INFLAMMATION "Inflammation is one of the most important and most useful of our host defense

mechanisms, and without an adequate inflammatory response none of us or our patients would

be living. It is also one of the most common means whereby our own tissues are injured."

(Slauson and Cooper, 2002)

Definition: It is the immediate local vascular and exudative reaction of living tissue against an

injurious agent (irritants). It is the reaction of vascularized living tissues to local injury.

The suffix “itis” is usually added to the inflamed organs as tonsil = tonsillitis.

Roles of inflammation:

1-Protection: i-Contain and isolate the injury.

ii-Destroy invading organisms and inactive toxins(dilutes, remove or localize).

2-Achieve healing and repair: i-Under ideal conditions the source of the tissue injury is eliminated, the inflammatory

response resolves and normal tissue architecture and physiological functions are restored

ii- The nature of the acute inflammatory reaction is intense and the affected area is

walled-off by the collection of inflammatory cells. This process results in destruction of

tissue by products of polymorphonuclear leukocytes and formation of an abscess.

iii-Failure to eliminate the pathological insult results in persistence of the inflammatory

reaction and spread out in the body.

iv-Chronic inflammation often leads to scar formation.

Causes of inflammation: They include

A-Endogenous causes:

i-immunological reactions (Ag-Ab reaction).

ii-some neurological and genetical disorders.

B-Exogenous Causes:

I-Non-living irritants: include

1-Physical irritants: as mechanical trauma, cold, heat or radiation.

2-Chemical irritants: as strong or concentrated acids or alkalis.

3-Neutrional irritants: as in vitamin or oxygen deficiencies.

II-Living irritants: include

1-Bacteria 2-Viruses 3-Fungi 4-Parasites

They produce their effect either through direct irritation or toxin production.

Remember:

The body defense mechanism either:

i-Local Body defense (local reaction): inflammation.

ii-Systemic body reaction: It is help the local one and include

-Humoral defense

-Cellular systemic defense (leukocytosis).

-Fever

Humoral defense: It is based upon the production of antibodies in the body fluid. It includes

agglutinin, lysin, opsonin, precipitin,…

NB: Antigen is a substance (protein in nature or polysaccharides) capable of inducing antibody

formation and combined specifically with it.

Haptens (incomplete antigens): It is combined specifically with antibodies; but fails to

stimulate their formation.

The response to injury and infection The mechanism for triggering the response the body to injury is extremely sensitive. Three

major events occur during this response:

1-An increased blood supply to the tissue ''in danger'': It is performed by vasodilation.

The inflamed tissue looks like containing greater number of blood vessels.

2-Increased capillary permeability: It is caused by retraction of the endothelial cells.

This permits larger molecules than usual to escape from the capillaries, and thus

allows the soluble mediators of immunity to reach the site of inflammation.

3-Leukocytes migrate out of the capillaries into the surrounding tissues: In the earliest

stages of inflammation, neutrophils are particularly prevalent, but later monocytes and

lymphocytes also migrate towards the site of infection.

Cardinal Signs of Acute Inflammation and Its Pathogenesis:

1-Redness (Rubor) 2-Hotness (Calor) 3-Pain (Dolar)

4-Swelling (Tumor or Edema) 5-Loss of Function (Functiolaesa)

1-Redness (Rubor):

The inflamed area usually appear red due to a great increase of blood in the inflamed part

due to dilation of capillaries and arterioles w opening of all collapsed capillaries.

NB: Dilation of capillaries caused by chemical mediator and dilation of arterioles caused by

nerve reflex.

Axon reflex mean that the stimuli pass from sensory nerve–ending up to the bifurcation of

the axon then travels in direction apposite to the normal toward the periphery and although

these stimuli are traveling along sensory nerve it has the capacity to dilate the arterioles.

Triple response of Lewis: Lewis 1927 proved that the dilation of capillaries caused by

chemical mediators and the dilation of arterioles caused by axon reflex.

It occurs when a blunt instrument (a corner of a ruler) is down firmly across the skin of arm

and illustrated the vascular change in the acute inflammation.

i-A red line appears rapidly in the site of contact.

ii-This red line is surrounded by a bright red-halo (flare) of about 3 cm in diameter.

iii-The red line becomes pale due to its swelling (wheal).

iv-The swelling increases and finally there is a pale wheal surrounded by a wide red flare.

In this experiment, 3 cardinal signs of inflammation (redness, hotness and swelling) are

evident.

Chemical Proof:

A comparison of the skin of a normal arm with another arm injected with adrenalin

(antihistaminic) before experiment by 10 minutes showed only the flare. This is indicating that

the red line and wheal are due to dilation of blood capillaries which is caused by histamine

(chemical mediators).

Axon-Reflex Proof:

If the nerve supply (sensory nerve ending) is cut 6-10 days before the experiment (allow

degenerating the nerve fiber), only red line and wheal are developed and the flare is not

appeared. This is indicating that the flare is due to dilation of arterioles which is caused by

nerve reflex.

Conclusion:

-Capillaries dilation is mediated by chemical mediators.

-Dilation of arterioles is mediated by axon reflex.

-Lymphatics are dilated in attempt to drain the exudate.

2-Hotness (Calor):

The inflamed area feels warmer than the adjacent normal area due to:

i-Blood from internal organs (warmer) rushes to the inflamed area.

ii-High metabolic rate of the inflamed area “as on fire or catching fire".

3-Pain (Dolor):

The inflamed area is painful because:

i-Pressure on nerve ending by exudate (edema).

ii-Liberated chemical mediators from damaging cells e.g. bradykinin sensitizing

the nerve endings.

iii-Changes in the pH of the exudate (acidic).

iv-Changes in the isotonicity of the fluids (hypertonic).

4-Swelling (Edema or Tumor):

The inflamed area is swollen due to:

i-Accumulation of exudate in the inflamed area (Exudation).

ii-Increase the blood inside the blood vessels (Active local hyperemia).

5-Loss of Function (Functiolaesa): It is due to

Wheal: it is the swelling which replaced the red line and it is due to dilation of blood capillaries by the action

of chemical mediators.

Flare: It is the inflamed area around the wheal (appeared after a period) due to dilation of the arterioles, which

is mediated by axon reflex (bright halo).

i-Pain

ii-Edema cause mechanical disability

iii- Destruction of tissue

iv-Interference with the activity of specific cells as of glandular organs.

The inflammatory process: It is composed of 4 major components:

1-Plasma Proteins:

They leaks to the perivascular space at the site of inflammation (swelling) and include:

i- Albumin and immunoglobulins

ii-Zymogens (inactive proteases) which activated and causing the initiation of

complement, fibrinolytic, coagulation and kinine system which are responsible for the

inflammatory response.

iii-Other protein systems are involved.

2-Fixed Tissue Cells:

They include:

i-Mast cells. ii-Fibroblasts iii-Endothelium

They are very important for initiation and maintaining the inflammatory process through

secretion of chemical mediators. They are either the targets of the primary irritant or the most

affected by the damage caused to the adjacent cells.

