Inflammation / dental courses

INFLAMMATION
Enflammare
Set a fire
INDIAN DENTAL ACADEMY
Leader in continuing Dental Education
www.indiandentalacademy.com

1. INTRODUCTION
2. HISTORY
3. CAUSES
4. CARDINAL SIGNS
5. TYPES OF INFLAMMATION
6. ACUTE INFLAMMATION
VASCULAR EVENTS
CELLULAR EVENTS

7. CHEMICAL MEDIATORS
8. MORPHOLOGICAL PATTERNS OF
ACUTE INFLAMMATION
9. CHRONIC INFLAMMATION
10. SYSTEMIC EFFECTS OF
INFLAMMATION
11.REGULATORS OF INFLAMMATION
12. FACTORS DETERMINIG VARIATIONS
IN RESPONSE

Introduction
Defined as
“Local response of living tissues to injury due
to any agent”
 Fundamentally protective response
 Ultimate goal is to get rid of intial cause cell
injury(microbes, toxins)
 Consequence of such injury(necrosis, tissues)
 without inflammation wounds go unchecked, never
heal

HISTORICAL HIGHLIGHTS
3000B.C Egyptians first described
1st century Celsus described cardinal signs
1793 John hunter inflammation not
disease, non specific response
that has salutary effect on host
1839 Conheihm used microscope to
observe changes in vessels

1880 Metchinkoff discovered phagocytosis
Paul ehrlich proposed humoral theory
of immunity
1908 Both got nobel prize
1924 Lewis explained role of chemical
mediators in inflammation

Pioneers of inflammation

EVOLUTION OF INFLAMMATION
Sponges , coelenterates body cavity is filled
with coelum, cells are called coelomocytes
Mollusca , urochordates body cavity is filled
With hemocele, cells are hemocytes
Amebocytes are seen in urochordates

Invertebrates respond to local injury by
Phagocytosis
Encapsulation(similar to granuloma formation)
Neutralization of noxious stimuli by hypertrophy of
cells
Chemical mediators are also seen in some
invertebrates
A F Rowley The evolution of inflammation ; journal of
inflammation vol-5 1996

CAUSES OF INFLAMMATION
LIVING
Bacteria
Viruses
Mycoplasma
Fungi
Protozoa
Parasites

Non living
Trauma - osteomyelitis Heat – burns
Ionizing radiation Uv light, infared
Chemicals , acids, alkalies Foreign body
Idiopathic

GENETIC VARIATIONS
Variations in inherited genes can place them
at risk/ predispose them to inflammatory Disease.
These usually don’t cause disease by themselves
Unless they are challenged by particular trigger

CARDINAL SIGNS OF
INFLAMMATION
Celsus (1St century)
1. RUBOR - redness
2. TUMOR - swelling
3. CALOR - heat
4. DOLOR - pain

FUNCTIO LAESA – loss of function (later added
by galen and virchow in 3rd century)

Rubor
Redness is due to
VASODILATION (DUE TO RELEASE OF MEDIATORS)
INCREASED BLOOD SUPPLY
TRIPLE RESPONSE OF LEWIS(1924)

RED LINE APPEARS IN A
FEW SECONDS
DUE TO VASODILATION OF
CAPILLARIE AND VENULE
FLARE
FLUSH AROUND
RED LINE
APPEARS SLOWLY DUE TO AXON REFLEX
CAUSING DILATION OF
ADJACENT ARTERIOLES
WHEAL
SWELLING
OEDEMA
APPEARS IN MINUTES DUE TO TRANSUDATION OF
FLUID INTO EXTRA VASCULAR
SPACE

CALOR
Due to increase in blood supply
Due to increase in metabolic activity in that area
Appreciation of heat is possible in superficial areas
with heat receptors… e.g : skin subcutaneous tissues
In deeper organs although associated with heat
in the area , it is not associated with perception of
increased heat

Due to release of mediators which stimulate nerve
endings
Occurs only when appropriate sensory N. endings
exists in inflamed area
Type of pain depends on extent of stimulus rather
than type of causative agent

REFERRED PAIN:
 Due to spread of pain stimuli along the
nerves to relevant spinal segment and relay of
pain sensation to other areas served by same
segmental distribution
 E.g Pain of myocardial ischemia referred to
left shoulder

PAIN CAUSED BY
INFLAMMATION OF
CHARACTER
SKIN BURNING , ITCHING
DENSE TISSUES LIKE PERITONIUM
BONE , ENCAPSULATED ORGANS DULL , BORING , ACHING
PROGRESSED TO SUPPURATION THROBBING
PUS REACHES TO SURFACE SHARP , DARTING ,LANCINATING
NERVE TRUNK BORING , TINGLING

TUMOR/SWELLING
Due to increased vascularity
Accumulation of fluid and cells in damaged part
EDEMA- Excess fluid in interstitial / serous cavities
it may be exudate / transudate in nature
PUS: Purulent exudate rich in leukocytes(mostly
neutrophils), debris of dead cells and in many cases
microbes

