INFLAMMATION

DR. POORVIKA. S
Ⅰ MDS
DEPT OF PAEDIATRIC AND PREVENTIVE
DENTISTRY
 CONTENTS
1. INTRODUCTION
2. CAUSES OF INFLAMMATION
3. CARDINAL SIGNS
4. TYPES OF INFLAMMATION
5. ACUTE INFLAMMATION VASCULAR EVENTS CELLULAR EVENTS
6. CHEMICAL MEDIATORS
7. MORPHOLOGICAL PATTERNS OF ACUTE INFLAMMATION
8. CHRONIC INFLAMMATION
9. SYSTEMIC EFFECTS OF INFLAMMATION
[Link] OF INFLAMMATION
[Link]
[Link]
 INTRODUCTION

Inflammation is defined as the local response of living mammalian tissues to injury due to any
agent. It is a body defense reaction in order to eliminate or limit the spread of injurious
agent, followed by removal of the necrosed cells and tissues.
 ETIOLOGICAL FACTORS:

🠶 Infective agents like bacteria, viruses and their toxins, fungi,

parasites.

🠶Immunological agents like cell-mediated and antigen-

antibody reactions.

🠶Physical agents like heat, cold, radiation, mechanical

trauma.

🠶 Chemical agents like organic and inorganic poisons.

🠶Inert materials such as foreign bodies

 CARDINAL SIGNS OF INFLAMMATION

Rubor
Tumor
Calor
Dolor
Functio Laesa
 TYPES OF INFLAMMATION

Short Duration.
Acute inflammation Lasts less than 2 weeks.
Represents early body reactions.
Resolves Quickly

Longer duration.
Chronic inflammation
Either after causative agent of
acute inflammation.
Or stimulus that induce chronic
inflammation from beginning.
(CHRONIC ACTIVE)
 Acute
inflammation

Vascular cellular

Altered
heamodynamic vascular Exudation phagocytosis
permeability
 A. HAEMODYNAMIC CHANGES
Transient vasoconstriction : Immediate
vascular response irrespective of the
type of injury. Mainly by arterioles.
Mild injury - 3-5 seconds & Severe injury
5 minutes.

Persistent progressive vasodilatation :

Mainly arterioles, others to a lesser
extent.
– obvious within half an hour of injury
– increased blood volume in
microvascular
bed of the area
– redness and warmth at the site of
 Progressive vasodilatation elevate the local hydrostatic
pressure
– transudation of fluid into the extracellular space –
swelling

Slowing or stasis
increased concentration of red cells, and thus, raised blood viscosity

Leucocytic Margination
- peripheral orientation of leucocytes (mainly neutrophils) along the vascular endothelium
- stick to the vascular endothelium briefly
- move and migrate through the gaps between the endothelial cells - extravascular space
- This is known is emigration.
 ALTERED VASCULAR PERMEABILITY

Accumulation of oedema fluid in interstitial compartment which comes from

blood plasma by its escape through the endothelial wall of peripheral vascular
bed.
Escape of fluid is due to vasodilatation and consequent elevation in hydrostatic
pressure - transudate.
Subsequently, the characteristic inflammatory oedema, appears by increased
vascular permeability of microcirculation – exudate.
MECHANISMS OF INCREASED VASCULAR PERMEABILITY

Contraction of endothelial cells.

Retraction of endothelial cells
Direct injury to endothelial cells
Endothelial injury mediated by leucocytes
Leakiness and neo-vascularization
 Contraction of endothelial cells

Affects venules exclusively.

Endothelial cells develop temporary gaps due to their

Contraction resulting in vascular leakiness.

Mediated by the release of histamine, bradykinin and

other chemical mediators.

Short duration (15-30 minutes) - immediately after

injury
 Retraction of endothelial cells

Structural re-organization of the cytoskeleton

of endothelial cells - Reversible retraction
at the intercellular junctions.