3-Leukocytes and Platelets:

They arrive to the site of inflammation by blood. The leukocytes are important to

phagocytize and degrade the organisms and debris; meanwhile the platelets do its function

within the vascular space through secretion of chemical mediators

4-Mediators of The Inflammatory Reaction:

They consist of proteins, acidic lipids and vasoactive amines, secreted by the above

mentioned and play an important role in inflammation.

Normal vascular anatomy and fluid exchange

A-Normal vascular anatomy

The lining endothelium of microcirculation varies in different organs. It can be classified

into four types:

1-Continous endothelium:

It is found in arteries, arterioles, venules, veins and capillaries in most organs. These types

of endothelium are connected to each other through pleomorphic intercellular junction.

2-Fenestrated type:

Definitions:

Edema: Excess fluid in interstitial tissue or body cavity. It may be exudate or transudate.

Exudate: It is an inflammatory extravascular fluid that has a high protein concentration and cellular

debris; specific gravity above 1.020.

Exudation: It is extravasation of fluid, proteins, and blood from vessels into the interstitial space or

body cavity.

Pus: It is a purulent inflammatory exudate rich in neutrophils and cell debris.

Pus cell: It is dead neutrophils and produce proteolytic enzyme.

Transudate: It is an extravascular fluid with low protein content and specific gravity below 1.012;

essentially an ultrafiltrate of blood plasma resulting from increased hydrostatic pressure

or decreased osmotic pressure.

It is present in capillaries of endocrine and exocrine glands, intestinal mucosa and renal

glomeruli. These vessels are fenestrated or opening where the endothelium is entirely missing

as in glomerular capillaries or is reduced to a cell membrane.

3-Sinusoidal endothelium:

It is found in liver and spleen and is characterized by presence of holes in endothelial cells

that permit passing of even large molecule from the vascular lumen.

4-Specialized endothelium:

It is presents in postcapillary venules of lymphatic organs. This type is large and columnar.

B-Normal fluid exchange:

It occurs via capillaries and under normal circumstances; there is a constant exchange of

nutrients (glucose) and cellular by products (Co2) between the blood and interstitium by:

1-Diffusion:

The most important means by which the plasma components cross continuous endothelium

is by diffusion. The solutes diffuse across the vascular wall from the side of high concentration

to the side of low concentration. Lipid soluble materials and water diffuse by direct crossing the

lipid bilayer of endothelial well.

2-Pore system:

Large non-lipid soluble molecules can’t pass by diffusion and they use the capillary

intercellular slits 6-7 nm in diameter or use a system of endothelial pores (pore system).

3-Bulk flow (Bulk transfer):

Although more solutes and fluid pass by diffusion there is also important processing with

the fluids and solutes pass across the vascular wall due to the difference in hydrostatic pressure

inside and outside the wall of vessels.

There are 4 forces responsible for this equilibrium:

1-Capillary Hydrostatic Pressure:

2-Hydrostatic Pressure of The Interstitial Space:

3-Plasma Colloid Oncotic Pressure:

4-Interstitial Fluid Colloid Oncotic Pressure:

Arteriolar Venular

Plasma hydrostatic pressure 30 mm Hg 17 mm Hg

Tissue hydrostatic pressure 8 mm Hg 8 mm Hg

Plasma colloidal osmotic pressure 25 mm Hg 25 mm Hg

Tissue colloidal osmotic pressure 10 mm Hg 10 mm Hg

(30-8) - (25-10) = (17-8) – (25-10) =

Net filtration or absorption* 7 mm Hg -6 mm Hg*

NB: If the fluid leakage is exceed the fluid returned by venules and lymphatic, edema develops.

NB: Starling's law:

Under normal conditions, the amount of fluid filtered out the arterial capillaries roughly equals

the fluid returned to the various capillaries.

Cells participating in inflammation

Acute Inflammatory Cells Chronic Inflammatory Cells

1-Neutrophils

2-Eosinophils Granulocytes

3-Basophils/ mast cell

1-Macrophages and epithelioid cells

2-Giant Cells

4-Lymphocytes (Agranulocytes) 3-Plasma cells

I-NEUTROPHILS (polymorphs, Polys, PMN's, Neuts):

Characteristics -High motility due to rapid amoeboid movement

-Respond to a wide variety of chemotaxic compounds

-Phagocytic and bactericidal activities

-Neutrophils are the major cellular defense system against bacteria

-Are a major part of the innate immune system-first line of defense.

-Crucial to the entire inflammatory process

-Neutrophils have surface receptors for complement fragment C3b and Fc portion of

immunoglobulin

-End cell-don’t divide

2 distinct pools of neutrophils in the blood:

1-Marginating Pool: Neutrophils within blood vessels but lying out of the flow -or-

"marginated" against the walls.

2-Circulating Pool: Neutrophils in circulation

- Circulating and marginating pools are approximately equal in size

- Neutrophils in the marginating pool can be mobilized very quickly

- Once neutrophils go out of the vasculature they do not return (Live 1-2 days in tissue)

2 major sources of reserve neutrophils are

1-marginating pool

2-bone marrow

Morphology of neutrophils: - 10-12 µm in diameter with a multilobed nucleus.

- Contain abundant cytoplasmic granules.

Several (up to 5) classes and subclasses have been identified:

1-Azurophil Granules (primary granules) large, oval and electron dense

2-Specific Granules (secondary granules) smaller, less dense and more numerous

3-Tertiary granules (gelatinase granules)

NB: Differentiating neutrophils from eosinophils in rabbits, guinea pigs, rats, reptiles, fish and

birds is difficult because the neutrophils have prominent eosinophilic granules and are difficult

to differentiate from eosinophils. They tend to be grouped together.

NEUTROPHIL GRANULE CONSTITUENTS

Constituents Granules

Azurophilic Granules Specific Granules Small or tertiary (only in

human: gelatinase granules)

A-Antimicrobial 1-Myeloperoxidase

2-Lysosomes

3- BPIP

4-Defensins

1-Lysosomes

2-Lactoferrin

B-Neutral

proteinases

1-Cathepsin G

2- Elastase

3-Proteinase 3

1-Collagenase

2-Complement activator

1-Gelatinase

2-Plasminogen activator

C-Acid Hydrolases 1-Cathepsins (B and D)

2-β-D-Glucuronidase

3-α-Mannosidase

4-Phospholipase A2

1-Phospholipase A2

1-Cathepsins (B and D)

2-β-D-Glucuronidase

3-α-Mannosidase

Cytoplasmic

membrane

receptors

1-CR3, CR4

2-FMLP-receptors

3-Laminin receptors

Others Chondroitin-4-sulphate 1-Cytochrom b

2-Monocyte-chemotactic factor

3-Histaminase

4-Vit B12 binding protein

1-Cytochrom b

BPIP: Bactericidal permeability increasing protein

FMLP: N-Formylmethionyl-leucyl-phenylalanine.

