Inflammation / orthodontic courses by Indian dental academy

INFLAMMATION

Introduction

One of the characteristic of living tissue is its ability to react to injury so

the survival of an individual depends on the ability of normal cells to respond

to damage. In fact without inflammation none of us would be alive to day.

The process of inflammation occurs as a part of our day to day lives.

Acute inflammation

Acute inflammation is the immediate and early response to injury.

This process is usually described by the “Suffix-itis” proceeded by the

name of the organ or is involved. Eg. Pulp – puptis

Causes of acute inflammation

1. Physical injury

a. Chemical injury

2. Microbial infections

3. Immuno logical mechanism induced injury

4. Necrosis induced

Physical

1. Mechanical trauma cutting/crushing

2. U.V. rays

Eg. Sunburn

3. Ionising radiation

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4. Injury due to cold and heat. Eg. Burns, frost bite

5. Clinical corrosive acids, alkali etc. which may be protoplasmic poisons.

In these are included certain body fluids which when stray from their

respiratory organs cause damage to the ts

6. Microbial infection – commonest cause viruses multiply intracellular

and destroy the cell.

Bacteria release specific exotoxins or endotoxins.

Parasites may cause some hyper sensitivity reactions.

7. Immunologic mechanism

These include diseases mediated by antigen antibody interaction as well

as those classified as type I and IV which cause an inappropriate reaction

which damages the tissues.

8. Necrosis: either due to hormonal changes or around an infarct.

Microscopic features

The essential physical characteristics of acute inflammation were

formulated by celsus 38 AD using the latin words.

Rubor, calor, tumour, dolor.

Rubor or redness is seen due to the dilatation of small blood vessels

within the damaged area.

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Heat or Calor

Increase in temperature is seen only in peripheral parts of the body e.g.

skin.

This is due to increased blood flow or hyperaemia which causes vascular

dilatation and the delivery of warm blood to the area.

Systemic fever which results from some of the chemical mediator may

also contribute.

Tumor or swelling which results for acidic mainly, and sometimes due

to physical mass of inflammatory cells migrating into the area.

Pain – dolor is the common feature for the patient it results partly from the

stretching and distortion of tissues due to inflammatory oedema and partly

from pus under pressure in an abscess cavity.

Some of the chemical mediators of inflmmation e.g. prostaglandins

induce pain.

Loss of function or function laesa was added to these signs in 1900 by

Virchow: According to Under wood movement of an inflamed part is

consciously and reflexly inhibited by pain while severe swelling may

physically immobilize the tissues.

Some special macroscopic features

Although the cardinal signs are same for all the organs there may be

some descriptive terms pertaining to certain organs.

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Serous inflammation

Catarrhal

Fibrinous

Haemorhagic

Suppurative

Membraneous

Pseudomembraneous

Necrotizing

Serous inflammation

Here there is abundant protein rich fluid exudates with a relatively low

cellular content. Vascular dilatation may be apparent to the naked eye due to

the serous surfaces having blood laden vessels on the surface e.g. blood shot

eyes in conjunctivitis.

Catarrhal Inflammation

When mucous hyper secretion accompanies acute inflammation e.g.

common cold.

Fibrinous

If the exudates contains fibrinogen which polymerizes into a thick fibrin

coating. Seen in acute pepiosteitis because the pericardium shows a bread and

butter appearance.

Haemorrhagic

Seen in severe vascular injury or depletion of coagulation factors e.g.

acute pancretitis (destruction of vascular walls).

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Suppurative

Seen when mucosed cells form pus which gets walled off to form on

abscess membraneous. The epithelium becomes coated with fibrin,

desquamated epithelial cells and inflammatory cells. E.g. gray membrane seen

in pharyngitis and lacyngitis.

Pseudomembraneous inflammation - describes superficial mucosal

ulceration with an overlying slough of disrupted mucosa fibrin mucous

inflammatory cells. This is seen in pseudomonas colitis following broad

spectrum antibiotic therapy.

