INTRODUCTION TO INFLAMMATION

CONCEPTION Inflammation is a complex reaction to injurious agents

that consists of vascular response, cellular reaction, and systemic reactions.

a defensive response fundamentally

be divided into acute inflammation and chronic inflammation

Inflammation is a protective response

. 

Purpose of inflammation:

1.To dilute, localize and destroy the injurious agent2.To limit tissue injury3.To restore the tissue towards normality

•Sometimes however inflammation may be harmful e.g. inflammation due to hypersensitivity reaction

•Inflammations are mostly indicated by suffix “itis” e.g. appendicitis

Type of inflammation:

1.Acute inflammation2.Chronic inflammation

Acute inflammation: It is an immediate response to an injurious agent and last for minutes, hours or a few days Histologically, it is associated with

a.Exudation of fluid, plasma proteinb.Migration of leukocytes predominantly neutrophil

 

Chronic inflammation: It persists for week or monthsHistologically, it is associated with

a.Proliferation of blood vessels and connective tissueb.Accumulation of lymphocytes and macrophage

Cause of inflammation:

1.Infectious agent: Bacteria, virus, fungi, and protozoa

2.Immunologic agent: Hypersensitivity reaction e.g. allergy rheumatoid arthritis

3.Physical agent: Mechanical injury like cut, cold, heat, radiation

4.Chemical agent: Strong acid, alkali, and phenol

INTRODUCTION TO INFLAMMATION

CARDINAL CLINICAL SIGNS acute inflammation has 5 cardinal signs:acute inflammation has 5 cardinal signs:

Rubor- RednessRubor- Redness

Calor- HeatCalor- Heat

Tumor- SwellingTumor- Swelling

Dolor- PainDolor- Pain

Loss of functionLoss of function

increased blood flowto the inflamed area

accumulation of fluid

release of chemicals that stimulate nerve endings

a combination of factors

Time course

Acute inflammation: Less than 48 hours

Chronic inflammation: Greater than 48 hours (weeks, months,

years)

Cell type

Acute inflammation: Neutrophils

Chronic inflammation: Mononuclear cells (Macrophages,

Lymphocytes, Plasma cells).

MEDIATORS OF ACUTE INFLAMMATION

A variety of endogenous chemical mediators play some important roles in the modulation of inflammatory response.

Originated from cells or plasma:

Cell-derived mediators:

sequestered in intracellular granules and synthesized in response to a stimulus

Plasma-derived mediators:

present in precursor form and activated by proteolytic cleavage

SUMMARY OF INFLAMMATORY MEDIATORS

Function Major mediators

Vasodilation 5-HT,histamine, bradykinin ,PGE2

Permeability 5-HT,histamine, C3a, C5a, PAF

Chemotaxis C5a, LTB4, cytokins

Fever Cytokines( IL-1, 6, TNF), PG

Pain PGE2 , bradykinin

Tissue damage Lysosomal enzymes , NO

Pathogenesis:

Three main processes occur at the site of inflammation, due

to the release of chemical mediators :

Increased blood flow (redness and warmth).

Increased vascular permeability (swelling, pain & loss of

function).

Leukocytic Infiltration.

Mechanism of Inflammation

1. Vaso dilatation

2. Exudation -

Edema

3. Emigration of

cells

4. Chemotaxis

The major local manifestations of acute inflammation, compared to normal.

(1) Vascular dilation and increased blood flow (causing erythema and warmth).

(2) Extravasation and deposition of plasma fluid and proteins (edema).

(3) leukocyte emigration and accumulation in the site of injury.

Changes in vascular flow (hemodynamic changes)

Slowing of the circulation

outpouring of albumin rich fluid into the extravascular

tissues results in the concentration of RBCs in small

vessels and increased viscosity of blood.

Leukocyte margination

Neutrophil become oriented at the periphery of vessels

and start to stick.

Changes that occurs in the site of inflammation: (in summary)

1.Release of various chemical substances like histamine, Bradykinin, serotonin, prostaglandin, several reaction products of compliment system, reaction products of blood-clotting system and multiple hormonal substance called lymphokines which cause overall process of inflammation

2.Vasodilation of local blood vessels, so increase in local blood flow to inflamed area (erythremia)

3.Increase permeability of capillaries with leakage of large quantities of fluid and plasma protein like fibrinogen into interstitial space (swelling)

4.Migration of large number of granulocytes and monocytes in tissue

5.Finally healing by growth of fibrous tissue

Lymphatics in inflammation:

Lymphatics are responsible for draining edema.