Function of Neutrophils in the inflammation:

1-Phagocytosis

Ingest, neutralize, and kill/destroy ingested material

Killing mechanisms:

a. Production of oxygen free radicals

b. Hydrogen peroxide

c. Lysosomal enzymes

2-Mediate tissue injury: i-Lysosomal enzymes are released into the extracellular space during phagocytosis

causing cell injury and matrix degradation

ii-Activated leukocytes release reactive oxygen species and products of arachidonic acid

metabolism which can injure tissue and endothelial cells

iii-These events underlie many human diseases (e.g. Rheumatoid arthritis)

3-Regulate inflammatory response : Via releasing chemical mediators:

i-Leukotrienes

ii-Platelet activating factor

Remark: The neutrophils have surface receptors for:

i-Fc receptor and Ab and C3b of complement.

ii-Platelet activating factor, receptor.

iii-Leukotrine B4, receptor.

iv-Leukocyte cell adhesion molecule.

II-EOSINOPHILS: Characteristics

1-Numerous at inflammatory sites which result from

Parasites

Allergic or Immunologic Disease

Some fungi

2-May be present in any exudate (1-5% WBC).

3-Phagocytic but less so than neutrophil

4-Present in tissues in contact with environment

Intestine

Skin

Mucous membranes

Lungs

5-Sensitive to corticosteroid therapy

Release from bone marrow

Cytokines important for production

(IL-3, IL-5 and GM-CSF)

6-Ratio of eosinophils

Blood: bone marrow: tissue

1: 200: 500

Morphology:

-Granules vary in size (dependent upon species), bilobed nucleus in all animals except in

rodent (C-shape).

-Granules stain with acid dye eosin - hence their name

-Slightly larger than neutrophils (12- 14 µm in diameter)

-Lysosomal granules contain a wide variety of catalytic enzymes similar to those in

neutrophils, except they do not contain lysozyme

-Antiparasitic proteins present in granules include

i-Major basic protein ii-Eosinophil cationic protein

Function i-Work to kill or damage helminths and other pathogens

ii-Cause and assist in hypersensitivity reactions (Type I hypersensitivities).

iii-Regulator of inflammation - particularly to mast cell products

iv-Killing helminths by antibody-dependent cell-mediated cytotoxicity

DISTINCTIVE CHARACTERISTICS OF EOSINOPHILS

CONSTITUENT OR PRODUCT FUNCTION

Major basic protein Parasite killing

Induces histamine release from mast cells

Neutralize heparin from mast cells

Eosinophilic cationic protein Parasite killing

Shortens coagulation time

Alters fibrinolysis

Arylsulfatase Inactivates leukotrienes (LTC4, LTD4, LTE4)

Histaminase Inactivates histamine

Phospholipase D Inactivates platelet-activating factor

III-BASOPHILS AND MAST CELLS

Characteristics: i- Basophils are rare circulating granulocytes

ii-Mast cells are found in perivascular sites

iii-Both derived from bone marrow

iv-Contain abundant cytoplasmic metachromatic granules

1-Metachromatic granules stain pink to blue with toluidine blue.

2-Result of high content of sulphated mucopolysaccharides (heparin).

v-Granules also contain histamine, proteases, + potent inflammatory mediators

vi-Receptors that bind the Fc portion of IgE antibody

vii-Major source of histamine - acute inflammation

viii-Produce cytokines (TNF-", IL-1,-3,-4,-6-,-8. IFN)

ix-Major cellular mediator of Immediate Hypersensitivity Reactions (Type I)

x-Don’t die after release of granules.

xi-In birds stimulate the gonadotrophic hormone.

Morphology: Mast cells - round nuclei with abundant cytoplasm filled with granules

Found in connective tissue in perivascular spaces

Contact with environment - (lung, gut, mm, skin)

2 subtypes

1-Mucosal mast cells: seen in gastrointestinal and respiratory tract

2-Connective tissue mast cells: found in the skin

Basophils: -from blood and multilobed or S shape nuclei

Are recruited to sites in hypersensitivities

Functions: 1-Intimately involved in acute inflammation

Release of histamine smooth muscle contraction and increase vascular permeability.

2-Involved in recruitment of Eosinophils (secrete ECF-A).

Cause other cells to secrete eotaxins

3-Generate Cytokines

IV-MACROPHAGES/ MONOCYTES Characteristics:

Macrophages:

i-Derived from circulating blood monocyte of bone marrow origin

ii-Some originate from immature resident mononuclear phagocytes

iii-“Histiocytes” another name for tissue macrophages

Monocytes:

-Do not have a large reserve pool in the bone marrow

-Remain longer in circulation, (24-72 hours)

-Are functional cells but require activation to become macrophages secrete various chemical

mediators.

-Monocytes migrate into tissues and then are called macrophages.

-Motile - but sluggish

-Life span: 30-60 days but can proliferate

Morphology: -Larger (15-20 µm) than neutrophils.

-Prominent, usually central nuclei, which may be folded or bean-shaped.

-Contain many lysosomes and have cytoplasmic extensions.

Function: 1-Phagocytosis:

i-Antimicrobial and phagocytic (Oxygen radicals) cell.

ii-Recruit other leukocytes (secrete several chemokines and cytokines)

iii-Stimulate or modulate other cell activity (vascular effects)

2-Secretory function:

Macrophages are capable of the production of large number of proinflammatory,

procoagulatory and immune regulatory products.

3-Help in repair:

i-Clean up or phagocytize necrotic debris in the wound.

ii-Simulate the growth of new local vessels (secret growth factors)

iii-Induce fibroblasts to migrate, divide and produce collagen.

iv-Induce systemic effects.

4-Regulation of granulocyte and monocyte pools:

During the inflammatory response or tissue injury, there is increased production of

granulocyte and monocytes in the bone morrow. The increased production is controlled by

hormonal-like factors secreted by macrophages at the site of tissue injury and via blood reach to

the bone marrow stimulating the stem cell to divided and differentiates to mature effectors cells.

NB: These substances known as some of these factors are:

i-M-CSF: (macrophage colony stimulating factor).

ii-G-CSF: (granulocyte colony stimulating factor).

iii-GM-CSF: (macrophage colony stimulating factor).

5- Modulation of tumor cell growth: via production of TNF.

6-Source of multinucleated giant and epithelioid cells

Types of giant cells:

1-Inflammatory giant cells.

2-Tumor giant cells.

3-Specific giant cells.

1-Inflammatory Giant cells: These types of cells are produced by fusion of several macrophages together to phagocytize

largest particles and they include:

A-Langhan’s giant cells:

They have many nuclei form wreath at the periphery i.e. arranged around the periphery of

the cytoplasm in the form of horse-shoe shape. They usually observed in TB, Actinomycosis

and Actinobacillosis.

B-Foreign body giant cells:

They have numerous nuclei (50-100) of the same size and shape and distributed

haphazardly in the cytoplasm (in the center, at one or both poles). They observed in the

presence of foreign material in the tissues as in the cases of silicosis or presence of splinters or

thorns or cat gut.

C-Touton giant cells:

The cells are two-toned (the nuclei arranged peripherally around central eosinophilic

cytoplasm with a rim of foamy cytoplasm peripheral to the nuclei).

NB: The Nuclei arranged as Langhan’s giant cells and they show in areas containing lipids.

2-Tumor Giant cells:

The nuclei are relatively few about 8 and of variable size and shape (produced by nuclear

division without cytoplasm division). They observed in malignant neoplasms of CT.

