRUNK

RIGHT JUGULAR TRUNK

LEFT SUBCLAVIAN TRUNK

RIGHT SUBCLAVIAN TRUNK

THORACIC (left lymphatic)DUCT

LYMPHATIC DUCT

SUPERIOR VENECAVA



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.

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


END-RESULT

--susceptibility to oncogene activation --suppression of suppressor gene function

development and progression of cancer.


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 inflammationsuggests 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


Aged residential phagocytes :macrophages & PMN’s within host

↓

inappropriate respiratory burst

↓

release of reactive nitrogen and oxygen intermediates

↓

decrease the ability to destroy pathogens


Aged dendritic cells (DCs)

↓

less efficient in activating T and B cells aged

↓

natural killer (NK) cells ↓ ability and efficiency

in killing tumor cells


↑ production of pro-inflammatory cytokines, IL-1, IL-6 and TNF-α, compared to young people


Up-regulated COX-2 and resulting ↑ production of PGE2

INTRODUCTION

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

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

HISTORY

CORNELIUS CELSUS

Rubor Calor Dolor Tumor

Rudolf Virchow

Functio laesa

John Hunter (surgeon in 1793)

“inflammation as a non-specific body response”


Julius Cohnheim(1889)provided first microscopic description of inflammation

Elie Metchnikoff(1880S) discovered the process of phagocytosis

Paul Ehrlich and Metchinikofftheory of immunity

Thomas Lewisdemonstrated that inflammation -

chemical mediators, most of them act locally


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

According to duration:- 1 Per-acute inflammation2 Acute inflammation3 Sub-acute inflammation4 Chronic inflammation

CLASSIFICATION

University of Babylon: www.uobabylon.edu.iq/uobColeges/ad_downloads/6_17350_197.pdf

According to the cause: - 1-Mechanical inflammationtrauma, blow, kick, or sprain 2-Physical inflammation: heat, cold, electricity, or radiation3-Chemical inflammation:alkali, acid4-Biological inflammationbacteria (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

ACUTEINFLAMMATION

CHRONICINFLAMMATION

CLASSIFICATION OF INFLAMMATION


SEROUS

FIBRINOUS

CATARRHAL

HAEMORRAGIC

PURULENT

ACUTE INFLAMMATION

Reide & Werner, Color Atlas of Pathology,, 2005


DIFFUSE

SUPPURATIVE

GRANULOMATOUS

FIBRINOID


Rubbin R, Strayer D; Rubbin’s Pathology, clinicopathologic foundation of medicine,2005, 5 th ed

DIFFERENCE BETWEEN EXUDATE AND TRANSUDATE

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



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


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

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

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

CAUSES

Bacteria Viruses &

their toxinsFungi

Animal parasitesNecrosis of

tissue

Allergy

Living

CARDINAL SIGNS OF INFLAMMATION

TUMOURRUBORCALOR DOLOR FUNCTIO LESA

Riede & Werner, Color Atlas of Pathology , 2004

TUMOURRUBOR CALOR DOLOR FUNCTIO LAESA

COMPONENTS OF INFLAMMATION


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.


• STIMULI • VASCULAR CHANGES

• TERMINATION

• CELLULAR EVENTS

ACUTE INFLAMMATION

Robbins And Cotran, Pathologic basics of diseases,2005, 7th edition

STIMULI

VASCULAR CHANGES

CHANGES IN VASCULAR FLOW AND CALIBER

Robbins And Cotran, Pathologic basics of diseases,2005, 7th edition

CHANGES IN VASCULAR FLOW AND CALIBER

VASOCONSTRICTION

RAPID BLOOD FLOW

(VASODIALATION)