Necrotizing inflammation in tissue pressure due to oedema may lead to

vascular occlusion and thrombosis which may result in necrosis. This

combined with bacterial putrefraction is called gangrene.

Microscopic changes

These can be studied under the following headings:

1) Vascular response

2) Swelling and exudation

Fluid exudates Cellular exudates (Phagocytosis)

3) Changes in other tissue components (The separation is artificial as all these things occur simultaneously in a inflammation).

Vascular response

Very initial and transient changes. Initially a transient vasoconstriction

is seen. These can be demonstrated in the human skin. Light stroking produces

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a white line this may be due to a mechanical stimulation of the blood vessels or

when irritating chemicals are applied.

Persistent vasodiltion

This vasoconstriction is followed by vasodilatation which persists for

the duration of the inflammation.

Arteriolar dilation causes

Blood to flow thru the thorough fare cannels to resins. Also per capillary

sphineters open up so, blood passes into the capillary bed. Therefore vessels

which were closed open up + caliber. Thus the inflamed part seems to contain

caliber also increase.

Lewis in 1924 noted that for stroking of the skin to results in a triple

response and his analysis of these events lead to the hypo thesis that lies lamine

liberated from damaged cells was an important factor in the vascular response.

What is the triple response, it consists of red line place and weal. As soon as

the human skin is stroked firmly with a sharp object. After a short latent period

a red line develops. First – bright red, later – cyanosed. This is sharply

demarcated and is due to capillary dilatation.

Flare

15-30 secs later a blotchy flare with crenated outline appears

surrounding the red line. This is due to arteriolar dilation.

If the nerve supply is cut off and the skin is pierced the reaction can be

seen but if the test is performed ten days later there is no reaction seen. This

shows that this is mediated via a local axor reflex.

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Weal

A weal may subsequently appear due to exudation of fluid through the

vessel wall.

As oedema decreases the weal becomes paler due to pressure on

capillaries.

Note: On role of nerves in vasodilatation.

Inflammation can occur in completely denervated tissues but nerves do

play a role e.g. axon reflex.

Conheim showed that if the nerve supply of rabbit ear is removed

vessels become constricted and un responsive. Injection of a test dose of

bacteria produces slow inflammatory reaction and relatively more tissue

destruction and damage.

Under normal conditions the autonomic nervous system plays a little

role in inflammation response.

Changes in Vessel Wall

Normal flow

Blood cells occupy central part of stream. The plasmatic stream has a

lower viscosity than whole blood. Therefore peripheral resistance is low.

Changes

1. Increased in blood velocity due to

arteriolar dilatation (short lived phase).

This is followed by slowing of the stream.

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2. Simultaneously WBC’s and Platelets

stick to vessels wall.

3. Endothelial cells become thickened

and appeared to be covered by a gelatinous layer.

These 3 features are

Stasis.

Leucocyte adherence.

Endothelial thickening.

Stasis

As the rate of flow into the thorough force channels increases, the

capillaries that are normally closed begin to open decreased, thus volume of

capillary bed increases greatly, so much so that blood flow slows and may stop

inspite of the increased amount of blood.

The more severe the injury the sooner the slowing develops may be

from few minutes – ½ hr / more

As the blood slows the red cells sometimes appear to merge forming a

homogenous yellow column filling the center.

Electron microscopy shows that they are closely packed into a rouleux

with eventual loss of their hemoglobin.

This column may remain still for min/hrs a days depending on the

injury. This curious form of circulatory arrest is called stasis which means

standing still.

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CHANGES IN ENDOTHELIAL LAYER

1. In inflammation the endothelial layer becomes swollen and thickened.

2. Swelling may reduce the lumen of a capillary.

3. In the initial stages of inflammation a transudate is seen which is an ultra

filtrate of plasma and contains little protein. Later on the vascular

permeability increases and exudation of a protein rich fluid is seen

which seeps out and leads to oedema.