3-Specific giant cells: They are pathognomonic for some specific diseases as.

i-Aschoff cells of rheumatic fever in the heart.

ii-Warthin-Finkeldy giant cells in measles.

iii-Spermatid giant cells in testicular degeneration.

NB: Dendritic cells:

i-Langerhans cells of epidermis.

ii-Follicular cells of nodal and splenic follicles.

iii-Interdigitating dendritic cells (in the T-lymphocyte areas of lymph node and spleen).

The relatedness of dendritic cells to other mononuclear phagocytes is based on their ability

to function as potent antigen–presenting cells but they are relatively poor at phagocytosis

V-LYMPHOCYTES AND PLASMA CELLS: Characteristics:

i-Principally involved in immune reactions

-Immediate antibody response.

-Delayed cellular hypersensitivity responses.

ii-Less motile than neutrophils and monocytes and non-phagocytic.

Plasma cells produce and release antibody (originate from B cells).

-Produced by lymphoid organs

-Migrate to lymphoid tissue (spleen, lymph node)

-Recirculate

Morphology: Heterogeneous in size (8-10 µm) and morphology

There are 2 types (T cells and B cells)

T-Lymphocytes:

T-cells differentiate in the thymus into 4 subsist 2 regulators T- helper

T- suppressor

2 effectors T- cytotoxic

T- delayed hypersensitivity

i-CD4 helper T cells: divided into

Th1: regulate the cellular immunity through interleukins and γINF.

Th2: stimulate the B cells to differentiate to plasma cells

ii-CD8: It either

T-cytotoxic: cytotoxic for tumor and infected cells with living organisms.

T-suppressor: suppress the activated T and B cells.

iii-Td for delayed hypersensitivity

Functions of T cells:

i-T- cell don't respond to free Ag but the Ag must be presented by APCs in context

with MHC molecules and these MHC molecules must be recognized as self molecule

by T-cells before the T-cell recognize the Ag. This dual recognition of Ag Only in

context with MHC is known as MHC restriction.

ii-T-cells are responsible for cellular immunity or cell-mediated immunity as immune

response without Ab involvement.

B-lymphocytes:

Functions of B lymphocytes:

i-The mature B-cells has immunoglobulin surface receptors (IgM/IgD), they act as

receptors for Ag (MHC-II and complement).

ii-Some cells differentiated to plasma cells to produce Ab.

iii-Other cells differentiated to memory cells that can survive for months without further

antigenic stimulation and on re-exposure to the same Ag. Some of these cells are rapidly

producing Ab.

iv-Plasma cells and other become memory cells.

Natural killer cells (NK):

1-It represent heterogeneous group of cells composed of cells from different lineages and they

are defined only by their functional attributes not by their histogenesis.

2-They can kill cells targets with out regard to Ag recognition or MHCI expression therefore

they are capable of MHC unrestricted cytotoxicity.

3-Large granular lymphocytes (LGLs) represent a subset of NK cells but not all NK cells are LGLs.

Mature post thymic T-Cells live for several months they not resident in any one lymphoid organs, but they

transverse from one lymphoid organ to another constitute the recirculating lymphocyte pool, however they

can found in paracortex of LN and non-follicular region of splenic white pulp. They contained round nucleus

and narrow rim of light blue cytoplasm which contain few azurophilic granules.

i-Represent 10% of the lymphocytes in the peripheral circulation.

ii-Mature B- cells circulate in the blood and lymph vessels W a half – life of 2 days , but Ag primed cells have

a longer life span.

iii-They can found in:

Cortical follicles of L.N.

Follicles of Peyer's patches

Follicles of splenic white pulp.

Activation of B cells: it is either by

1-T-cell independent mechanism:

-It involve antigens that have repeating epitopes as polysaccharides with cross link adjacent surface

immunoglobulin on the B-cell, this crass linking signals the B-cell to proliferate and differentiate.

2-T-cell dependent mechanism:

-Depend on the help T-cells and involve protein fragment antigens.

-The B-cell recognizes the Ag by its surface Ab internalizes it a process it (mechanism similar done by

APCs and presents if on the surface bound to MHC-II Molecules.

-The Ag is then presented to T-cell which becomes activated and produces particular growth factors for

the B-cell to divide to make memory cells or causing it to terminally differentiate to plasma cells.

4-These cells:

i-Don’t express TCR

ii-Don't rearrange the genes associated with TCR.

iii-May or may not express CD8.

Functions of NK:

i-Recognize changes on virus – infected cells and destroy them by an extra cellular killing

produce molecule that damage infected cells membrane destruction.

ii-Recognize changes in the cell membranes of cancer cells recognize them.

iii-Recent observation suggests that NK cells kill cells express low levels at MHCI molecules.

iv-TL12 and TNF stimulate NK cells to release interferon,

VI-PLATELETS AS INFLAMMATORY CELLS

NOTE: In addition to their role in hemostasis and coagulation, platelets are very important in

inflammation. Primary hemostasis is a part of the inflammatory response.

Products from activated and/or aggregated platelets:

-Fibrinogen -Fibronectin

-Coagulation factors VIII and V -Serotonin

-Histamine -ADP, ATP

-Ca++ cations -Thromboxane A2

-Complement-cleaving proteases -Platelet Activating Factor

-Growth factors -P-selectins

Contributions to the inflammatory response

-Release constituents that increase vascular permeability

-Release constituents that may provide local amplification

-Release cationic inflammatory mediators

-Release enzymes that can directly activate C5

-Chemotactic activity for leukocytes

MAJOR COMPONENTS OF THE INFLAMMATORY RESPONSE:

I-Vascular Changes:

i- Change in the caliber (diameter) of blood vessels.

ii-Changes in the blood flow.

iii-Changes in the vascular wall.

II-Cellular Events:

i-Margination (from the axial to periphery) as a result of slowing or stasis of blood.

ii-Adhesion, pavementation and transmigration to the wall of blood vessels.

iii-Emigration and chemotaxis (accumulation of leukocytes at sites of injury)

PLATELETS AS INFLAMMATORY CELLS i-Lysosomal-like granules constituents

ii-Release action is a secretory degranulation

iii-Respond to vascular injury

iv-Accumulate in vessels adjacent to inflamed areas

v- Interact with immune-complexes as well as microorganisms

vi-Initiate intravascular inflammation

vii-Enzymes can further damage endothelium

viii-Adhesion to subendothelium (collagen)

iv-Phagocytosis and degranulation (activation of inflammatory cells and removal

of stimulus).

I-Vascular Changes: i-Changes in the caliber of blood vessels:

1-Transient vasoconstriction:

Narrowing of the arterioles immediately after injury results from smooth muscle

contraction of the arterioles, which mediated by damaging stimulus. It disappears within

3 to 5 seconds.

2-Long-standing vasodilation:

i-The next response is widespread dilation of arterioles and venules due to relaxation of

smooth muscles caused by chemical mediators (mostly prostaglandin).

ii-The collapsed capillaries are opened and the tissue become hyperemic (Rubor) and

warm (Calor).

iii-Halo or flare develops and radiate peripherally from the injured site. The cause of this

flare results from (axon reflex) which cause dilation of arterioles. It extend throughout

the stage of acute inflammation.

ii-Changes in the blood flow (blood stream):

1-Acceleration of the blood flow:

i-Initially the blood flow very rapidly due to sudden and rapid dilation of blood vessels

in the inflamed area. It lasts for minutes or hours depending on the severity and nature of

the irritant.