Edema: An excess of fluid in the interstitial tissue

or serous cavities; either a transudate or an

exudate

Transudate: An ultrafiltrate of blood plasma

permeability of endothelium is usually

normal.

low protein content ( mostly albumin)

Exudate:

A filtrate of blood plasma mixed with inflammatory cells and

cellular debris.

permeability of endothelium is usually altered

high protein content.

MORPHOLOGIC AND FUNCTIONAL CHANGES

The two main components of the acute inflammatory:

The microcirculatory response

The cellular response

THE MICROCIRCULATORY RESPONSE

vasodilation and stasis

increased permeability

exudation of fluid

THE MICROCIRCULATORY RESPONSE

A. vasodilation and stasis

in the microcirculation a transient vasoconstriction (induced by action of mediators)

dilation of arterioles, capillaries, and venules (hyperemia)

stasis

THE MICROCIRCULATORY RESPONSE

B. increased permeability

in venules and capillaries

active contraction of actin filaments in endothelial cells

direct damage to endothelial cells

leukocyte-mediated endothelial injury

transcytosis increased

permeability increase

(reversible)

THE MICROCIRCULATORY RESPONSEB. increased permeability in venules and capillaries

Three phases of increased permeability in acute inflammation:

(1) an immediate phase

(2) a delayed response

(3) a prolonged response

These permeability changes are effected by various chemical mediators

THE MICROCIRCULATORY RESPONSE

C. exudation of fluid

exudation: increased passage of fluid out of the microcirculation because of increased vascular permeability

the composition of an exudate approaches that of plasma, but rich in proteins

fibrinogen is converted to fibrin rapidly exudation should be distinguished from transudation

Grossly, fibrin is seen on an acute inflamed serosal surface that changes to a rough, yellowish bread andbutter-like surface, covered by fibrin and coagulatedproteins.

THE MICROCIRCULATORY RESPONSE

C. exudation of fluid

The functions of exudation:

(1) dilute the offending agent

(2) cause increased lymphatic flow, conveying noxious agents to the draining lymph nodes to facilitating a protective immune response

(3) flood the area with plasma, which contain numerous defensive proteins

THE CELLULAR RESPONSE

leukocyte infiltration plays an important role

in limiting the spread of injury

in defending the host tissue

Acute inflammation is characterized by the active

emigration of inflammatory cells from the blood into the

area of injury.

THE CELLULAR RESPONSE

Extravasation: the process of the leukocytes from the vessel lumen to the interstitial tissue.

3 steps of extravasation :

(1) margination, rolling and adhesion to

endothelium in the lumen

(2) transmigration across the endothelium

(3) migration toward the site of injury

THE CELLULAR RESPONSE

A. types of cells involved neutrophils

(polymorphonuclear leukocytes)

phagocytic cell of the macrophage system

lymphocytes and plasma cells

THE CELLULAR RESPONSE

B. margination, adhesion and transmigration of neutrophils

THE CELLULAR RESPONSE

C. emigration of neutrophils

take 2-10minutes

intercellular junctions

basement membrane

THE CELLULAR RESPONSE

D. chemotactic factors

chemotaxis: In the interstitial tissue, neutrophils move toward the site of injury, oriented along a chemical gradient.

chemotactic factors: Govern the active emigration of neutrophils and the direction in which they move.

THE CELLULAR RESPONSEE. Phagocytosis

Recognition

opsonization: the agent has been coated with immunoglobulin or complement factor 3b (opsonins).

Engulfment

the agent + opsonins phagosome

Microbial killing phagosome fuses with lysosomes, therefore the enzymes can

access to the engulfed microorganism and kill them

engulfment

PROCESS OF PHAGOCYTOSIS

THE CELLULAR RESPONSE

F. Erythrocyte

The orderly flow of blood is disturbed in the dilated vessels

Erythrocyte form heavy aggregates and sludging

Erythrocyte enter an inflamed area passively

Diapedesis

Hemorrhagic inflammation

Walling-off effect of inflammation:

One of the first results of inflammation is to “wall off” the area of injury from the remaining tissue. The tissue space and the lymphatics in the inflamed area are blocked by fibrinogen clots, so that fluid barely flow through the space.  This walling-off process delays the spread of bacteria to toxic products

Different line of defense process of inflammation: 

A.First-line defense:

Tissue macrophage is the first line of defense.