The mechanisms behind the increased vascular permeability are as follows:

1. Endothelial cell contraction inter cellular gaps widen.

Mediators - Histamine

- Brady kinin

- Leukotreines

- Seen mostly in venules 20-60m in diameter

2. Junctional retraction some cytokine mediators induce structural

reorganisation of the cytoskeleton. This is a reversible change and may

occur 4-6 after injury.

3. Direct endothelial injury – this is seen in several injury this may result in

immediate sustained response or delayed prolonged leakage.

4. leukocyte dependant cellular injury may be a result of leukocyte

adherence to endothelium, releasing toxic oxygen and enzymes leading

to endothelial injury.

5. Increased transcytosis via an intra cellular vesiculovacular pathway.

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Due to all these factors the permeability is increased and leukocytes and

erythrocytes escape. First the neutrophils then monocytes, macrophages and

R.B.C.s

The leukocytes cellular events are:

1. Margination and rolling.

2. Adhesion and transmigration.

3. Migration in interstitial tissue towards chemotactic stimulus.

The cellular exudates consists of leukocytes and may be some RBC’s.

How the cells escape or the Leucocyte cellular events.

Exudation and swelling

This is the most characterized feature of acute inflammation in the

higher animals. This exudates has a fluid and cellular compartment. The

formation of inflammatory exudates depends on several reasons.

Normally

32 mm Hg – arteriolar

12 mm Hg – Venous end.

Mean colloid osmatic pressure pr-25 mm Hg which is equal to the mean

capillary pressure.

Although fluid leaves through the pre capillary areteriole. It is returned

in equal amounts by the post capillary venule.

So the net flow is maintained at zero.

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INFLAMMATION

A pressure – 50mm Hg

Venous pressure – 30mm this is (due to arteriolar dilatation).

At the same time osmotic pressure is reduced to 20mm Hg because of

protein leakage across the venule. This leads to extravasation of fluid.

The crucial factor in the formation of an exudate is an increased

permeability of the vessel wall to plasma proteins.

Experiment

If trypan blue is injected intravenously into an animal the dye becomes

bound to plasma albumin and does not readily leave the circulation.

When inflammation is seen the albumin can be seen to pass the inflamed

area as the exudates forms.

Function of the fluid exudates

All the constituents of plasma are poured into the area of inflammation.

1. The clinical importance of this fluid is that along with fluid even drugs

present in plasma will be seen here.

So drugs in inflammation should be given early as it is obvious that they

are merely carried to the inflamed area via the exudates and are in no way

concentrated.

2. The fluid dissolves local irritants if any.

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3. It has high fibrinogen content which results in a fibrin clot this has 3

main functions:

i. It forms a union between severed tissues as in a cut.

ii. May form a barrier against bacterial invasion.

iii. It aids phagocytosis.

4. The cellular component

As the vasoconstriction permeability increases the leukocytes

erythrocytes escape out of these the 1st to appear are the neutrophils which are

seen in 2-9 minutes followed by monocytes macrophages and erythrocytes.

The leukocytes cellular events are as follows:

1. Margination and rolling.

2. Adhesion and transmigration.

3. Chemotaxis and activation.

4. Phagocytosis and degranulation.

Margination and Rolling

As vasoconstriction permeability increases fluid exists the vascular

lumen, blood flow slows. So, leukocytes settle out of the central column.

Marginate to the vessel periphery, also they tumble on the endothelial

surface transiently sticking along the way. This is called Rolling.

These 2 processes are mediated by the binding of complementary

adhesion molecules on the leukocytes and endothelial surfaces similar lock and

key mechanism.

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Adhesion and Transmigration

Eventually the leukocytes firmly adhere to the endothelial surface

(adhesion) before crawling between the cells and through the membrane into

the extravascular (diapedesis) space.

The leukocytes vary

6-24 hrs – Neutrophils

24-47 – monocytes but neutrophils are short lived.