2-Slowing of the blood flow:

i-Hemoconcentration (increase blood viscosity) is due to escape of exudate into the

inflamed area through the wall of blood vessels.

ii-Protruded-swollen endothelium inside the lumen of blood vessels together with

increase the capillary bed that resist the blood flow (mechanical resistance).

iii-Margination and pavementation of the leukocytes to the inflamed endothelium.

iv-The impaired action of plasmatic zone which exchanged position with axial cellular

zone. The latter is controlled by “Centripetal force”.

3-Stasis of the blood stream:

It is due to thrombosis of the blood vessels (obstruction) at inflamed area.

iii-Changes in the vascular wall:

A-Vascular endothelium become swollen, rounded and projected into the lumen of bv.

B-Changes in vascular permeability:

Increased vascular permeability is one of the clearest changes that occur during

inflammation leading to swelling or edema. Five mechanisms of increased vascular

permeability are described:

1-Formation of endothelial gaps in venules: (Immediate Transient Response)

i-Endothelial cell contraction: Rapid Widening of intercellular junctions (gaps).

Mediators: histamine, bradykinin, leukotrienes.

Binding of mediator to receptor contraction.

Short lived 15 - 30 minutes

Reversible

Affects only venules

(Capillaries and arteries not affected)

ii-Endothelial retraction: Delayed and prolonged

Cytoskeletal and junctional reorganization

Reversible

Structural reorganizing of cytoskeleton - disruption of endothelial junctions

Starts 4-6 hours lasts and lasts 24+ hours

Mediators: tumor necrosis factor (TNF), interleukin-1 (IL-1), Interferon-gamma

(γINF)

2-Direct endothelial injury: (Immediate Sustained Response)

Arterioles, venules and capillaries affected

Lasts for several hours to days until vascular structures are repaired or thrombosed

Causes: Damage directly to endothelium

Severe burns or lytic bacterial infections

Milder damage-delayed prolonged leakage (2 to 12 hours)

Some toxins, thermal injury

3-Leukocyte dependent endothelial injury

Cause: leukocytes aggregate and adhere to endothelium

Become activated release toxic oxygen species and proteolytic enzymes, which

then cause endothelial injury or detachment resulting in increased permeability.

Sites: venules (at neutrophils can adhered).

Time: late response

4-Increased transcytosis

i-Transport of fluid through endothelial cells by channels of interconnected, uncoated

vesicles and vacuoles (vesiculovacuolar organelles).

ii-Certain factors (vascular endothelial growth factor) can increase the number and size

of these channels. May be important method used with histamine and other chemical

mediators.

5-Leakage from regenerating capillaries

Cause: Proliferating endothelial cells are leaky.

Time: Seen in repair process.

Mediators: VEGF (vascular endothelial growth factor).

There are three pattern of vascular leakage

i-Immediate transient response occurs due to mild injury and lasts for 30 minutes under the effect

of chemical mediators. This response occurs mainly in postcapillary venules due to increase the

hydrostatic pressure.

ii-Immediate sustained response occurs immediately after severe injuries and lasts for several hours

to several days. It involves all vessels leading to increase vascular permeability and the formation of

inflammatory exudate.

iii-Delayed prolonged response occurs due to mild to moderate injury starting after injury peaking 2

to 6 hours and gradually subsides by 8 hours as in case of sunbathing. The Leakage occurs from

venules and capillaries from damaged endothelium.

Chemical mediators of vascular permeability

Types of Mediator Characteristics

Vasoactive Amines Histamine and serotonin - Stored in mast cells, basophils and platelets as granules

Plasma kinins (Bradykinin principle vasoactive amine)

- Generated from plasma precursors by enzymatic cleavage

Complement Fragments C5a and C3a - Work indirectly by causing WBC’s to release mediators

Leukotrienes LTC4, LTD4, LTE4 (independent of neutrophils)

LTB4 – works dependently via neutrophils

Prostaglandins PGE2 and PGI2 – vasodilation & potentiates vascular leakage

TXA2 – causes vascular leakage

Cytokines

Interleukin 1 (IL-1)

Tumor necrosis factor (TNF)

Derived from WBC’s

Induce “Second Phase”

Platelet Activating Factor (PAF) Works on endothelium and WBC’s

II-Cellular Events: The movement of leukocytes (primarily neutrophils and monocytes) from peripheral blood

to the area of inflammation is one of the most important manifestations of acute inflammation.

The sequence of events in the extravasations of leukocytes from the vascular lumen to the

extravascular space can be divided into 4 steps:

i-Margination and Rolling: the leukocytes pushed out from the central axial to periphery

and come in contact with endothelial lining as a result of slowing or stasis of blood. Rolling

of the leukocytes along the vasculature is mediated through transient interactions between

selectin proteins and their carbohydrate ligands.

NB: In normal blood vessels the cellular elements of blood are present in a central (axial zone)

leaving a cellular cell free area of plasma in contact with vessel wall (peripheral zone).

ii-Adhesion, Pavementation andTransmigration:

Adhesion and transmigration occur by interaction between complementary adhesion

molecules on leukocytes and endothelium.

The mechanisms of adhesion involves both:

1-Endothelial dependent mechanism.

2-Leukocyte dependent mechanism.

1-Endothelial dependent mechanism:

-The endothelial cells of postcapillary venules in the site of inflammation become enlarged,

plumped and synthesized new receptors (normally absent) under the effect of IL-1 and INF.

-These receptor proteins interact with complementary proteins on leukocytes leading to

adhesion.

There are 3 classes of adhesion molecules :

a-Immunoglobulin superfamily. b-Integrin family c-Selectin family

These three classes include many different molecules that are important in cell-to-cell

interactions in the immune response, but there are 4 major endothelial adhesion proteins

involved in leukocyte-endothelial interactions which are 2 fast acting selectins (E and P) and 2

late acting immunoglobulin (ICAM and VCAM).

I-Endothelial-dependent mechanism: 1-E-selectin:

i-It peak 2-4 hrs after exposure to cytokines (IL-1 and TNF–α) and disappear within 12-24

hrs without repeated stimulation.

ii-It mediates the adhesion of neutrophils.

2-P-Selectin:

i-It found in the cytoplasmic Weibel–Palade bodies of resting endothelial cells and during

endothelial activation it redistributed to the endothelial cell membrane within minutes to

mediate adherence.

3-ICAM (intercellular adhesion molecule):

4-VCAM (Vascular cell adhesion molecular):

i-They appear on the endothelial cell membrane in response to cytokines (as IL-1 and

TNF-α) but appear later and persist for longer period of time.

ii-ICAM-1 mediates endothelial adhesion with most leukocytes (neutrophils, monocytes

and lymphocytes) .

iii-VCAM-1 is more important in lymphocytes and monocytes adhesion to endothelium.