Within minutes after inflammation begins, the macrophage already present in tissue like histiocytes, alveolar macrophage, being their phagocytic action Mechanism:

Product of inflammation

Activates tissue macrophage

Rapid enlargement of these cells

These macrophages break loose from their attachments and become mobile

Serves are first line of defense during the first hour or so

B.Second-line defense:

Neutrophilic invasion of inflamed area is a second line of defense

•Within the first hour or so after inflammation begins, large number of neutrophils begin to invade the inflamed area from the blood. This invasion is due to products from inflamed tissue.

•Thus within several hours after tissue damage begins, the area becomes well supplied with neutrophils, because the blood neutrophils are already mature cells, they are ready to begin immediately their scavenger functions for killing bacteria and removing foreign matter. 

C.Third-line defense:

A second macrophage invasion of the inflamed tissue is a third line of defense •Along with invasion of neutrophil, monocyte from blood enter the inflamed tissue and after hours enlarge to form macrophage

• Monocytes in blood are few in number also storage pool of monocytes in bone marrow is less• In addition to that monocytes require few hours to acquire full phagocytic capacity.

Therefore, the buildup of macrophages in inflamed tissue and to become dominant phagocytic cell of inflamed tissue is much slower than that of neutrophils requiring several days to several weeks .

D.Fourth-line defense

Increased production of granulocytes and monocytes by the bone marrow is a fourth line of defense.

 Increased production is due to stimulation of granulocytic and monocytic progenitor cell of bone marrow

 It takes 3-4 days before newly form granulocyte and monocyte reach the stage of leaving the bone marrow

 If the stimulus from inflamed tissue continues, the bone marrow can continue to produce these cells in tremendous quantities for months and even years, sometimes at rates of production 20 to 50 times normal.

ACUTE INFLAMMATION HAS ONE OF FOUR OUTCOMES:

Abscess formation

Progression to chronic inflammation

Resolution--tissue goes back to normal

Repair--healing by scarring or fibrosis

Inflammation Outcome

Acute Inflammati

on

Resolution

Chronic Inflammati

onAbsce

ss

Sinus

Fistula

Fibrosis/Scar

Ulcer

Injury

FungusVirus

CancersT.B. etc.

Feedback control of macrophage and neutrophil response:

There are five major important factors that play dominant role in the control of macrophage-neutrophil response of inflammation.

They are:

1.Tumor necrosis factor (TNF)

2.Interleukin-1 (IL-1)

3.Granulocyte-monocyte colony stimulating factor (GM-CSF)

4.Granulocyte colony stimulating factor (G-CSF)

5.Monocyte colony stimulating factor (M-CSF)

These factors increase production of granulocyte and monocyte by bone marrow

 

These factors are formed by:

1.Activated macrophage

2.T-cell in the inflamed tissue

3.Other inflamed tissue cell

Pus:

When neutrophil and macrophage engulf large number of bacteria and necrotic tissues, all neutrophil and many, if not most of macrophage die, so after several days, a cavity is formed in inflamed tissue

This cavity contains varying portion of necrotic (dead) tissue, dead neutrophils, dead macrophage, and tissue fluid. Such a mixture is called pus and cavity, which contain pus, is called abscess.

After the infection has been suppressed, dead cells and necrotic tissue in pus gradually autolyze over a period of days and the end products are usually absorbed into surrounding tissues until most of evidence of tissue damage is gone.

Leucopoiesis: Process of production of WBC under normal physiological condition 

Granulopoiesis: The process of production of granulocytes under normal physiological condition. 

Leukocytosis: Increased number of WBC above its upper normal limit Is increase in total white cell count above 11,000/mm3 in peripheral blood in adult

The particular white cell series affected varies with underlying cause 

Neutrophilia:

1.Infection: e.g. abscess, acute appendicitis, tonsillitis, bacterial pneumonia 2.Non-infectious inflammatory disorder like rheumatic fever3.Tissue injury due to infarction: Myocardial infarction, burn, surgery4.Hemorrhage5.Stress: Childbirth, severe pain

Eosinophilia:

1.Helminthic infection: Hookworm, roundworm, tapeworm, filariasis2.Allergic reaction: Asthma, hay fever, urticaria3.Familial eosinophilia4.Tropical eosinophilia5.Loeffler’s syndrome

Lymphocytosis:

1.Bacterial disease: Whooping cough, tuberculosis2.Viral disease: Viral hepatitis, chicken pox, mumps, infectious mononucleosis3.Protozoal disease: Chronic malaria, kalazar

Leukopenia: Means reduction in total white cell count below 4000/mm3

Causes:1.Bacterial infection: Typhoid and paratyphoid fever2.Viral infection: Influenza, measles3.Aplastic anemia4.Megaloblastic anemia5.Hyperspleenism6.X-ray irradiation7.Cytotoxic drug

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