Chemotaxis and Activation

After extravasation, the leukocytes emigrate towards the site of injury

along a chemical gradient in a process called chemotaxis.

Both exogenous and endogenous factors may act for chemotaxis.

1. Soluble bacterial products.

2. Components of the complementary system.

3. Products of the lipoxygenase pathway of arachidonic acid metabolism.

4. Cytokines especially those from the chemokine family.

Besides stimulating slow motion these factors also induce other

leukocyte responses called leukocyte activation.

Phagorytosis & degranulation

Phagocytoses and the release of lysosomal enzymes are 2 of the major

benefits of leukocyte. Accumulation at the site of inflammation. It has 3 steps:

i) Recognition and attachment of the particle to the leukocytes.

ii) Engulfment with formation of a phagocytic vacuole.

iii) Killing on degradation of the injected material

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Chemical mediators of inflammation

Although the chemical mediators may be vital to the process it is neither

possible nor desirable to remember every mediator in detail.

*Mediators derive from plasma or by local production from cells.

Plasma derived ones are present as circulating precursors that must be

activated to achieve their biologic properties.

Cell derived ones are sequestered in intra cellular granules and are

secreted or synthesized in response to a stimuli.

*Most mediators may bind to specific receptors on target cells.

*They may also have direct enzymatic and or toxic activities.

Some mediators may stimulate target cells to release secondary effector

molecules.

These may have activities similar to the initial molecules so, they may

amplify a particular response or they may also have opposing activities thus

they regulate the initial response.

Mediators may be short lived i.e. once released they may quickly decay

or are inactivated by enzymes.

The major reason for this check is that most of the mediators have

harmful effects.

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Effects of Acute inflammation

Acute inflammation has local and systemic effects both of which may be

beneficial or harmful. The local effects are clearly beneficial but they may also

cause harm.

Beneficial effects

Dilution of toxins such as those produced by bacteria these are then

carried via lymphatics.

Entry of antibodies this is because of increased vascular permeability

into the extravascular space. Where they may lead to lysis or phagocytosis of

microorganism.

They also neutralize the toxins.

Transport of drugs to the place where bacteria are multiplying. Fibrin

formation from exuded fibrinogen, impedes movement of microorganism traps

them facilitates phagocytosis.

Harmful effects

1. Digestion of normal tissue by enzymes this may cause vascular damage.

2. Swelling in some tissue may be very harmful e.g. in children the

swelling of epiglottis in haemophilus influenza may result in death.

3. Inappropriate response some times the responses may be in appropriate

e.g. a reaction to an antigen which is not harmful to the individual as is

seen in hypersensitivity reactions. Such reactions may be life threatening

e.g. extrinsic asthma.

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Sequelae of Acute inflammation

Sequelae depends on

Type of tissue involved.

Amount of ts destruction which depend on nature of injurious agent.

Resolution

Means complete restoration of tissue after an episode of acute

inflammation.

Conditions which favour resolution are:

1. Minimal cell death and its damage.

2. Regenerative capacity of the organism.

3. Rapid destruction of causative agent.

4. Rapid removal of fluid and debris by good local vascular drainage.

Sequence Of Events Leading To Resolution May Be:Phagocytosis of bacteria

Intracellular killing

Fibrinolysis

Phagocytosis of debris

Disappearance of vascular dilatation

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Suppuration

Is the formation of pus – Pus is a mixture of

- Living and dying neutrophils and bacteria.

- Cellular debris.

- Globules of liquid.

Factors : Causative agent must be persistent e.g. pyogenic bacteria. Once pus

accumulates it gets surrounded by a “PYOGENIC MEMBRANE” consisting

of:

- Sprouting capillaries.

- Neutrophils.

- Occassional fibroblasts.

Such a collection is called an abscess, the special feature of this abscess

is that bacteria within it are inaccessible to antibodies and antibiotic drugs, thus

e.g. acute osteomyelitis is very difficult to treat.