II-Leukocyte-dependent mechanism:

i-One of which is termed (lymphocyte function-related Antigen-1; LFA-1), which is the

leukocyte receptor for endothelial ICAM adhesion protein. So patient with leukocyte

adhesion deficiency (LAD) have a mutation in the B2 chain of the LFA-1 molecule, thus

fail to localize leukocytes to damage tissue with impaired healing and life-threading

inflection. B1 : VLA

Integrins: They include: B2 : LFA

B3 : Similar in action to VLA

ß1 Integrins: are composed of a group of six adhesion proteins called very late antigen (VIA)

protein (so named because the first two proteins isolated from this group). They were induced

on lymphocytes, weeks after primary antigenic stimulate

VLA-4: is constitutively expressed on resting lymphocyte and monocytes and this protein is

the ligand for VCAM-1.

Leukocyte adhesion and Transmigration Endothelial Molecule Leukocyte Receptor Major Role

P-Selectin Sialyl-Lewis X

PSGL-1

Rolling (neutrophils, monocytes,

lymphocytes.

E-Selectin Sialyl-Lewis X

Rolling, adhesion to activated endothelium

(neutrophils, monocytes, T cell).

ICAM-1 CD11/CD16 (integrins)

(LFA-1, Mac-1)

Adhesion, arrest, transmigration (all

leukocytes)

VCAM-1 α4β1 (VLA4)

(integrins)

α4β7 (LPAM-1)

Adhesion (eosinophils, monocytes,

lymphocytes)

GlyCam-1 L-Selectin Lymphocyte homing to high endothelial

venules

CD31 (PECAM) CD31

NB: Due to E–selectin and P-selectin, the first cells seen in the inflammatory exudate is neutrophils.

Weibel-Palade bodies: They are rod-shaped intracytoplasmic bundles of microtubules derived

from Golgi complex and they are specific for vascular endothelium.

iii-Emigration and Chemotaxis into interstitial tissue:

A-Emigration: It is the migration of the leukocytes from capillaries and postcapillary

venules to the inflamed area. The process starts after adhesion and include:

1-The leukocytes migrate along pores between the endothelial cells to reach the site

of injury

2-They forced or insert pseudopodia through the intercellular junction and bulge

through and the rest of the cell follows.

3-Then the leukocytes break the basement membrane under the effect of active

enzymatic digestion.

4-They crawl over other elements, such as fibrin or tissue cells, toward their

destination. 5-RBCs often passive follow the emigrating leukocytes by diapedesis.

B-Chemotaxis:

It is the force (attractant agent) that attracts leukocytes into the inflamed or damaged.

This process occurs under the effect of attraction factors called chemotactic factors.

There are several endogenous and exogenous chemotactic agents:

i-Soluble bacterial products (leukotaxine).

ii-Complement component especially C3a and C5a.

iii-Arachidonic acid metabolites (lipoxygenase pathway as Leukotrine B4).

iv-Cytokines as IL-8 (released from activated neutrophils, macrophages,

lymphocytes, mast cells and basophils).

iv-Phagocytosis and degranulation:

It is activation of inflammatory cells and removal of stimulus.

The phagocytosis occurs in three steps:

1-Recognition and attachment:

The leukocytes are attached to most microorganisms. This process is facilitated by

serum protein called opsonin.

2-Engulfment:

The foreign particle is engulfed by phagocytic cells forming phagocytic vacuole.

The phagocytic vacuole fuses with lysosome to become a phagolysosome in

which the ingested particle is exposed to the lysosomal enzymes. Some of the

enzymes kill microorganisms, and others digest the remnants.

3-Microbial killing and degranulation:

By phagosome enzymes (hydrogen peroxidase, myeloperoxidase, toxic oxygen

based radicals as superoxide) through oxygen dependent or independent

mechanism. During phagocytosis, phagocytes show respiratory burst (oxygen

consumption) to produce reactive oxygen metabolites (O2 superoxide and H2O2)

NB: This is a passive process (not need energy).

-adherence to endothelium

-amoeboid movement

-RBCs have not any effect on the inflammatory process.

Leukocytes only travel along surfaces (a mostly fibrin) and can't swim in the fluid.

to kill phagocytized microorganisms, damage tissue and modulate some cell

function.

Exudation and exudates components: I-Fluid (humoral) Exudate.

II-Cellular Exudate.

I-Fluid Exudate:

i-The exudates dilute toxic substances formed within the body or introduced from outside.

ii-The dilution decrease or abolish the damaging effect of the irritant.

iii-Exudates carry all plasma proteins including fibrinogen and Igs. (antibodies).

iv-The exudates carry leukocytes.

v-The exudates bring all the components of the plasma enzyme system to initiate, control

and resolve the inflammatory process.

The enzyme system in the exudate are:

1-Clotting (coagulation) cascade: NB: Cascade means step-by-step sequence.

The clotting cascade may be initiated by activation of either:

i-Intrinsic pathway:

It is initiated by activation of Hageman factors (factor XII) by contact of the XII with

negatively charged surfaces as vascular wall denuded from endothelium.

ii-Extrinsic pathway:

It is initiated by activation of factor (VII) stable factor by thromboplastin (tissue factor).

NB: Thromboplastin is hydrophobic protein manufactured by normal and activated

macrophages, endothelium, fibroblasts and other fixed cells.

Both pathways converge at the activation of factor X which ultimately results in production of

thrombin and conversion of fibrinogen to fibrin.

i-Fibrinogen is important for clot formation and the prevention of further loss of blood.

ii-Fibrin is very important in the inflammatory process due to :

1-Provid essential matrix for the chemotactic migration of leukocytes into the

inflamed area because leukocytes can not swim in a pool of liquid plasma i.e. fibrin

gel provides a substrate for leukocyte migration (surface).

2-Provides a scaffold for granulation tissue formation and new capillaries in repair.

3-Act as physical barrier to confined the irritants and its spread to the adjacent tissue.

4-Important for phagocytosis.

II-The kinin system: -The Hageman factor (XII) is activated by prekallikrein and high molecular weight

kininogen (HMWK) in the intrinsic coagulation cascade and the prekallikrein is activated

to kallikrein which digests kininogen plasma protein zymogen to generate the vasoactive

peptide bradykinin.

-The prekallikrein and HMW kininogen circulate as a biomolecular complex.

NB: Kallikrein can initiate the conversion of C5 to C4a.

Function of the Bradykinin:

i-Increase the vascular permeability by inducing endothelial contraction

and widening of endothelial-gap junctions.

ii-Causes vasodilation, thus amplifying the increased vascular permeability.

iii-Activates phospholipase A2 which liberates arachidonic acid and AA-metabolites

that have powerful vasopermeability effects.

iv-Induces local pain.

III-Fibrinolytic system: The fibrinolytic system removes the fibrin of clot by 3 ways:

1-Direct degradation of the fibrin by leukocytic fibrinolytic enzymes released from living

and dead leukocytes in the area of inflammation.

2-Direct phagocytosis of fibrin by phagocytic cells especially macrophages.

3-Dissolution of the fibrin by activation of plasmin that is the most important plasma

degrades fibrin into fibrin-split products, which are soluble and removed via lymphatics.