EXUDATE TRANSUDATE
Edema of inflammed tissues
due to alteration in normal permeability
of small bvs
Ultrafiltrate of blood plasma that results from
osmotic/hydrostatic imbalance across the
vessel wall
Inflammatory edema Non inflammatory edema
High protein(2.5-3.5g/dl) readily coagulates
due to high fibrinogen
Low protein (>1g/dl)mainly albumin
low fibrinogen, no tendency to coagulate
Specific gravity >1.018
ph <7.3
Specific gravity low<1.015
ph>7.3
Glucose is low(<60mg/dl) same as plasma
LDH is high LDH is low
Many cells, inflammatory , parenchymal cells Few cells mainly mesothelial cells and cellular
debris
e.g: purulent exudate such as pus Edema in congestive cardiac failurewww.indiandentalacademy.com

TYPES OF INFLAMMATION
Acute inflammation
Rapid response to an injurious agent that serves to
deliver mediators of host defense , leukocytes and
plasma proteins to the site of injury
Chronic inflammation
Inflammation of prolonged duration in which active
inflammation, tissue destruction, and attempts at
repair are proceeding simultaneously

ACUTE CHRONIC
ONSET IMMEDIATE DELAYED
DURATION FEW DAYS UPTO MONTHS, YEARS
CAUSATIVE AGENTS
BACTERIA
INJURED TISSUES
PERSISTENT ACUTE ,
FOREIGN BODY , VIRAL
AUTOIMMUNE
MAJOR CELLS
NEUTROPHILS ,BASOPHILS
MONOCYTESMACROPHAGES
MONONUCLEAR CELLS
MONO,LYMHPHOCYTES
PLASMA CELLS
FIBROBLASTS
PRIMARY
MEDIATORS
VASOACTIVE AMINES EICOSANOIDS
OUTCOMES
RESOLUTION
ABSCESS FORMATION
CHRONIC INFLAMMATION
TISSUE DESTRUCTION
FIBROSIS
NECROSISwww.indiandentalacademy.com

ACUTE
INFLAMMATION
VASCULAR
HEMODYNAMIC
CHANGES
ALTERED
VASCULAR
PERMEABILITY
CELLULAR
EXUDATION PHAGOCYTOSIS

INJURY
TRANSIENT
VAOCONSTRICTI
ON
MILD
3-5SECONDS
SEVERE
5MINUTES
HEMO
DYNAMIC
CHANGES
PERSISTENT
PROGRESIVE
VASODILATION
INCREASED
BLOOD
VOLUME
LOCAL
ELEVATION OF
HYDROSTATIC
PRESSURE
red heat edema

Five mechanisms of increased vascular
permeability
Venules,vasoactiv
mediators
Imm transient
Venules
IL-1, TNF
DELAYED
Persists till
intercellular
junction
forms
Toxins
Chemicals
Imm,
sustained

1.Mediators bind to endothelium
 Activates intracellular signaling pathways
 Lead to phosphorylation of contractile proteins like
myosin
 Imm…….15 to 30 minutes……..so transient
2.Cytokines cause structural reorganisation of
cytoskeleton causing retraction
3. Direct injury……….sustained…….till vessel wall
repaired
4. Neutrophils while migrating secrete proteases, ros

 In places like bbb tight junctions exisist
between endothelial cells
 Cell cytoplasm communicates with exterior
through a process called transcytosis
 Vesicles are formed from cytoplasm
 Called vesiculovacular organelle
 In infl……inc VDGF..............inc in no these
channels…..leadin to inc vas.perm

INCREASED
VASCULAR
PERMEABILITY
ESCAPE
OF
PROTEINS
FLUID
DECREASE
INTRAVAS
CULAR
OSMOTIC
PRESSURE
INCREASED
OSMOTIC
PRESSURE OF
INTERSTITIAL
FLUID
OUT
FLOW
OF FLUID
INCREASED
CONCENTRATION
OF BLOOD CELLS
RAISED
VISCOSITY
SLOWING
STASIS

CELLULAR EVENTS
EXUDATION
The escape of fluid, protein, and blood cells from
vascular system into interstitial tissue/body cavities
Changes leading to migration are
Changes in formed elements of blood
Rolling and Adhesion ,Emigration
Chemotaxis

NORMAL
AXIAL FLOW
• RBC , WBC in the centre
• Peripheral zone of plasma
INFLAMMATION
• Leakage of plasma-narrowing of peripheral zone
• Redistribution of leukocytes to periphery-
MARGINATION
EMIGRATION
• Endothelium is virtually lined by leukocytes –pavementing
• Tumble slowly , adhere transiently –ROLLING ADHESION
• After firm adhesion leukocytes insert pseudopods into
intercellular junctions and escape into extra vascular space

ADHESION MOLECULES INVOLVED IN INFLAMMATION
SELECTINS
3 closely related proteins( P, E , L) function in adhesion
They differ in their cellular distribution
L-SELECTIN/CD62L
Expressed in lymphocytes/other leukocytes
Founds on tips of microvillus projection of leukocytes
Facilitating it interaction with ligands on endothelium

