Inflammation Seminar by Dr Pratik

Good
Morning….
Presented by
- Dr Pratik Pipalia, CODS, DVG

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

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

INTRODUCTION
HISTORY
DEFINITION
CAUSES
CARDINAL SIGNS OF INFLAMMATION
TYPES OF INFLAMMATORY REACTIONS

ACUTE INFLAMMATION
VASCULAR EVENTS
CELLULAR EVENTS
CHEMICAL MEDIATORS OF INFLAMMATION

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

SUMMARY OF MEDIATORS OF INFLAMMATION
INFLAMMATORY CELLS
OUTCOMES IN INFLAMMATION
EVENTS IN THE RESOLUTION OF
INFLAMMATION
CHRONIC INFLAMMATION
APPLIED ASPECTS

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
ed, Vol 2,2009

LYMPHATIC
CAPPILLARIES
LYMPHATIC
VESSELS
LYMPH NODES
LYMPH TRUNKS
ed, Vol 2,2009

ed, Vol 2,2009

LEFT JUGULAR
TRUNK
RIGHT JUGULAR
TRUNK
LEFT
SUBCLAVIAN
TRUNK
RIGHT SUBCLAVIAN
TRUNK
THORACIC (left
lymphatic)
DUCT
LYMPHATIC DUCT
SUPERIOR VENECAVA
ed, Vol 2,2009

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 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

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

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 Metchinikoff
theory of immunity
Thomas Lewis
demonstrated 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 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

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

ACUTE
INFLAMMATION
CHRONIC
INFLAMMATION
CLASSIFICATION OF INFLAMMATION

SEROUS
FIBRINOUS
CATARRHAL
HAEMORRAGIC
PURULENT
ACUTE
INFLAMMATION
Reide & Werner, Color Atlas of Pathology,, 2005

CHRONIC
INFLAMMATION
DIFFUSE
SUPPURATIVE
GRANULOMATOUS
FIBRINOID

Rubbin R, Strayer D; Rubbin’s Pathology, clinicopathologic foundation of medicine,2005, 5th 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
toxins
Fungi
Animal parasites
Necrosis of tissue
Allergy
Living

CARDINAL SIGNS OF INFLAMMATION
Riede & Werner, Color Atlas of Pathology , 2004

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.

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

VASOCONSTRICTION

VASODIALATION

SLOWING DOWN OF CIRCULATION AND INCREASED PERMEABILITY OF
MICROVASCULATURE

CHANGES IN VASCULAR PERMEABILITY
INCREASED
NORMAL

NORMAL MICROCIRCULATORY CONTROL
NORMAL PERMEABILITY & STRUCTURE OF
MICROCIRCULATION

NORMAL MICROCIRCULATORY CONTROL
SYSTEMIC
FACTORS
LOCAL
FACTORS

NORMAL PERMEABILITY & STRUCTURE OF
MICROCIRCULATION

OUTWARD
MOVEMENT
OF FLUID
INWARD
MOVEMENT
OF FLUID
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
INWARD
MOVEMENT 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

MARGINATION
, ROLLING &
ADHESION
EMIGRATION
& DIAPEDESIS
CHEMOTAXIS

NORMAL AXIAL FLOW

MARGINATION & PAVEMENTING
Harsh mohan, essentials of pathology for dental students,2005,3rd edition
Riede & Werner, Color Atlas of Pathology , 2004 Thieme

ADHESION

EMIGRATION AND DIAPEDESIS

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

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

CHEMO
ATTRACTANT
EXOGENOUS ENDOGENOUS

 Exogenous Agents – Bacterial Products
 Endogenous Agents

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
DEGRADATION
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

RECOGNITION & ATTACHMENT
ENGULFMENT

RECEPTORS FOR OPSONINS
Promotes phagocytosis
Opsonization
Opsonins
Antibodies, Complement Proteins , Lectins.