4-These fibrin-split products are chemotactic for neutrophils.

IV-The complement cascade: Definition: The complement is a complex system containing more than 30 various

glycoproteins in low concentration in normal serum in the form of components, factors,

regulators or receptors. It presents in an inactive form but is activated to form an enzyme

cascade and is not increased in the serum after immunization.

There are 3 pathways of complement activation:

i-Classical Pathway: is activated by immune complex.

ii-Lectin Pathway: is activated by carbohydrate.

iii-Alternative Pathway: is activated by other substances, mainly of bacterial origin.

Immune complexes Carbohydrate Activating Surfaces

Collections

C1q MBP C3b

C1r C1r P

C1s MASP C1s D

C4 C4 C4 B

C2 C2 C2

C3

C3b

C5b678(9)n (MAC)

NB: Plasmin is derived from plasma zymogen plasminogen this conversion can by initiated by:

-Activated Hageman factor -WHMWK -Prekallikrein

-Plasminogen activator as:

-Urokinase–like plasminogen activator (UPA): It is found in plasma.

-Tissue plasminogen activator (TPA): It made by endothelium and macrophages.

-Plasmin can directly initiate the conversion of HMWK to bradykinin which has powerful vasoactive

and proinflammatory functions.

Plasmin activates C3 to form C3a and Cab.

If the fibrinolytic system not controlled, uncontrollable hemorrhage occur.

Classical

Pathway

Lectin

Pathway

Alternative

Pathway

MBP: mannan-binding protein; MASP: MBP-associated serine protease; B: factor B; D: factor D;

P: properdin; MAC: membrane attack complex: lysis bacteria, parasites and foreign cells)

Biological effects of complement activation:

1-Cytolysis:

It means destruction of target cells by lysis of the cell membrane:

i-Cytoxicity in case of nucleated cells.

ii-Hemolysis in case of RBCs

iii-Bacteriolysis in case of bacteria.

The cytolysis is due to the formation of MAC (56789). MAC is hydrophobic in nature.

2-Anaphylaxis:

-C3, C4 and C5 peptides termed anaphylatoxins. They responsible for degranulation of

mast cell and release of histamine which increase vascular permeability and cause smooth

muscle contraction.

3-Chemotaxis:

-C5a acts as chemotactic for neutrophils

-C3b acts as an opsonin promoting phagocytosis of C3b-coated material by way of C3b

receptors on macrophages, neutrophils and eosinophils.

NB: The complement system is not entirely autonomous because other enzymes the fibrinolytic

and kinin systems can activate complement components by themselves.

Kallikrein can initiate the conversion of C5 to C5a plasmin can activate C3 to C3a and C3b.

Mediators of Inflammation Mediators: They are substances that direct the vascular and cellular event in inflammation.

They can originate from the damaged fixed cells at the site of inflammation or from the

migrating cells under the effect four plasma enzyme systems collectively or individually.

They can be divided into 6 classes:

1-Vasoactive Amines.

2-Granular constituents other than vasoactive amines.

3-Arachidonic acid metabolites (lipid mediators).

4-Platelet Activating Factor (PAF).

5-Oxidizing reagents. 6-Cytokines.

1-Vasoactive Amines:

The vasoactive amines are mediators that are preformed and stored in the granules of mast

cells, basophils, eosinophils and platelets. They include:

i-Histamine:

It is the prototypic vasoactive amine fund in the granules of mast cells, basophils,

eosinophils and platelets.

ii-Serotonin:

It is found in the mast cells and platelets. It is more important in rodents.

Functions:

-Histamine causes vasodilation, increase the vascular permeability and smooth muscle

contraction. The principal mechanism of its release is by formation of immune complex on

the mast cells (Type I hypersensitivity).

-Serotonin has the same effect of histamine.

2-Granular constituents other than vasoactive amines:

i-Mast cells:

Mast cells contain preformed compounds contribute to the immediate response associated

with degranulation including:

Proteases as tryptase and chymase that digest the basement membranes of B.Vs.

increasing the vascular permeability.

Proteoglyceans as heparin and chondroitin sulfate which serve to stabilize and protect

proteases from antiproteases.

Chemotactic factors as (ECF-A) eosinophil chemotactic factor of anaphylaxis which

attract eosinophils, and neutrophil chemotactic factor for attraction of neutrophils.

ii-Granulocytes and macrophages:

Granulocytes and macrophages contain lysosomal granules that fuse with the phagocytic

vacuoles to form phago-lysosomes releasing proteases and enzymes to kill bacteria, fungi

and protozoa.

If these contents released extracellular they create tissue damage and contribute to the

initiation and evolution of the inflammatory response.

NB: Small quantities of the lysosomal constituents are released during phagocytosis and

large quantities after dying and lysis of cells.

3-Arachidonic acid metabolites (lipid mediators)

The major constituents of cell membranes are phospholipids. Cellular phospholipases,

especially phospholipase A2 and C are activated during inflammation and degrade

phospholipids to arachidonic acid. The arachidonic acid has a short half-life and can be

metabolized by two major routes:

i-Cyclo-oxygenase Pathway: It produces prostaglandins, prostacyclin, and thromboxanes.

ii-Lipoxygenase pathway: It produces leukotrienes and lipoxins.

Phospholipase A2 and C

Cyclo-oxygenase Lipoxygenase

15-lipoxygenase 5-lipoxygenase

Thromboxanes 5-HPETE, 5-HETE

Prostacyclin

PGH2 15-HPETE Leukotrienes

(LT-ABCDEF) Slow reacting substances of anaphylaxis

PGD2 PGE2 PGF2 LXA4 LXB4

Prostaglandins (Lipoxins)

HPETE: hydroperoxy-eicosatetraenoic acid. HETE: hydroxy-eicosatetraenoic acid.

Phospholipids in cell membrane

Arachidonic acid

TXB2 TXA2 PGG2 PGI2

Functions of arachidonic acid metabolites:

A-Leukotrienes:

They have potent effects on many different cells, including endothelium and leukocytes:

LTC4, LTD4 and LTE4 are known as slow-reacting substances of anaphylaxis (SRS- A)

that has characteristic effects of immediate hypersensitivity reactions and are much more potent

than histamine:

i-Induced smooth muscle contraction and bronchospasm.

ii-Increased vascular permeability by endothelial contraction.

iii-Vasoconstriction, platelets aggregation and neutrophils adherence to endothelium.

iv-LTB4 stimulates chemotaxis, phagocytosis, degranulation and leukocyte adhesion.

B-Lipoxins:

They stimulate granulocytes and cause chemotaxis as LTB4 but have no effect on the

vascular permeability and the leukocyte adhesion to endothelium.

C-Prostaglandins:

They induce:

i-Vasodilatation

ii-Inhibit platelet aggregation and suppress neutrophil adherence to endothelium.

NB: Thromboxane is produced by monocytes and macrophages as well as activated platelets. It

causes platelet to aggregate, vasoconstriction, and constriction of airways.

4-Platelet Activating Factor (PAF):

It is a lipid mediator, which produced by stimulated neutrophils, monocytes, macrophages,

lymphocytes, basophils, mast cells, endothelial cells and platelets.