E-SELECTIN
Previously know as endothelial leukocyte
adhesion molecule
Expressed on cytokine activated endothelial cells
P-SELECTIN
Present on secretory granules of platelets
also found in granules of endothelial cells

INTEGRINS
30 structurally homologus proteins
promote cell-cell/cell-matrix interactions
IMMUNOGLOBULIN SUPER FAMILY ADHESION
MOLECULES
ICAM VCAM
Leukocytes express CHOligands for selectins, integrins
These are low affinity reactions
Fast off rate…easily disrupt by flowing blood
As a result bound WBC detach and bind again
roll along endothelial surface

ENDOTHELIAL
MOLECULE
LEUKOCYTE RECEPTOR ROLE
P-SELECTIN SIALYL-LEWIS X ROLLING
E-SELECTIN SIALYL –LEWIS X ROLLING ,ADHESION
ICAM-1 CD 11/CD18 INTEGRINS ADHESION,
TRANSMIGRATION
VCAM-1 ALPHA 4, BETA 1 ADHESION

CHEMOTAXIS
Locomotion oriented along a chemical gradient
Chemokines acts chemoattractants for specific leukocytes
C-X-C Chemokine / alpha chemokine NEUTROPHILS
C-C Chemokine/beta chemokine
Acts On Eosinophils, Basophils, Monocytes, Lymphocytes
e.g: MCP, EOTAXIN
C-Chemokine/gamma LYMPHOCYTES

Chemokines mediate their activities by binding to
seven transmembrane coupled receptor
Receptors are CXCR, CCR, CR
(CXCR-4, CCR-5 act as co receptor for viral envelope
glycoprotein of HIV and thus are involved in entry
and binding of virus)
chemokines stimulate leukocyte recruitment
and control normal migration of cells through various
tissues

Leukocyte activation
Once recruited to site of injury, they must be activated
Stimuli are
 Microbes, Necrotic cells
 Ag-Ab complex
 cytokines
Leukocytes express a number of receptors
on their surface
 Toll like receptors – recognize LPS
 Cytokine receptor

leukocyte activation

PHAGOCYTOSIS
DEFINED AS
Process of engulfment of solid
particulate material by cells
Steps involved are
Recognition and attachment stage
Engulfment stage
Digestion/degradation stage

RECOGNITION AND ATTACHMENT
The process of coating a particle , such as
microbe to target it for phagocytosis is called
OPSONISATION
substances are called opsonins
Main opsonin present in serum are
IGg opsonin(Fc) PMN possess receptor
C3b opsonin

• Tuftsin is a phagocyte enhancing material in serum
• Acts directly on cell to stimulate phagocytosis
• 2 types of disorders
1. congenital an abnormal peptide competitively inhibit
2.deficiency seen in splenectomy
• Due to lack of tuftesin releasing enzyme from spleen.

Engulfment
This is accomplished by formation of pseudopod
around particle due to actin filament beneath cellwall
Eventually complete closure of particle with in a
phagosome created by plasma membrane
Limiting membrane of phagocytic vacuole fuses with
Lysosome - phagolysosome

Oxygen
dependent
Reactive
metabolites
Oxygen
independent
granules of
phagocytic cell
Killing
degrading
Nitric oxide

Oxygen dependent
By production of reactive oxygen metabolites
HOCl , HOI , HOBR , HYDROGEN PEROXIDE, HYDROXYL
NADPH OXIDASE present in cell membrane of
phagosome reduces it to superoxide anion

MPO dependent killing
 MPO acts on hydrogen peroxide in presence of
halides to form hypohalous acid
 This is more potent antibacterial agent

MPO independent killing
 Mature macrophages lack MPO
 They carry out bactericidal actions by
forming hydroxyl ions

Oxygen independent
 Agents released from phagocytic cells
donot require oxygen
 These include
Lysosomal hydrolases
Permeability increasing factors
Defensins
Cationic proteins

Chemical mediators of inflammation

Chemical Mediator Of Inflammation
• Also called permeability factors
• Induce their action by binding to specific
receptors on target cells
• Stimulate target cell to release secondary
effector molecules
Two types:
1. Cell derived
2. Plasma derived

VASOACTIVE
AMINES
ARACHIDONIC
ACID
METABOLITES
LYSOSOMAL
COMPONENTS
PAF
CYTOKINES
NITRIC
OXIDE
CELL
DERIVED
MEDIATORS
Platelets
Neutrophils
Monocytes
Endothelium
Fibroblast
Smooth muscle

Histamine
 First autacoid to be discovered
 Formed from histidine by decarboxylation
 Synthesized in all tissues
 More in skin , lungs , GIT
 Stored in high concentration in mast cells and
basophils
 Involved in inflammation and anaphylactic reactions