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

SUMMARY OF MEDIATORS OF
INFLAMMATION
OUTCOMES IN INFLAMMATION
EVENTS IN THE RESOLUTION
OF INFLAMMATION
CHRONIC INFLAMMATION
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
Tortora GJ, Derickson BH, Principles of anatomy and physiology,12th ed, Vol 2,2009

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
ed, Vol 2,2009

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
ed, Vol 2,2009

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

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
ed, Vol 2,2009

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
ed, Vol 2,2009

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 gaps
Richest source - mast
cells Granules
Also found in basophils
& platelets
HISTAMINE
Rubin E, Farber JL, Essential Pathology, 1990, 1st Edition

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

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

Arachidonic Acid
Leukotrienes
LTC4, D4, E4
Cyclooxygenase5-Lipoxygenase
Prostaglandins
Prostacyclins
Cell Damage
Cell Membrane
Phospholipids

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

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)

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
Myeloperoxidase
Lysozymes
Defensins
Bactericidal permeability
increasing proteins
Elastase
Cathepsin protease3
Glucoronidase
Mannosidase
Phospolipase

NEUTROPHIL
Lysozymes
Collagenase
Lactoferrin
Histaminase
Plasminogen activator
FMLP receptors
C3b proteins

GRANULES
EXTRA CELLULAR
SPACE
VACUOLES
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-antitrypsin
Macroglobulin)

• GENETIC
DEFECIENCIES
• DEFECTS IN
LEUKOCYTE
FUNCTION
LEUKOCYTES
APPLIED ASPECTS

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

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

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

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

NEUROPEPTIDES
- substance P
- neurokinin

OTHER MEDIATORS
HYPOXIA INDUCED FACTOR la
URIC ACID

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

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
• 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

COMPLIMENT
CLOTTINGKININ

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

RESULTS OF COMPLEMENT ACTIVATION
Tortora GJ, Derickson BH, Principles of anatomy and physiology,
12th ed, Vol 2,2009

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

CLOTTING SYSTEM
EXTRINSIC PATHWAY INTRINSIC PATHWAY

MOST LIKELY MEDIATORS OF INFLAMMATION

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

• INF-1, TNF
• PROSTAGLANDINS
FEVER
• PROSTAGLANDINS
• BRADYKININ
PAIN
• NEUTROPHIL & MACROPHAGE LYSOSOMAL ENZYME
• OXYGEN METABOLITES
TISSUE DAMAGE

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
:
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 : 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
T
Y
P
E
S

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

CAUSE
S
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.

LYMPHOCYTE
EOSINOPHILS
TISSUE MACROPHAGES
MAST CELLS

ORIGIN
MONOCYTES & MACROPHAGES
HALF-LIFE
STRUCTURE
CONTENTS
FUNCTION
TYPES

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

ROLES OF ACTIVATED MACROPHAGES

OTHER CELLS IN CHRONIC INFLAMMATION

Chronic Nonsuppurative Inflammation
DEFINITION: Chronic inflammation without suppurative
tissue 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.

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 consisting
of 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

LOCAL EFFECTS
SYSTEMIC 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
Reset the
TEMPERATURE HIGH-POINT

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

CRP & Fibrinogen +
FIBRINOGEN
RBC

LEUKOCYTOSIS
15,000 OR 20,000 Cells/pl,
LEUKEMOID REACTON
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 & PERIAPICAL INFLAMMATION
Focal
Pulpitis
Acute Chronic
Apical Periodontitis
Radicular cyst
Osteomyelitis
Diffuse
Periostitis
AbscessCellulitis
Acute
Acute
Chronic
Chronic
Periapical
granuloma
Periapical
abscess

Infectious Disease – AA , P. Gingivalis , etc
Begins As Gingivitis
Bacterial Plaque – Mediators
MMP’s – collagenase , proteoglycans , etc
PDL Destruction – Immune Response ( Hypersensitivity)
PERIODONTAL INFLAMMATION

 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
T
Y
P
E
S

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 planus

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)

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 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

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

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

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 immunofluorescence
with salt split, revealing monoclonal IgG4 deposits, under fluorescent
microscope, on the epithelial side of separation in A1 A2

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% : 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

IFN-γ tissue damage (Kokuba et al,1999)
expression correlates with HSV-protein expression

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

 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 MUCOSA BETEL QUID HABIT
CONSTANT
IRRITATION
ACTIVATED T-CELL &
MACROPHAGES
↑ IL-6, TNF, IF-γ, TGF-β
CHRONIC
INFLAMMATION
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

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)

Inflammation is the 7th hallmark of
cancer

chronic inflammatory infiltrate
( inflammatory cells +cytokines)
characterizing
chronic disorders
↓
main cause of Tissue
malignancy
It has been suggested that :

Pathways connecting
inflammation & 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

Prostaglandin
Promotes 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 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.

COX-2 is
Overexpressed
in Multiple
Components of
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.

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

Inflammation Seminar by Dr Pratik

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