Abscess

This abscess usually points and bursts, abscess cavity collapses and is

obliterated by organization and fibrosis leaving a small scar.

If it forms in a hollow viscus, the mucosal layers of the outflow tract

may become fused and lead to empyema such deep seated abscess sometimes

discharge their pus along on abnormal connection between the abscess and skin

lined by granulation tissue called sinus.

If this results in an abnormal tract connecting 2 mucosal surfaces it is

called a fistula.

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The fibrous walls of long standing abscess may become complicated by

dystrophic calcification.

Organisation

Organisation is the replacement of tissues by granulation tissue. This

happens when:

1. Large amounts of fibrin are formed which cannot be removed by

fibrinolytic enzymes.

2. Large volumes of tissue become necrotic and the dead tissue is not

digested.

3. Exudate and debris cannot be removed or discharged.

During organization new capillaries grow into the inflammatory

exudates macrophages migrate into the zone fibroblasts proliferate resulting in

fibrosis.

Sometimes the fibrin is not easily removed and capillaries grow into the

fibrin accompanied by macrophages and fibroblasts.

Eventually fibrous adhesion occurs between the parietal and visceral

plasma.

If the agent causing inflammation is not removed the inflammation may

progress to the chronic phase.

In addition to the organization the character of the cellular exudates

changes with lymphocytes plasma cells and macrophages.

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CHRONIC INFLAMMATION

The word chronic applied to any process implies that the process has

extended over a long period of time.

But in the case of the word chronic inflammation the word chronic takes

on a specific meaning i.e. the type of cellular reaction differs from acute

inflammation.

Chronic inflammation may be defined as an inflammatory process in

which lymphocytes, plasma cells and macrophages predominate and which is

usually accompanied by formation of granulation tissue resulting in fibrosis.

Chronic inflammation may follow acute or may start primarily in the

chronic form.

P.C.I. is the response in which there are all the histologic features of C.I.

and no initial stage of acute inflammation is seen.

Chronic inflammation is characterized by:

1. Infiltration with mononuclear cells.

Macrophages

Lymphocytes

Plasma cells.

2. Tissue destruction

3. Repair involving new vessel proliferation (angiogenesis) and fibrosis.

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Causes

I. Primary chronic inflammation.

a. Resistance of infective agent to phagocytosis and intra cellular

killing.

b. Foreign body reaction.

c. Some autoimmune diseases e.g. rheumatoid arthritis contact

hypersensitivity.

d. Specific disease of unknown aetiology – ulcerative colitis.

e. Primary granulomatous disease – sarcoidiosis.

f. Transplant reflection involves chronic inflammation response.

II. Progression from acute inflammation

If there is suppuration

Deep seated access cavity

Delayed / inadequate drainage

Scarring due to granulation tissue in growth

Another feature is the presence of indigestible material e.g. keratin from

a ruptured cyst, fragments of necrotic bone and inert foreign body materials.

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III. Recurrent bouts of inflammation and repair

- Will usually result in the clinicopathological cavity of

chronic inflammation.

Macroscopic features

These are:

1. Chronic ulcer : with a base lined by granulation tissue and fibrous tissue

extending through the muscle layers of the wall.

2. Chronic abscess : e.g. in osteomyelitis

3. Thickening of the wall of a hollow viscous e.g. Cohn’s disease.

Macroscopic features

Granuloma formation.

Fibrosis – this is the most prominent feature.

Microscopic features

The cellular infiltrate consists characteristically of lymphocytes plasma

cells and macrophages.

A few eosinophils may be present but neutrophils are scarce.

Macrophages are one component of the mononuclear phagocytic system

consisting of closely related cells of bone marrow origin.

When monocytes reach the site of inflammation. They activated into

macrophages. After activation the macrophages help in mediating tissue

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destruction angiogenesis and fibrosis which is characteristic of chronic

inflammation.

Unlike acute inflammation in which the macrophage eventually die or

go into the lymphatics.

In chronic inflammation they persist. They may also fuse to form giant

multi-nucleated cells.