Mediated by cytokines such as

Interleukin-1 (IL-1) and Tumor necrosis
factor (TNF)-α
 Direct injury to endothelial cells
Causes cell necrosis and appearance of physical
gaps at the site of detatched endothelial cells.

Process of thrombosis is initiated at the site of

damaged endothelial cells.

Affects all levels of microvasculature.

Either appear immediately after injury and last for

several hours or days – severe bacterial infections

Or delay of 2-12 hours and last for hours or days -

moderate thermal injury and radiation injury
 Endothelial injury mediated by leucocytes

Adherence of leucocytes to the endothelium at the site of

inflammation.

Activation of leucocytes - release proteolytic enzymes and toxic

oxygen.

Cause endothelial injury and increased vascular leakiness.

Affects mostly venules and is a late response.

 Leakiness and Neo-Vascularisation

Newly formed capillaries under the influence of vascular

endothelial growth factor (VEGF) during the Process of repair
and in tumors are excessively leaky.
 CELLULAR EVENTS :
Consists of 2 processes
Exudation of leucocytes.
Phagocytosis.

Exudation of leucocytes

Changes in the formed elements of blood.

Rolling and adhesion
Emigration
Chemotaxis
 CHANGES IN THE FORMED ELEMENTS OF BLOOD
The normal axial flow consists of central stream of
cells comprised by leucocytes and RBCs and
peripheral cell free layer of plasma, close to
vessel wall.

Later, central stream of cells widens and peripheral

plasma zone becomes narrower because of loss
of plasma by exudation.

This phenomenon is known as margination.

Neutrophils of the central column come close to

the vessel wall – pavementing.
 ROLLING AND ADHESION
Peripherally marginated and pavemented neutrophils slowly roll over the endothelial cells
lining the vessel wall (rolling phase).

Transient bond between the leucocytes and endothelial cells becoming firmer (adhesion
phase).

The following molecules bring about rolling and adhesion phases –

-Selectins

-Integrins

-Immunoglobulin gene superfamily adhesion molecule

 EMIGRATIO
N
After sticking of neutrophils to endothelium,

The former move along the endothelial surface till a suitable site between the endothelial
cells is found where the neutrophils throw out cytoplasmic pseudopods.

Cross the basement membrane by damaging it locally –

collagenases and escape out into the extravascular space –

emigration

Diapedesis - escape of red cells through gaps between the

endothelial cells
 CHEMOTAXI
S
After extravasating from the blood, Leukocytes migrate toward sites of infection or
injury along a chemical gradient by a process called chemotaxis.
They have to cross several barriers - endothelium, basement membrane, perivascular
myofibroblasts and matrix.
Potent chemotactic substances or chemokines for neutrophils
– Leukotriene B4 (LT-B4)

arachidonic acid metabolites.

– Components of complement system - C5a and C3a in particular.

– Cytokines

– Interleukins, in particular IL-8

 PHAGOCYTOSIS

The process of engulfment of solid particulate material by the cells.

2 main types of phagocytic cells –

- Polymorphonuclear neutrophils (PMNs)

- Macrophages

This phagocytic cells releases proteolytic enzymes - lysozyme, protease,

collagenase, elastase, lipase, proteinase, gelatinase and acid hydrolases.
The microbe undergoes the process of phagocytosis in following
3 steps : –
Recognition and attachment
Engulfment
Killing and degradation
 RECOGNITION AND ATTACHMENT

Phagocytosis is initiated by the expression of surface receptors on macrophages.

Its further enhanced when the microorganisms are coated with specific proteins,
opsonins.

Establish a bond between bacteria and the cell membrane of phagocytic cell.

– Major opsonins are

• IgG opsonin .

• C3b opsonin

• Lectins
 ENGULFMENT

Formation of cytoplasmic pseudopods around the particle due to activation of actin

filaments around cell wall.