SLOWING OF THE CIRCULATION

STASIS

Rubin E, Farber J L, Essential pathology, 1990, 1st edition

NORMAL


INFLAMED



VASOCONSTRICTION


VASODIALATION


SLOWING DOWN OF CIRCULATION AND INCREASED PERMEABILITY OF MICROVASCULATURE

CHANGES IN VASCULAR PERMEABILITY

INCREASE

D

NORMAL

NORMAL MICROCIRCULATORY CONTROL

NORMAL PERMEABILITY & STRUCTURE OF MICROCIRCULATION

NORMAL MICROCIRCULATORY CONTROL

SYSTEMIC FACTORS

LOCAL

FACTORS

SYSTEMIC

LOCAL

VASCULAR SMOOTH MUSCLES

AUTONOMIC NERVOUS SYSTEM→

CONDITIONS IN INDIVIDUAL TISSUES

→ METABOLIC ACTIVITY

LOW HIGHArterioles- CONTRACTED Blood Flow- DIMINISHED

Arterioles- RELAX Blood Flow- ENHANCED

NORMAL PERMEABILITY & STRUCTURE OF MICROCIRCULATION

OUTWARD MOVEMENT OF FLUID

INWARD MOVEMENT OF FLUID

FORCES

STARLING’S HYPOTHESIS

Rubin E, Farber J L, Essential Pathology, 1990, 1st Edition

OSMOTIC PRESSURE OF INTERSTITIAL

FLUID

TISSUE HYDROSTATIC

PRESSURE

INTRAVASCULAR HYROSTATIC

PRESSUE

OSMOTIC PRESSURE OF

PLASMA PROTEINS

OUTWARD MOVEMENT OF

FLUID

INWARDMOVEMENT OF

FLUID

Rubin E, Farber JL, Essential Pathology, 1990, 1st Edition

NORMAL FLUID EXCHANGE ACUTE INFLAMMATION

Harsh Mohan, Essentials Of Pathology For Dental Students,2005,3rd Edition

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

GAPS DUE TO ENDOTHELIAL CONTRACTION


DIRECT INJURY


LEUKOCYTE DEPENDENT INJURY


INCREASED TRANSCYTOSIS


ANGIOGENESIS


LEUKOCYTE ADHESION

AND

TRANSMIGRATION

CHEMOTAXIS

LEUKOCYTE ACTIVATION

PHAGOCYTOSIS

CELLULAR EVENTS


LEUKOCYTIC EVENTS

MARGINATION ,

ROLLING &

ADHESION

EMIGRATION &

DIAPEDESIS

CHEMOTAXIS


NORMAL AXIAL FLOW

Harsh Mohan, Essentials Of Pathology For Dental Students,2005,3rd Edition

MARGINATION & PAVEMENTING

Harsh mohan, essentials of pathology for dental students,2005,3rd editionRiede & Werner, Color Atlas of Pathology , 2004 Thieme

ADHESION

Harsh Mohan, Essentials Of Pathology For Dental Students,2005,3rd EditionRiede & Werner, Color Atlas of Pathology , 2004

EMIGRATION AND DIAPEDESIS

Harsh Mohan, Essentials Of Pathology For Dental Students,2005,3rd EditionRiede & Werner, Color Atlas of Pathology , 2004

LEUKOCYTIC ADHESION AND TRANSMIGRATION

ADHESION•COMPLIMENTARY ADHESION MOLECULES

TRANS-MIGRATION

•CHEMOATTRACTANTS •CYTOKINES

Kumar, Abbas, Fausto ; Robbins And Cotran, Pathologic Basics Of Diseases, 2005, 7 th Edition

COMPLIMENTARY ADHESION MOLECULES

SELECTINS

INTEGRINS

Ig SUPERFAMILY

MUCIN like glycoproteins

Harsh Mohan, Essentials Of Pathology,2005, 3rd ed

Robbins And Cotran, Pathologic Basics Of Diseases,2005,7thed




CHEMOTAXIS

CHEMO

ATTRACTANT

EXOGENOUSENDOGENOUS


Exogenous Agents – Bacterial Products Endogenous Agents

C5a.Leukotriene β4.Cytokines,Chemokine family (IL-

8)


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


LEUKOCYTIC ACTIVATION

production of cytokines

LPS


PHAGOCYTOSIS

Robbins And Cotran, Pathologic Basics Of Diseases, 2005, 7th Edition

Phagocytosis :

is the process of Uptake of extracellular particulate matter by cells

PHAGOCYTOSIS

RECOGNITION &

ATTACHMENT

KILLING OR

DEGRADATI

ON

ENGULFMENT


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


OPSONIZATION


OPSONISATION

RECOGNITION & ATTACHMENTENGULFMENT



RECEPTORS FOR OPSONINS


Promotes phagocytosis

Opsonization

Opsonins Antibodies, Complement Proteins , Lectins.