Under appropriate conditions they also have a capacity to proliferate.

Other cells seen in chronic inflammation are:

T- Lymphocytes

B

- Plasma cells

- Eosinophils

Eosinophils are characteristics found in inflammatory sites around

parasitic infections or as part of immune reactions mediated by

immunoglobulins associated with allergies.

T and B lymphocytes are brought into the inflammatory site by the same

adhesions and chemokines that bring monocytes.

Plasma cells produce antibodies against antigens in the inflammatory site, or

against altered tissue components.

Granulomatous Inflammation

Granulomatous inflammation is a distinctive pattern of chronic

inflammation characterized by aggregation of activated macrophages that have

acquired an enlarged squamous cell like or epitheloid appearance.

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Granulomas are seen in the following conditions:

Bacterial – e.g. tuberculosis (most common).

Parasitic – Schistosomiasis.

Fungal – Blastomycosis.

Inorganic metals / dusts – Silicosis

Foreign body – Sutures / vascular grafts.

Unknown – Sarcoidiosis

Agranuloma can be basically called as an aggregation of epitheloid

histiocytes.

These cells are:

- Large vesicular nuclei.

- Plenty of cytoplasm

- Elongated.

Some times they may be conveled into multinucleate giant cells. These

giant cells form when indigestible matter accumulates for e.g. – Silica, Bacteria

which have indigestible walls containing mycolic acids and waxes.

Some which contain about 100 nuclei are thought to develop by accident

when 2 more macrophages attempt to engulf the same particle simultaneously.

Their cell membranes fuse and the become one e.g. Langhans giant cell foreign

body 9C Toutons 9C.

Role of Lymphatics

The lymphatic system helps to drain and sample fluid accumulated in

the extravascular matrix.

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It acts as a second line of defense whenever a local inflammatory

response fails to contain and neutralize injurious agents.

Lymphatics also delivers the antigens and lymphocytes from peripheral

sites to more central lymphnodes where T cells, B cell and the appropriate

antigen presenting cells can all gather to mount an immune response.

Lymph flow is increased in inflammation and is important in the

resolution of the inflammatory response.

It helps to drain the oedema fluid extravasated leukocytes and cellular

debris from the extravascular space.

At the same time they may also cause disintegration of the injurious

agent so, secondary inflammatory involvement of the lymphatic channel or

regional lymphatic lymphnodes may develop these may then drain to larger

lymphatics and then into the blood stream where they may cause bacterimia.

Systemic factors

1. Fever / Pyrexia

2. Constitutional symptoms

3. Weight loss

4. Reactive hyper plasia of R.E.S.

5. Hematological changes.

- E.S.R.

- Leukocytosis

- Anaemia

- Amylodiosis

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Fever

This is due to compound known as endogenous pyrogens which act on

the hypo thalamus to set the thermoregulation mechanisms at a higher

temperature.

Constitutional symptoms

Includes – Malaise

- Anorexia

- Slow wave sleep

- Nausea

Weight loss – Due to negative nitrogen balance is common in chronic

inflammation.

R.E.S.

Local or systemic lymphnode enlargement is seen commonly and

spleenomegaly is seen in specific infections.

Haematological changes

Increased E.S.R. is seen

- Neutrophilia pyrogenic infection eosinophilia in allergic

disorders lymphocytosis in chronic inflammation

monocytosis in bacterial infections.

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Anaemia

Because of blood loss in the inflammatory exudates.

Haemolysis

Bone marrow depression.

Amytodiosis

May also be seen in long standing chronic infections.

CONCLUSION

Inflammation is the first response to any harmful stimulus. It is one of

the main component of body’s defense mechanism at this point the clinician

should intervene and with a thorough knowledge of the process.

The clinician can stop the process where the beneficial effects stop and

harmful effects begin.

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Contents

1. Introduction

2. Acute Inflammation

3. Chronic Inflammation

4. Sequalae

5. Conclusion

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