HISTAMINE RECEPTORS
RECEPTOR TYPE LOCATION
BIOLOGICAL
EFFECTS
H1 SMOOTH MUSCLE
ENDOTHELIAL CELLS
VD, BRONCHOCONSTRICTION,
ACUTE ALLERGIC RESPONSE
H2 GASTRIC PARIETAL CELLS VD , SECRETION OF GASTRIC
ACID
H3 CNS NEUROTRANSMISSION
MODULATE WAKEFULLNESS
COGNITIVE ABILITY
FOOD CONSUMPTION
H4 MAST CELLS
EOSINOPHILS
T-CELLS
DENDRITIC CELLS
REGULATE IMMUNE
RESPONSE
ROLE IN CHEMOTAXIS

Exocrine glands
salivary , sweat
lacrimal , bronchial secretion
pancreas , gastric
Arterioles , capillaries , venules
Vasodilation , systemic hypotension
Increased permeability(edema)
smooth muscle
Bronchus , uterus, contraction
GIT

Screen clipping taken: 1/5/2013, 7:29 PM

HISTAMINE ANTAGONISTS/ ANTI HISTAMINES
Bovet got nobel prize in 1944
Inhibit action of histamine by blocking receptor
Inhibit enzyme histidine decarboxylase
(atypical antihistamines)
H1 ANTAGONISTS: USED TO TREAT ALLERGY
First generation second generation
Chlorpheneramine Fexofenadine
Diphenhydramine Loratidine
Promethazine, hydroxyzine Levo Cetrizine

serotonin
 Also called 5-hydroxytryptamine(5HT)
 Formed from L-Tryptophan
 Present in platelets and enterochromaffin cells
 Actions are similar to histamine
 Vaso constrictor

ARACHIDONIC ACID METABOLITES
 20 CARBON PUFA
 Derived from dietary source
 Conversion of linoleic acid
 Does not occur freely in cell but esterified
in membrane phospholipids

Phospholipase
A2

Cell membrane
phospholipids
Arachidonic acid
PGD2,PGE2,PGF2
PROSTACYCLIN
PGI2
THROMBOXANE
TXA2
PGG2
PGH2+FREE
RADICALS
PHOSPHO
LIPASE A2
Calcium
Various
kinases
Cycloo
oxygenase
Vd
Inhibit
platelet
aggregation
Vasoconstriction
Promotes
aggregation
Vasodilation
Potentiates
edema
Cyclooxygenase
pathway

ARACHIDONIC
ACID
5-HYDROPEROXYEICOSATETRAENOIC ACID
5-HPETE
LEUKOTRIENE A4
LEUKOTRIENE
C4,D4,E4
LEUKOTRIENE
B4
LIPOXIN
A4
LIPOXIN B4
12 LIPO
OXYGENASE
55 LIPO
OXYGEN
ASE
CHEMOTAXIS
5-HETE
VASO,
BRONCHO
CONSTRICTION
INC
PERMEABILITY
CHEMOTAXIS
CELL
ADHESION
VD
Inhibits
CHEMOTAXIS
LIPOOXYGENASE
PATHWAY

MYELOPEROXIDASE
ACID HYDROLASE
NEUTRAL PROTEASE
ELASTASE PROTEINASE
CATHEPSIN
NON SP COLLAGENASE
LYSOZYME
LACTOFERRIN
COLLAGENASE
GELATINASE
HISTAMINASE
PLASMINOGEN
ACTIVATOR
ALKALINE PHOSPHATASE
SMALLER
SPECIFIC
SECONDARY
LARGER
AZUROPHILIC
PRIMARY
LYSOSOMAL COMPONENTS

 Neutral proteases are capable of degrading
various extracellular component
 Collagen, Basement membrane,
 Fibrin, Elastin, Cartilage
 Also cleave C3 and C5 directly releasing
anaphylotoxins
 This results in tissue destruction
Because of its destructive effects ,if initial
leukocyte infiltration if left unchecked results in
tissue damage

PLATELET ACTIVATING FACTOR

IL-1
TNF
ENDOTHELIAL
INCREASED
LEUKOCYTE
ADHERENCE
PGI SYNTHESIS
PROCOAGULANT
ACTIVITY
LEUKOCYTE
EFFECTS
INCREASED
CYTOKINE
SECRETION
IL-1 AND 6
FEVER
INCREASED
SLEEP,ACUTEPHASE
PROTEINS
DECREASED APETITE
NEUTROPHILIA
FIBROBLASTS
INCREASED
PROLIFERATION,
COLLAGEN,PROTEASE
PGE SYNTHESIS

NITRIC OXIDE METABOLITES
 Factor released from ENDOTHELIAL CELLS
 Also called ENDOTHELIAL DERIVED RELAXING
FACTOR
 Also from MACROPHAGES and NEURONS in brain
 Synthesized from L-ARGININE by enzyme
nitric oxide synthetase(NOS)
3 types
eNOS endothelial produced at low levels
nNOS neuronal calcium influx cause rapid production
iNOS inducible (cytokines)