Eventually plasma membrane gets lysed and fuses with nearby lysosomes –
phagolysosome.
 KILLING AND DEGRADATION

Killing of microorganism take place by Antibacterial substances further

degraded by hydrolytic enzymes

Sometimes this process fails to kill and degrade some bacteria like tubercle
bacilli.
 Disposal of microorganisms

Intracellular mechanisms –
[Link] bactericidal mechanism by oxygen free radicals
• MPO-dependent
• MPO-independent .
[Link] bactericidal mechanism by lysosomal granules –
[Link]- oxidative bactericidal mechanism

Extracellular mechanisms
Granules
Immune mechanisms
 CHEMICAL MEDIATORS OF INFLAMMATION
🠶 CELL- DERIEVED:

SOURCE MEDIATORS ACTION

MAST CELLS HISTAMINE VASODILATION.
INCREASE PERMEABILITY

PLATELETS SEROTONIN INCREASE PERMEABILITY

INFLAMMATORY CELLS PROSTAGLANDINS VASODILATION

LEUKOTRINES INCREASE PERMEABILITY.

TISSUE DAMAGE
LYSOSOMAL ACTIVITIES

CYTOKINES TISSUE DAMAGE & FEVER

 PLASMA-DERIEVED MEDIATORS

Clotting & Fibrin Split Increase

Fibrinolytic Products Permeability
System
Kinin System Kinin/ Increase
Bradykinin Permeability

Complement Anaphylatoxins Increase

System Permeability
VASOACTIVE AMINES
• HISTAMINE STIMULI :
 Injury
SOURCE :  Immune reactions
1) Mast cells in C.T  Fragments of complement
adjacent to blood vessels  -C3a , C5a
2) Blood basophils  Neuropeptides such as
3) Platelets  substance P
 Cytokines IL – 1 , 8
SEROTONIN
SOURCE : STIMULI :
 Platelet aggregation after
1) Platelets
2) Enterochromaffin cells contact with collagen ,
 thrombin
3) nervous tissue
4) mast cells Action: vasodilatation, increased vascular
permeability, itching and pain
 ARACHIDONIC ACID METABOLITES
•A fatty acid with 2 main sources :

 Directly through diet

Through conversion of essential fatty acid, linoleic acid to arachidonic
acid

Cyclo-oxygenase ARACHIDONIC
ARACHIDONIC ACID
pathway Lipo- ACID METABOLITES
CYCLO – oxygenase Pathway
OXYGENASE LIPO – OXY – GENASE
PATHWAY PATHWAY
• Prostaglandin - PGD2 , E2 ,  5 – HETE
F2.  Leukotrienes
• Thromboxane A2
• Prostacyclin
Platelet activating factor
•First described in early 1970’s by Jacques Benvinste
•Source:
 Platelets
 Basophils
 Mast cells
 Neutrophils
 Macrophages
 Endothelial Cells
•F unctions:
 Platelet aggregation
 Vasoconstriction and Bronchoconstriction
 At extreme low concentration cause vasodilation, increased
vascular permeability
 Increased leukocyte adhesion
 Chemotaxis
 CYTOKOINES

Protein that transmit signals from one cell to another.

Also called INTERLUKINES

Two types : PRO-INFLAMMATORY & ANTI-INFLAMMATORY

PRO-INFLAMMATORY: Produced by activated macrophages &

involved in up- regulation of inflammatory reactions,

i.e.. Promotes inflammation

ANTI-INFLAMMATORY: Immunoregulatory molecules that controls pro-

inflammatory cytokines response.
 PRO-INFLAMMATORY CYTOKINES

• INCREASE CARTILAGE DEGRADATION

• BONE RESORPTION
TNF-α • INDUCE APOPTOSIS
• STIMULATE PITHER CELLS TO STIMULATE CYTOKINES
• INHIBIT PROTEOGLYCAN SYNTHESIS
• UPREGULATE MMP EXPRESSIONS
IL-1β • STIMULATE PRO-ANGIOGENIC FACTOR RELAESE

• REDUCE CHONDROCYTE PROLIFERATION

• INCREASE MMP-2 ACIVITY
IL-6 • INCREASE AGGRECANASE MEDIATED PROTEOGLYCAN
ACTIVITY
Major cytokines in inflammation
Chemokines:
•Chemokines are a family of small proteins that act primarily as chemo
attractants for specific type of leukocytes .
OXYGEN METABOLITES
 Released by activated neutrophils and macrophages.