ENGULFMENT STAGE




O2-Dependent - H2O2 HOCl

O2-Independent - lysozyme, cationic proteins, defensins, lactoferrin

NO -Dependent



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


PROCESS OF PHAGOCYTOSIS

ThankYou

…

Good Morning…

ACUTE INFLAMMATION

VASCULAR EVENTS

CELLULAR EVENTS

CHEMICAL MEDIATORS OF INFLAMMATION

CHEMICAL MEDIATORSOF 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





INFLAMMATION OF ORAL TISSUES

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


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


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


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


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


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


CHEMICAL MEDIATORS

CELL DERIVED

PLASMA

DERIVED

CHEMICAL

MEDIATORS


PROPERTIES OF MEDIATORS

Triggered by microbial products / host

proteins.

Specific mechanism of action

Amplify/antagonize each other

Short lived

Potentially harmful

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

Principal mediator of immediate transient response

↑ vascular permeability-venular gapsRichest source - mast cells GranulesAlso found in basophils & platelets

HISTAMINE

Rubin E, Farber JL, Essential Pathology, 1990, 1st Edition

SEROTONIN

mediator of inflammation↑ vascular permeabilitysource –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


PROSTAGLADINS

LEUKOTRIENES

ARACHIDONIC ACID

METABOLITES

Arachidonic Acid

Leukotrienes

LTC4, D4, E4

Cyclooxygenase

5-Lipoxygenase

Prostaglandins

Prostacyclins

Cell Damage

Cell Membrane Phospholipids

Rubin E and Farber JL , Essential Pathology,1st ed

Antibody ResponseProduced by platelets, basophils, mast cells, PMN, monocytes / macrophages, & endothelial cells

low concentrations -vasodilation & ↑ venular permeability

PAF causes vasoconstriction

PLATELET ACTIVATING FACTORS(PAF)



Also - increased leukocyte adhesion to

endothelium, chemotaxis,

degranulation, and the oxidative

burst.

Boost synthesis of other mediators-

eicosanoids, by leukocytes and other

cells

LYSOSOMAL CONSTITUENTS OF LEUKOCYTES

NEUTROPHIL


PRIMARY (AUZUROPHILIC) GRANULES

Myeloperoxidase LysozymesDefensinsBactericidal permeability

increasing proteinsElastaseCathepsin protease3GlucoronidaseMannosidasePhospolipase

PATHOGEN AND TISSUE DESTRUCTION

NEUTROPHIL

SECONDARY (SPECIFIC) GRANULES

Lysozymes Collagenase LactoferrinHistaminasePlasminogen activatorFMLP receptors C3b proteins


GRANULES

EXTRA CELLULAR SPACE

VACUOLES

specific granules

azurophil granules

more readily

by lower concentrations of agonists

require high levels of agonists to be released extracellularly


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.


FUNCTIONS

PROTEASES

ANTIPROTEASES

(a1-antitrypsinMacroglobulin)


• GENETIC DEFECIENCIES

• DEFECTS IN LEUKOCYTE FUNCTION

LEUKOCYTES

APPLIED ASPECTS



LEUCOCYTE ADHESION PROTEINS (LAD)

LAD-1 – Defective Biosynthesis of β 2 chainLAD -2 – absence of E- selectin Antibodies to Adhesion Molecules

GENETIC DEFICIENCIES of leukocytes


DEFECTS IN LEUKOCYTE FUNCTIONDISEASE 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


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


CYTOKINES & CHEMOKINES

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.


Compliment Protein Cascade

Antibody Response


INTERLEUKINS

Molecularly defined cytokines are called interleukins, implying that they mediate communications between leukocytes

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


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



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


CHEMOKINES


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.

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


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



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


released extracellularly from WBC

production dependent-activation of the NADPH oxidative system.

Extracellular release -↑chemokines (e.g., IL-8), cytokines amplifies inflammatory response