ROLE IN INFLAMMATION
 Potent vasodilator
 Reduces platelet aggregation
 Reduce leukocyte adhesion
 Inhibit several features of mast cell
induced inflammation
 Endogenous regulator for leukocyte recruitment
 No and its derivatives are microbicidal
NO is an endogenous compensatory mechanism
that reduces inflammatory response

kinin
clotting
Fibrino
lytic
comple
ment
PLASMA
DERIVED

COMPLEMENT SYSTEM
 Consists of 20 component proteins and
their cleavage products
 Found in plasma
 Function in both innate and adaptive immunity
 In process of complement activation a number
of components are elaborated that cause
- Increased vascular permeability
- Chemotaxis
- Opsonisation

C3a and C5a
 Stimulate histamine release
 Anaphylotoxins
 They have effects similar to mast cell mediators
C5a
 Activates LOX pathway
 Powerful chemotactic agent
 Role in leukocyte adhesion
C3b
 Acts as opsonin

REGULATION OF COMPLEMENT ACTIVATION
The activation of complement is controlled by
cell associated and circulatory regulatory proteins
Regulation of C3 and C5convertase
 Regulators function by enhancing dissociation
of convertase complex
 E.g: decay accelerating factor
 Proteolytic cleaving of C3b

Binding of active complement components by
specific proteins in plasma
 C1 binding to immune complex is blocked by
C1 INHIBITOR(C1INH)
 Deficiency of C1INH is associated with
HERIDITARY ANGIONEUROTIC EDEMA
Episodic edema in skin, extremities, laryngeal
and intestinal mucosa provoked by stress/trauma

KININ SYSTEM
Hageman factor [XII]
Activated Hageman Factor [XIIa]
prekallikrein activator (fragment of XIIa)
Plasmakallikrein Kallikrein
HMW Kininogen Bradykinin
Contact with
-ve charged
Collagen,Basement
membrane
cofactor for
Activation of
XII
chemotaxis
C5 to C5a

BRADYKININ
 Potent vasodilator
 Increases vascular permeability( lower BP)
 Causes constriction of smooth muscles
 Pain
 But the actions are short lived
 As it is quickly inactivated by kininase
 Any remaining kinin is inactivated by passage of
plasma through lung (degraded by ACE)
SO ACE INHIBITORS PREVENTS
DEGRADATION THERE BY FURTHER LOWERING BP

Ca
PL

FACTOR XIIa
PRE KALLIKREIN KALLIKREIN
PLASMINOGEN PLASMIN FIBRIN FIBRINOGEN
THROMBIN
C3 C3a
KININ
SYSTEM
COMPLEMENT
CLOTTING
SYSTEM
FIBRINOLYTIC
SYSTEM

FACTOR 1 FIBRINOGEN
FACTOR 2 PROTHROMBIN
FACTOR 3 TISSUE FACTOR/ thromboplastin
FACTOR 4 CALCIUM
FACTOR 5 PROACCELERIN
HMW KININOGEN FITZ GERALD FACTOR
FACTOR 7 PRO CONVERTIN /STABLE FACTOR
SERUM PROTHROMBIN CONVERSION
ACCELERATOR
FACTOR 8 ANTI HEMOPHILIC FACTOR/AHFA
FACTOR 9 PLAS.THROMBOPLASTIN COMP
CHRISTMAS FACTOR / AHB
FACTOR 10 STUART / PROWER
FACTOR 11 PLASMA THROMBOPLASTIN ANTECEDENT
FACTOR 12 HAGEMAN FACTOR
FACTOR 13 FIBRIN STABILISING FACTOR
PRE KALLIKREIN FLETCHER FACTORwww.indiandentalacademy.com

Morphological patterns of acute inflammation
Serous inflammation
 Marked by outpouring of thin fluid
 Derived either from plasma
 Or secretions of mesothelial cells
lining peritoneal, pleural, pericardial cavities
 E.g: skin blister resulting from burn
viral infection causing fluid accumulation
either within or immediately beneath epidermis

Fibrinous inflammation
 Due increased permeability, severe injury large
molecules such as fibrinogen pass vascular barrier
 Fibrin is formed and deposited in extracellular space
 Fibrinous exudates are removed by fibrinolysis,
clearing of debris by macrophages
 If it is not removed it may stimulate ingrowth of
fibroblasts, blood vessels leading to scarring

Suppurative/purulent inflammation
 Characterised by formation of pus
 An accumulation of pus in enclosed
tissue spaces - ABSCESS
 Certain bacteria like staphylococci
produce this localised suppuration
 E.G: Brain abscess
Pyelo nephritis

ULCER
 Is A Break In Continuity Of
Epithelium Due To Necrosis Or
Pathologic Death Of Tissues
Extending Into Submucosa
 Common sites are mucosa of mouth, stomach
 In acute stage infiltration with polymorphs is seen
 In chronic ulcers infiltration by plasma cells,
lymphocytes, macrophages associated with
fibroblastic proliferation

Microbes
Toxins
trauma
ACUTE
INFLAMMATION
RESOLUTION
Clearance of injurious stimuli
, mediators
Replacement of injured cells
Normal function
PROGRESS
HEALING
HEALING
FIBROSIS
Loss of function
LOCALISATION
abscess
HEALING
Chronic inflammation
Angiogenesis
Mononuclear cell
infiltrate
Viral
infections
Persistent injury
Autoimmune
diseases
outcomes

CHRONIC INFLAMMATION
Chronic inflammation is of prolonged
duration(weeks/ months) in which active
inflammation, tissue destruction, and
attempts to repair are proceeding
simultaneously….