 Superoxide oxygen, hydrogen peroxide , hydroxl ion.

•ACTION :

 Endothelial cell damage and thereby increasing vascular

•permeability
Damage to cells and tissue matrix by activating protease and inactivating

anti protease
Nitric Oxide

 It is formed by activated macrophages during the oxidation of

arginine by the action of enzyme, NO synthase.

 NO plays the following roles in mediating inflammation:

a) mediates in vascular dilation

b) Anti-platelet activating agent
c) Possibly microbicidal action
Plasma derived mediators
Kinin system

 Vasoactive peptides derived from plasma proteins called

• kininogens by action of proteases called kallikreins.

 Braykinin increases vascular permeability; contraction of smooth

muscle; dilation of blood vessels; pain when injected into skin
The Clotting system

The actions of fibrinopeptides in

inflammation are:
 increased vascular permeability
 chemotaxis for leucocyte
 anticoagulant activity .
Fibrinolytic system

 Kallikrein along with plasminogen activator converts

plasminogen to plasmin.
 Plasmin acts on fibrin & forms fibrin split products.
 Plasmin also activates C 3 to C3a
Complement system

 C omplement activation elaborates several cleavage products which

mediate in inflammatory response
 Critical step in activation is the
proteolysis of C 3.
 This can occur in pathways:
 Classic pathway
 Alternate pathway
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
Outcomes of acute inflammation
 CHRONIC
INFLAMMATION
Inflammation of prolonged duration (weeks to months to years) in
which active inflammation, tissue injury, and healing proceed
simultaneously.
Causes of Chronic Inflammation

Persistent infections

• Certain microorganisms associated with intracellular infection such as

tuberculosis, leprosy, certain fungi etc.

Prolonged exposure to nondegradable but partially toxic substances

either endogenous lipid components which result in atherosclerosis or
exogenous substances

• such as silica, asbestos.

 Progression from acute inflammation:
•Acute inflammation almost always progresses to chronic
inflammation

Autoimmunity:

•Autoimmune diseases such as rheumatoid arthritis and systemic lupus

erythematosis are chronic inflammations from the outset.
Types of chronic inflammation

Specific - when the injurious agent cau ses a characteristic histologic

tissue response e.g. tuberculosis, leprosy, syphilis.

Non-specific - when the irritant substance produces a

• nonspecific chronic inflammatory reaction with formation of granulation

tissue and healing by fibrosis e.g. chronic osteomyelitis, chronic ulcer.

Cells of chronic inflammation

•Monocytes and Macrophages are the primary cells.

•These cells constitute the mononuclear- phagocytic system.

•Macrophages are scavenger cells of the body.

•T-Lymphocytes are primarily involved in cellular immunity

•B-lymphocytes and Plasma cells produce antibodies.

•Mast cells and eosinophils appear predominantly in response to parasitic

infestations & allergic reactions.

FEATURES OF CHRONIC INFLAMMATION
[Link] cell infiltration – phagocytes and lymphoid cells
macrophages- most important cells

2. Tissue destruction or necrosis

proteases, elastases, cytokines etc released by activated

macrophages

3. Proliferative changes- blood vessels and fibroblasts proliferate

forming granulation tissue.

thereby healing by fibrosis and collagen laying.

GRANULOMATOUS INFLAMMATION

• Granuloma is defined as circumscribed tiny lesion about 1mm in diameter

composed predominantly of collection of modified macrophages called epitheloid
cells and rimmed at the periphery of lymphoid cells.