OXYGEN-DERIVED FREE RADICALS

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

OXYGEN DERIVED FREE RADICAL

NEUROPEPTIDES

- substance P- neurokinin

OTHER MEDIATORS

HYPOXIA INDUCED FACTOR la

URIC ACID

Good Morning…

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

Commercially available mediators

Histamine

Nitric oxide

PGE2 Misoprostole

PGI2 iloprost, cisaprost

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

Thrombopoietin• thrombocytope

nia due to myelosuppressive therapy

Recombinant Interleukin –11• severe

thrombocytopenia due to myelosuppresive therapy

IL- 3• Chemotherapy

induced myelosuppresion

International Journal of Pathology; 2004; 2(1):47-58






COMPLIMENT

CLOTTING

KININ



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






CLEAVAGE OF C3



MEMBRANE ATTACK COMPLEX



MEMBRANE ATTACK COMPLEX

RESULTS OF COMPLEMENT ACTIVATION


Factor XII Factor XIIa

Prekallikrein Kallikrein

Plasminogen Plasmin

Fibrin

Tissue plasminogen activator

HMWK BRADYKININ

Fibrin degradatio

n products

KININ & FIRINOLYTIC SYSTEM

Burkets oral medicine,10th ed,2003

CLOTTING SYSTEM

EXTRINSIC PATHWAY INTRINSIC PATHWAY



MOST LIKELY MEDIATORS OF INFLAMMATION

TUMOURRUBORCALOR DOLOR FUNCTIO LEASA

MOST LIKELY MEDIATORS OF INFLAMMATION

VASODIALATION

• PROSTAGLANDINS

INCREASED VASCULAR PERMEABILITY

• VASOACTIVE AMINES• C3a & C5a (through liberating amines)• BRADYKININ• LEUKOTRIENE C4,D4,E4,PAF

CHEMOKINES

• C5a• LEUKOTRIENE B4• OTHER CHEMOTACTIC LIPIDS• BACTERIAL PRODUCTS


FEVER

• INF-1, TNF• PROSTAGLANDINS

PAIN

• PROSTAGLANDINS• BRADYKININ

TISSUE DAMAGE

• NEUTROPHIL & MACROPHAGE LYSOSOMAL ENZYME• OXYGEN METABOLITES



OUTCOMES OF INFLAMMATION

MORPHOLOGIC PATTERNS OF ACUTE INFLAMMATION

ACCORDING TO THE TYPE OF EXUDATE

Serous Inflammation

Catarrhal inflammation

Fibrinous inflammation

Suppurative inflammation

Hemorrhagic inflammation

Allergic inflammation

necrotizing inflammation

lymphocytic inflammation

fetal inflammation

Riede & Werner, Color Atlas of Pathology,1st ed,2001

SPECIAL FORMS OF ACUTE INFLAMMATION

SEROUS INFLAMMATION

DEFINITION: Acute inflammation with exudate of fibrin-free serum.i.e. skin blister, Rhumatoid artheritis

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.

SUPPURATIVE INFLAMMATION

DEFINITION: Inflammation with exudate consisting primarily of neutrophils and cellular debris.


ABSCESS[ localised] PHLEGMON[ diffuse]

DEFINITION: Abscess are localized collection of purulent inflammatory tissue caused by suppuration buried in a tissue, organ or confined space

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

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.

NECROTIZING INFLAMMATION

DEFINITION: Acute inflammation in which tissue necrosis predominates.

Ulcerous necrotizing. Diffuse necrotizing. Gangrenous

TYPES


DEFINITION: Acute inflammation with focal necrosis extending into the submucosa or deeper and covered with fibrinous exudate. eg. ANUG, peptic ulcer

ULCEROUS NECROTIZING INFLAMMATION


DIFFUSE NECROTIZING INFLAMMATION

DEFINITION: Acute inflammation with rapidly spreading necrosis & an ineffective or absent leukocyte reaction. eg. Necrotizing fascitis


GANGRENOUS INFLAMMATION

DEFINITION: Putrid disintegration of necrotizing inflammation due to infestation with anaerobic putrefactive bacteria.


DEFINITION : chronic inflammation is inflammation of prolonged duration (weeks or months) in which active inflammation, tissue destruction, and attempts at repair are proceeding simultaneously.

Chronic nonsuppurative inflammation;

— Chronic suppurative inflammation;

— Granulomatous inflammation

CAUSES

Persistent infections

Prolonged exposure to potentially toxic agents

Autoimmunity

MORPHOLOGIC FEATURES

Mononuclear Cell Infiltration

Macrophages, Lymphocytes & Plasma Cells .

Tissue Destruction

Persistent stimuli or Inflammatory Cells.

Healing By Connective Tissue Replacement

Angiogenesis & Fibrosis.


CHRONIC INFLAMMATORY CELLS

LYMPHOCYTE

EOSINOPHILS

TISSUE MACROPHAGESMAST CELLS

ORIGIN

MONOCYTES & MACROPHAGES

HALF-LIFE

STRUCTURE

CONTENTS

FUNCTION

TYPES

MACROPHAGES

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


TYPES

Kupffer cell (liver)

Microglia (CNS)

Histiocytes (spleen)

Alveolar macs (lung)


ROLES OF ACTIVATED MACROPHAGES


OTHER CELLS IN CHRONIC INFLAMMATION

MAST CELLS

EOSINOPHILS

LYMPHOCYTES


Chronic Nonsuppurative Inflammation

DEFINITION: Chronic inflammation without suppurativetissue liquefaction.