CAUSES
1.Persistent infections
 By tubercle bacilli, certain virus, fungi
 These organisms are of low toxicity
 Evoke an immune reaction called
delayed type of hypersensitivity
 Leading to formation of a granuloma

Macrophages
Dendritic cells
critical for induction
of t-h cells
IL-
12
IF
IF-Y
ACTIVATES
MACROPHAGES
CAUSE RELEASE
OF PDGF
FIBROSIS
MECHANISM OF TYPE IV HYPERSENSITIVITY IN FORMATION OF
GRANULOMA

• Antigen binding to mannose receptor(mhc) on
surface of macrophage
• This act as antigen presenting cell
• Ag bearing macrophage(icam-1) interacts with
receptor on t-cells(cd11a cd2)
• Helper t cells - MHC CLASS II
• Cytotoxic t cells – MHC CLASS I

2. Prolonged exposure to potentially toxic agents
Either Exogenous/ Endogenous
 Exogenous : Silica when inhaled for prolonged
periods, results in inflammatory lung disease
SILICOSIS
 Endogenous : Toxic plasma lipid components lead
to inflammatory process of arterial wall
ATHEROSCLEROSIS

3. AUTO IMMUNITY
 Immune reactions develop against individuals own
tissues
 Autoantigens evoke a self perpetuating immune
reaction that results in chronic tissue damage and
inflammation
 E.g: Rheumatoid arthritis
Systemic lupus erythematosus

ROLE OF INFLAMMATION IN AUTOIMMUNITY

Chronic inflammation is characterised by
1. Infiltration with mononuclear cells which include
macrophages, lymphocytes, plasma cells
2. Tissue destruction induced by persistent offending
agent or by inflammatory cells
3. Attempts at healing by connective tissue
replacement of damaged tissue
accomplished by proliferation of blood
vessels (angiogenesis), fibrosis

Mononuclear cell infiltration
 Macrophage is dominant cell in chronic inflammation
 It is component of mononuclear phagocyte
system(MPS)
 Previously called reticuloendothelial system
 Comprises blood monocytes, tissue macrophages
 Half life of blood monocyte is about 1day
 Tissue macrophage is several months to years

Connective tissue(histiocytes)
Spleen(sinusoidal lining cells)
Serous cavity(peritoneal pleural)
Skin(langerhans cells)
Synovia(A cells)
INFLAMMATION
Exudate macrophages
Epitheloid cells
Multi nucleated giant cells

MECHANISM OF MACROPHAGE ACCUMULATION IN
TISSUES ,CONTINUOUS RECRUITMENT FROM
MICROCIRCULATION
STIMULI ARE
CHEMOKINES BY
ACTIVATED
MACROPHAGES
LYMPHOCYTE
MCP-1
C5a
PDGF
TGF-ALPHA
FRAGMENTS FROM
BROKEN COLLAGEN
FIBRONECTIN
CYTOKINES
OXIDISED
LIPIDS

Other cells in chronic inflammation are
 Lymphocytes, plasma cells, eosinophils and mast
cells
 LYMPHOCYTES are involved in both types of immune
reactions(humoral , cell mediated)
 Lymphocytes(B, T) use various adhesion molecules
and chemokines to migrate in to inflammatory sites
 Lymphocytes , macrophages interact in a
bidirectional way

 Microbial ag should be recognised as non self
 This require immunological memory and specificity
 This property resides in lymphocytes

EOSINOPHILS
 Abundant in immune reactions mediated by IgE
 And in parasitic infections
Granules contain major basic protein
 A highly cationic protein toxic to parasites
 Also causes lysis of mammalian epithelial cells

MAST CELLS
 Basophils in tissues
 Participate in both acute and chronic
 Express on their surface receptors
which bind to Fc portion of IgE
 Degranulation cause release of mediators such as
histamine, PAF, eicosanoids, neutral proteases

TYPES OF CHRONIC INFLAMMATION
 When injurious agent causes a characteristic
histological tissue response – SPECIFIC
 E.g: TB , Leprosy
 Histologically characterized by granuloma formation
 when irritant produces a non specific inflammatory
reaction with formation of granulation tissue and
healing by fibrosis – NON SPECIFIC
 E.g: chronic osteomyelitis , ulcer
 Histologically Non specific cell infiltration

GRANULOMATOUS INFLAMMATION
GRANULOMA IS A FOCUS OF CHRONIC
INFLAMMATION CONSISTING OF MICROSCOPIC
AGGREGATION OF MACROPHAGES THAT ARE
TRANSFORMED INTO EPITHELIUM LIKE CELLS
SURROUNDED BY A COLLAR OF MONONUCLEAR
LEUKOCYTES , PRINCIPALLY LYMPHOCYTES ,
OCCASIONAL PLASMA CELLS