• The word Granuloma is derived from granule meaning circumscribed granule

like lesion and oma which is a suffix commonly used for true tumors.
Pathogenesis of Granuloma
 FUNGAL
BACTERIAL HISTOPLASMOSI PARASITIC
TB LEPROSY S
BLASTOMYCOSI
SCHISTOSOMI
SYPHILITIC
S ASIS
GUMMA
CRYPTOCOCCUS

FOREIGN BODY
SUTURE , ANY
INORGANIC
PROSTHESIS , METALS,DUST UN KNOWN
VASCULAR S SILICOSIS SARCOIDOSIS
GRAFT BERYLLOSIS
Composition of Granuloma

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

[Link] 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

[Link] occurs due to bacteraemia.

It is thought to be mediated through release of factors like prostaglandins,

interleukin-1 and TNF-α in response to infection.
2. Leucocytosis commonly accompanies the acute inflammatory reactions, usually in the
range of 15,000- 20,000/μl.

When the counts are higher than this with ‘shift to left’ of myeloid cells, the blood picture is
described as leukaemoid reaction.

Usually, in bacterial infections there is neutrophilia; in viral infections lymphocytosis; and in

parasitic infestations, eosinophilia.

Typhoid fever, an example of acute inflammation, however, induces leucopenia with relative
lymphocytosis
• Lymphangitis-lymphadenitis is one of the important manifestations of localised
inflammatory injury.

• The lymphatics and lymph nodes that drain the inflamed tissue show reactive
inflammatory changes in the form of lymphangitis and lymphadenitis.

• This response represents either a nonspecific reaction to mediators released from

inflamed tissue or is an immunologic response to a foreign antigen.

• The affected lymph nodes may show hyperplasia of lymphoid follicles (follicular
hyperplasia) and proliferation of mononuclear phagocytic cells in the sinuses of
lymph node (sinus histiocytosis)
• Shock may occur in severe cases.

Massive release of cytokine TNF-α, a mediator of inflammation, in response to

severe tissue injury or infection results in profuse systemic vasodilatation, increased
vascular permeability and intravascular volume loss.

The net effect of these changes is hypotension and shock. Systemic activation of
coagulation pathway may occur leading to microthrombi throughout the body and
result in disseminated intravascular coagulation (DIC), bleeding and death.
Acute phase reactants
Certain cellular protection Some coagulation proteins
factors (e.g. α1- (e.g. fibrinogen, plasminogen, Transport proteins (e.g.
antitrypsin, α1- von Willebrand factor, factor ceruloplasmin,
chymotrypsin): protect VIII): They generate factors to haptoglobin): They carry
the tissues from cytotoxic replace those consumed in generated factors.
and proteolytic damage. coagulation.

Stress proteins (e.g. heat Immune agents (e.g. serum

shock proteins): They are amyloid A and P component, C- Antioxidants (e.g.
molecular chaperons who reactive protein): CRP is an ceruloplasmin are active
carry the toxic waste opsonising agent for phagocytosis in elimination of excess of
within the cell to the and its levels are a useful indictor oxygen free radicals.
lysosomes. of inflammation in the body
REGULATION OF INFLAMMATION

• Acute phase reactants. A variety of acute phase reactant (APR) proteins are
released in plasma in response to tissue trauma and infection. Their major role is
to protect the normal cells from harmful effects of toxic molecules generated in
inflammation and to clear away the waste material.
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 RESOLVINS , OMEGA 3

 CONCLUSION
Inflammation is a vital part of the immune system's response to injury and
infection.

It is the body's way of signalling the immune system to heal and repair
damaged tissue, as well as defend itself against foreign invaders, such as
viruses and bacteria.

A better understanding of inflammatory response pathways and molecular

mechanisms will undoubtedly contribute to improved prevention and treatment
of inflammatory diseases.
 REFERENCES

[Link] Mohan Text Book of Pathology 5th [Link]

publication.
[Link] and Cotran Pathologic Basis of Disease 7th edition
[Link] and Hall Text Book of Medical Physiology 11th edition
[Link] Textbook of Medical Physiology 6th edition
[Link] R, Sivapathasundharam B Shafer’s textbook of oral
pathology. 5thedition. Elsevier publication.