Chronic Suppurative Inflammation

DEFINITION: This may occur as a chronic mucopurulent inflammation or a chronic granulomatous inflammation(a special form of suppurative inflammation).

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



MORPHOLOGIC VARIANTS OF GRANULATING INFLAMMATIONS

— Chronic abscess;— Chronic fistula;— Chronic ulcer.


CHRONIC PERIAPICAL ABSCESS

CHRONIC FISTULA

CHRONIC ORAL ULCER

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.


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.



TUBERCULOUS GRANULOMA

PSEUDOTUBERCULOUS GRANULOMA

SARCOID GRANULOMAS

RHEUMATIC GRANULOMA

RHEUMATOID GRANULOMA

DEFINITION: Large circumscribed granulomas consistingof epithelioid cells with central caseous necrosis and an outer layer of lymphocytic cells.(referred to as a TUBERCLE )


Eg: Tuberculosis Leprosy Syphilis





DEFINITION: Often ill-defined granulomas consisting of macrophages and epithelioid cells with central necrosis with granulocytes.

(Reticocytically absessing granuloma)

eg: Histoplasmosis Cryptococcosis Typhoid fever




DEFINITION: Small granulomas of epithelioid cells (noncaseating epithelioid granulomas) without central necrosis (caseation) and with an outer layer of collagen fibers.

SARCOID GRANULOMAS


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)


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


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


EFFECTS OF INFLAMMATION

LOCAL EFFECTS

SYSTEMIC EFFECTS


LOCAL EFFECTS

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 :

SYSTEMIC EFFECTS IN INFLAMMATION

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)

FEVER

PYROGENS PG synthesis (PGE) in Hypothalamus

Neurotransmitter cAMP

Reset the TEMPERATURE

HIGH-POINT

PYROGENS

EXOGENOUS PYROGENS (Bacterial LPS)

ENDOGENOUS PYROGENS

(Leukocytes→cytokines

→ IL-1, TNF)

ACUTE PHASE PROTEINS

C-reactive protein (CRP) Fibrinogen Serum amyloid A protein

(SAA)

C-reactive protein (CRP) Fibrinogen Serum amyloid A protein

(SAA)

HEPATOCYTES Up regulated by CYTOKINES

IL-6

IL-1/ TNF

CRP & Fibrinogen

+bacterial

CELL WALL

OPSONINS &

fix compliment

FIBRINOGEN

RBC

LEUKOCYTOSIS

15,000 OR 20,000 Cells/pl,

LEUKEMOID REACTON

Prolonged infections

CSF

Proliferation of precursors in the bone marrow

Chills

Rigors

Malaise

Anorexia

Decreased sweating

Increased pulse and blood

pressure

OTHER MANIFESTATIONS OF ‘SIRS / APR’


SOFT TISSUES

HARD TISSUES

ORAL SOFT TISSUE inflammationS

PULPITIS

PERIODONTITIS

RECURRENT APTHOUS ULCERS

ORAL LICHEN PLANUS

ORAL SUBMUCOUS FIBROSIS

ORAL CANCER

ORAL HARD TISSUE inflammationS

ALVEOLITIS

OSTEITIS

OSTEOMYELITIS

ARTHRITIS

MISCELLANEOUS inflammation

FOLLICULITIS

DERMATITIS

RHINITIS

SINUSITIS. . . .

PULPAL & PERIAPICAL INFLAMMATION

PULPAL INFLAMMATION

PULPAL INFLAMMATION

PULPAL INFLAMMATION

PULPAL & PERIAPICAL INFLAMMATION

Focal

Pulpitis

Acute Chronic

Apical Periodontitis

Radicular cyst

Osteomyelitis

Diffuse

PeriostitisAbscess

Cellulitis

Acute

Acute

Chronic

Chronic

Periapical

granuloma

Periapical abscess

PERIODONTAL INFLAMMATION

Infectious Disease – AA , P. Gingivalis , etc

Begins As Gingivitis

Bacterial Plaque – Mediators

MMP’s – collagenase , proteoglycans , etc

PDL Destruction – Immune Response ( Hypersensitivity)





Minor

Major

Herpetiform


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

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

TYPES

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

ORAL LICHEN PLANUS

Erosive lichen planus Bullous lichen planus

Gingival lichen planusScully C, Carrozzo M. British Journal of Oral and Maxillofacial Surgery 46 (2008) 15–21

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

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

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

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



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.