BACTERIAL
TB LEPROSY
SYPHILITIC GUMMA
FUNGAL
HISTOPLASMOSIS
BLASTOMYCOSIS
CRYPTOCOCCUS
PARASITIC
SCHISTOSOMIASIS
FOREIGN BODY
SUTURE , ANY
PROSTHESIS ,
VASCULAR GRAFT
INORGANIC
METALS,DUSTS
SILICOSIS
BERYLLOSIS
UN KNOWN
SARCOIDOSIS

Epitheloid cells
They are modified macrophages/
histiocytes which are somewhat elongated, having
pale staining abundant cytoplasm, vesicular, lightly
stained slipper shaped nucleus
 Cell membrane of adjacent epitheloid cell is closely
apposed due to hazy outline
 They are weakly phagocytic

GIANT CELLS
 Formed by fusion of epitheloid cells
 May have 20/more nuclei
 Nuclei present centrally- FOREIGN BODY TYPE
 Nuclei at periphery like horse shoe/ ring/clustered at
two poles- LANGHANS TYPE
 They are also weakly phagocytic
 Produce secretory products which helps to remove
invading agents

NECROSIS
 It is feature of some granulomatous conditions
 E.g: caseation necrosis in TB
FIBROSIS
 Due to proliferation of fibroblasts at periphery of
granuloma

Factors favouring formation of granuloma
1. Presence of poorly digestible irritant
2. Presence of cell mediated immunity to irritant
implying role of hypersensitivity in granulomatous
inflammation
Types of granuloma
1. FOREIGN BODY GRANULOMA : Material can be
seen in center when viewed with polarised light
2. IMMUNE GRANULOMA : Due to microbes capable
of activating cell mediated immunity

SYSTEMIC EFFECTS OF
INFLAMMATION

LPS EXOGENOUS
PYROGENS
TNF,IL-1
ENDOGENOUS
PYROGENS
INCREASE
CYCLOOXYGENASE
PGE2 STIMULATE
RELEASE OF CYCLIC
AMP
RESET
TEMPERATURE
SET POINT AT
HIGHER LEVEL
FEVER

• Temperature > 40C
• Triggers cold receptors
Severe
Inflammation
• Pallor
• A feeling of coldness of skin
surface
Reflex
Vasoconstriction
Of Vessels
RIGOR
Shaking
Exaggerated
shivering which
occurs with a high
fever

Changes in pulse rate
 Increase in temperature accompany increase in
pulse
 For every 1 degree F rise in temp pulse increase by
10beats/minute
 Conversely bradycardia occurs in typhoid fever

Acute phase proteins
 Mostly synthesized in liver
 Clinical concentration increase 100fold in
inflammation
 E.g: CRP, serum amyloid A protein(SAA), Fibrinogen
 Cytokines upregulate their synthesis by stimulating
hepatocytes
 CRP, SAA acts as opsonins and fix complement

They have beneficial effects in acute inflammation
but in chronic prolonged production leads to
secondary amyloidosis
CRP
 Levels increased in infection , inflammation
 Tissue necrosis , malignancy , auto immune diseases
 It binds to phosphocholine on dead / dying cells and
activate complement
 Enhances phagocytosis by microbes
 Marked increase indicates risk for CVD , hypertension
diabetes

LEUKOCYTOSIS
 Common feature of especially for bacterial infections
 Count increase by 15,000 to 20,000cells/cumm
 If it increase up to 1lakh – LEUKEMOID REACTION
(but splenomegaly, lymphadenopathy, hemorrhages
are absent)
MYELOID LEUKEMOID
TB, MENINGITIS
ENDOCARDITIS
BURNS
MERCURY POISONING
LYMPHOID LEUKEMOID
INFECTIOUS
MONONUCLEOSIS
TB, PERTUSIS
CHICKEN POX
MEASLES

INITIAL
INCREASE
ACCELERATED
RELEASE OF
CELLS DUE TO
TNF, IL-1
INCREASE IMMATURE
NEUTROPHILS IN
BLOOD
PROLONGED
INFECTION
INCREASED
COLONY
STIMULATING
FACTORS
INCREASED CELLS FOR
COMPENSATION OF
CELL LOSS
LEUKOCYTOSIS

NEUTROPHILIC LEUKOCYTOSIS BACTERIAL INFECTIONS, MI,
BURNS
EOSINOPHILIC LEUKOCYTOSIS PARASITIC INFESTATIONS,
ASTHMA, ALLERGIES
BASOPHILIC LEUKOCYTOSIS
(RARE)
INDICATIVE OF
MYELOPROLIFERATIVE DISEASE
(CML)
MONOCYTOSIS
(COMMON IN CHRONIC)
TB, ENDOCARDITIS, COLLAGEN
VASCULAR DISEASE(SLE),
INFLAMMATORY BOWEL
DISEASE(ULCERATIVE COLITIS)
LYMPHOCYTOSIS TB, VIRAL(HEP-A, CMV, EBV)www.indiandentalacademy.com

LPS
(TNF, IL-1)
TISSUE
FACTOR
EXPRESSION
BY
ENDOTHELI
AL CELLS
INTIATES
COAGULATI
ON
DIC
CYTOKINES LIVER INJURY
FAILURE TO
MAINTAIN
NORMAL
GLUCOSE
SHOCK

OVER
PRODUCTION OF
NO
BY CYTOKINE
ACTIVATED
CARDIAC
MYOCYTES
HEART FAILURE
DIC
HEART
FAILURE
HYPOGLYCEMIA
SEPTIC
SHOCK

LYMPHANGITIS- LYMPHADENITIS
 Lymphatics and lymphnodes that drain the
inflammed tissue show reactive inflammatory
changes
 This is a non specific reaction to mediators released
from inflammed tissues
 LYMPHANGITIS Inflammation Of Lymphatic Vessels
And Channels
 LYMPHADENITIS Inflammation of lymph node

REGULATION OF INFLAMMATION
1. ACUTE PHASE PROTEINS
Alpha 1 anti trypsin:
 It Is a Protease Inhibitor
 Protects Tissues From Enzymes Of Inflammatory Cells
 Especially Neutrophil Elastase
 In Absence Degradation Of Elastin
 If This Occur In Lungs , This Leads To Respiratory
Problems

 Protease inhibitor
 Hapatglobin
 It Scavangers Hb Released Into Circulation
 Potent Antioxidant
 Resist Cell Oxidative Stress
 Inhibits COX , LOX

2. CORTICOSTEROIDS
 Endogenous glucocorticoids act as anti inflammatory
agents
 Their levels are increased in infection , trauma by self
regulating mechanism
3. Supressor T cells / regulator T cells
 Modulate immune system
 Maintain tolerance to self antigens

4. Anti inflammatory chemical mediators
propree
RESOLVINS
RvS
OMEGA 3

FACTORS DETERMINING
VARIATIONS IN INFLAMMATORY
RESPONSE

FACTORS INVOLVING THE ORGANISM
Type of injury and infection
 Lung reacts to pneumococci by occurrence of
pneumonia
 While it responds to tubercle bacilli by
granulomatous inflammation
Dose
 Concentration of organism in small dose form local
lesions
 Large dose cause severe spreading infections

Portal Of Entry
 Vibrio cholera is not pathogenic if injected sub
cutaneously but cause cholera if swallowed
Product Of Organisms
 Certain products cause spread of infection
 e.g : streptokinase by streptococci
coagulase by staphylococci

FACTORS INVOLVING THE HOST
1. AGE : very young, very old are less able to combat
infection because of lack of inflammatory response
Many elderly patients respond with a chronic
inflammatory response which in young patients have
provoked acute response
2. DAMAGE TO BONE MARROW AND RETICULO
ENDOTHELIAL SYSTEM

3. ANTIBIOTIC THERAPY
 Antibiotics decrease inflammation because clearing
infection removes reason for inflammation
 Inflammatory response is modified depending on
how the agent respond to therapy

4. Diet
 when you eat your body forms PG’s from nutrients
in diet
 This can be inflammatory / anti inflammatory
 Imbalance in diet leads to formation of
inflammatory PG
 On other hand omega-3 fatty acids , antoxidants ,
phyto nutrients can produce anti inflammatory PG

FOODS HIGH
SATURATED FAT
MEAT EGGS DAIRY
PRODUCTS
COFFEE
CONTAINS CRP
PROCESSED MEATS
COOKING FOODS AT
HIGH TEMP
CAUSE RELEASE OF
TOXINS
TRANS FAT
INTAKE OF
PROCESSED FRIED
FOODS
HIGH GLYCEMIC
INDEX CHO
INSULIN CAUSE
METABOLISM OF AA
PRO INFLAMMATORY FOODS

ANTI
INFLAMMATORY
FOODS

CONCLUSSION
WAR AND INFLAMMATION
 Both are stereotyped responses to outside threats
 There are specialised troops(immune cells)
 Supply routes(vessels)
 Communication and intelligence(mediators)
 Huge array of lethal weapons(enzymes)
IN WAR AS IN INFLAMMATION THERE IS
DAMAGE TO BOTH ENEMY AND FRIENDLY FORCES
AND SEVERE DAMAGE TO BATTLE FIELD ITSELF

PROBABLY YOUR OWN
DEATH WILL BE CAUSED
BY YOUR LAST
INFLAMMATORY
RESPONSE

References
1. Robbins and Cotran Pathologic Basis
of Disease 7th edition
2. Guyton and Hall Text Book of Medical
Physiology 11th edition
3. Harsh Mohan Text Book of Pathology
5th edition
PRESENTED BY
ANUSHA.V
PG-1ST YEARwww.indiandentalacademy.com

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