ORAL MUCOSABETEL QUID

HABITCONSTANT IRRITATION

ACTIVATED T-CELL & MACROPHAGES

↑ IL-6, TNF, IF-α, TGF-β

CHRONIC INFLAMMATI

ON

Duration & frequency of the

habit

↑ susceptibility due to Fe+ & Vit B12

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 SOral Oncology 2006:42;561– 568

collagen-related genes CoL1A2, COL3A1,CoL6A1, COL6A3 and COL7A1

(altered- ingredients in the quid)

definite TGF-β targets

Induced in fibroblasts at early stagesof the disease.

may contribute to increasedcollagen levels in OSF


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:


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


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

IMMUNE-MEDIATED SUB-EPITHELIAL BLISTERING DISEASES (IMSEBD)

PEMPHIGUS VULGARIS

Circulating Antibodies Directed Against Desmoglein 3 &

HLA class II alleles

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)

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.


Hematoxylin-eosin, original magnification x 40. Direct immunofluorescencewith 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)

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


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 .

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

ETIOLOGY

70%-80% : HSVOthers includeInfectious agents : Hepatitis viruses(A,B,C), EB virus, Mycoplasma pneumoniae, haemolytic streptococci, rickettsia, coccidiodomycosis, histoplasmosis, TrichomonasImmune conditions : Hepatitis B immunisation, IBD,SLEFood additives or : Benzoates, nitrobenzene, perfumes, terpenesChemicals Drugs : Sulphonamides, Cephalosporins, Aminopenicillins, Oxicam NSAIDs, Anticonvulsants, even corticosteriodsGenetic : 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);67-76Farthing P, Bagan JV, Scully C. Oral Diseases 2005:11;261-267

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

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

HISTOPATHOLOGY OF EM MINOR.

Other inflammatory conditions


Minor

Major

Herpetiform


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

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.


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

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)

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)

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)


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.


ORAL MUCOSABETEL QUID

HABITCONSTANT IRRITATION

ACTIVATED T-CELL & MACROPHAGES

↑ IL-6, TNF, IF-γ, TGF-β

CHRONIC INFLAMMATI

ON

Duration & frequency of the

habit

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 .

IMMUNE-MEDIATED SUB-EPITHELIAL BLISTERING DISEASES (IMSEBD)

PEMPHIGUS VULGARIS

Circulating Antibodies Directed Against Desmoglein 3

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)

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

ETIOLOGY

70%-80% : HSVOthers includeInfectious agents : Hepatitis viruses(A,B,C), EB virus, Mycoplasma pneumoniae, haemolytic streptococci, rickettsia, coccidiodomycosis, histoplasmosis, TrichomonasImmune conditions : Hepatitis B immunisation, IBD,SLEFood additives or : Benzoates, nitrobenzene, perfumes, terpenesChemicals Drugs : Sulphonamides, Cephalosporins, Aminopenicillins, Oxicam NSAIDs, Anticonvulsants, even corticosteriodsGenetic : HLA-B15, HLA-B35, HLA-A33, HLA-DR53, HLA-DQBI*0301 (recurrent) HLA-DQBI*0402 (rare allele associated with extensive mucosal invovement)

ORAL CANCER

Inflammation is the 7th hallmark of cancer

chronic inflammatory infiltrate ( inflammatory cells +cytokines)

characterizingchronic disorders

↓

main cause of Tissuemalignancy

It has been suggested that :

Pathways connectinginflammation & cancers

• 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

The Roles of Tumor-Associated Macrophages in Tumor Progression

ProstaglandinPromotes Cell Growth

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)

Evidence of a COX-2 Dependent Role in NeoplasiaEpidemiological 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 Studiesw Sulindac and other NSAIDs attenuate intestinal tumor and xenografted cancer cell growth in mice.

Cellular Studiesw 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 Modelw Mice defective in COX-2 have a dramatic reduction (86%) in colorectal polyp formation.

COX-2 is Overexpressed

in Multiple Components of

Cancer

CONCLUSION 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.

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

http://www.goodreads.com/author/show/23470.Bill_Gates

PPT Available @http://www.4shared.com/file/0qV66d9k/


Health & Medicine

Inflammation Seminar by Dr Pratik