It has proinflammatory effects including:

i-Vasodilation

ii-increase vascular permeability

iii-Chemotaxis

iv-Stimulation of granulocytes

v-Platelets aggregation

vi-Induction of local inflammatory cells to produce other mediators.

5-Oxidizing reagents:

During phagocytosis, neutrophils and macrophages are stimulated to produce a number of

oxygen metabolites (reactive oxygen) which is released into the surrounding tissues creating

tissue damage and progression of the inflammatory response.

6-Cytokines: Definition: They are polypeptides that provide the necessary means for cell to

communicate with one another. They link between many different cells produced by

stimulated cells to the extracellular environment to influence the same cells acutocrine or neighboring cells paracrine or exert systemic effect.

Types of Cytokines:

i-Interleukins (IL). ii-Interferons (IFN).

iii-Chemokines. iv-Growth Factors (GF).

v-Colony stimulating Factor (CSF).

Functions of cytokines:

i-They play a crucial roles in immunity, inflammation and hematopoiesis.

ii-They affect on the nature of inflammatory response by activation of number of cells

either fixed as endothelium or migratory cells (leukocytes).

iii-The most important cytokines involved in the inflammation are IL-1 and TNF-α which

produced by activated macrophages and IFN-γ and TNF-α which produced by activated

lymphocytes. They activate fixed cells (endothelium) to secrete adhesion molecules and

other inflammatory cells.

NB: Activation means quantitative changes in the level of expression of specific gene products

(proteins) to perform new functions.

Cytokines activate the endothelial cells:

Endothelial cells respond to cytokine activation signals by:

i-Hyertrophy (becoming more plump) and the generation of E- selection, ICAM-1 and

VCAM -1 adhesion molecules to mediate leukocytes adhesion to the endothelial surface

which followed by emigration.

ii-Increase its expression of MHC class I and II to facilitate the recognition of antigens

between immune cells.

iii-Becomes more thrombogenic i.e. clotting become more easily induced through:

a-Increase production of thromboplastin (tissue factor) which activates the

extrinsic coagulation cascade.

b-Decrease production inactivates thrombin on the endothelial surface.

iv-Produce their own cytokines especially IL-1 (which is essential in activation and

clonal expansion of antigen primed lymphocytes) in response to specific cytokines as

TNF–α and IFN- ß.

Cytokines activate leukocytes to:

1-Produce more LFA-1 molecules in their cell membrane to attach more efficiently the

ICAM-1 expressing endothelium.

2-Reach their full functional potential e.g.:

i-IL-1 activate lymphocytes proliferate and differentiate to effectors cells in

response to Ag.

NB: -Cytokines may be called immunocytokines or interleukins.

-They comprise interleukins, initially through to be produced by leukocytes (lymphokines) through to

be produced by lymphocytes (monkines) through to be produced by monocytes, interferon, colony

stimulating factors and others chemokines.

-Cytokines share certain characteristics:

-Usually synthesized by a cell in response to a stimulus and once produced are secreted, they aren’t

stored performed within cells.

-The same cytokine is produced by various cell types and the individual cytokine act on many different

types pleiotropic and may affect various cells in different ways.

-Many similar functions are shared by different cytokines i.e. their actions are abundant.

-Cytokines often influence the synthesis of and affect the actions of other cytokines.

-Cytokine actions mediated by binding to specific receptors on target cells. They tend to be very potent

-ILI, TNF and interferon involved in innate immunity and others involved in acquired immunity i.e. act

to control the activation growth and differentiation of immune cells.

ii-IFN-γ help macrophages and IFN- α help neutrophils to phagocytize and kill

foreign organisms much more efficiently.

iii-Cytokine-primed macrophages and neutrophils increase their biosynthesis

and / or release of lysosomal enzymes granule contents (neutrophil) cytokines

and reactive O2 intermediates.

3-Cytokines increase the intracellular calcium in leukocytes which activate cellular

phospholipase A2 to liberate AA. from the cell.

Cytokine influence the fixed structural cells to:

-Increase healing and repair e.g. cytokines induce fibroblasts to divide and produce more

collagen and proteolytic enzymes.

Cytokines have endocrine effect which induce systemic signs of inflammation:

This effect is defined collectively as the acute-phase response which has 5 components:

1-Fever:

It is elevation of the body temperature above the normal limit that caused by exogenous

pyrogens of bacterial or fungal origin. The bacterial pyrogens cause disintegration of tissue and

leukocytes which release endogenous pyrogens (IL1, IL6, cachectin and TNF-α) stimulate

thermoregulatory center in the hypothalamus to decrease cutaneous blood flow and heat dissipation Fever.

Function of Fever:

i-It has bacteriostatic and bactericidal effects.

ii-In viruses: stimulate the cells to produce the interferon.

iii-It enhances the phagocytosis.

iv-It stimulates the cells to produce antibodies.

2-Hepatocyte acute–phase protein production:

The liver is stimulated to produce a number of proteins including:

Group Individual Proteins

A-Positive Acute-Phase Reactants (APRs)

i-Major APRs

ii-Complement Proteins

iii-Coagulation Proteins

iv-Proteinase inhibitors

v-Metal-binding Proteins

vi-Other Proteins

-Serum amyloid A, CRP, Serum amyloid P component.

-C2, C3, C4, C5, C9, B, C1-inhibitor and C4 binding protein

-Fibrinogen, von Willebrand factor.

-Antitrypsin, Antichymotrypsin, Antiplasmin, heparin

cofactor II, Plasminogen activator inhibitor I.

-Haptoglobin, hemopexin, Ceruloplasmin, Manganese

superoxide dismutase.

-Acid glycoprotein, heme oxygenase, Lipoprotein, leukocyte

protein I, Lipopolysaccharide-binding protein, Mannose-

binding protein.

B-Negative APRs -Albumin, Pre-albumin, Transferrin, ..

3-Leukocytosis:

Definition: It is an increase of the leukocytes. It is usually associated with pyogenic bacteria,

toxemia and severe hemorrhages.

4-Increases in plasma copper and decreases in plasma iron and zinc:

These changes can be considered unique protective host mechanisms because it has been

shown that the host and the invading microorganisms are in competition for iron and zinc.

While, the copper is required for upper immune functioning and increase in copper is

secondary to increase in plasma concentration of copper binding protein (ceruloplasmin).

5-Catabolic processes:

If the acute-phase response is long lasting chronic inflammation, it leads to catabolism in

the form of muscle wasting, weight loss and weakness.

TNF-α (cachectin) suppress synthesis of lipoprotein lipase which is required for the

utilization of serum triglycerides so they can't utilize leading to empyema and weight loss. IL-

1, has similar but minor effect.

CLASSIFICATION OF INFLAMMATION Purpose: Using specific criteria, it is possible to provide a brief description evaluation, also

known as morphologic diagnosis, for each type of inflammatory response.

Duration Extent Distribution Exudate Anatomic modifiers Organs

Peracute Mild Focal Serous Interstitial Nephritis

Acute Moderate Multifocal Catarrhal Parenchymatous

i-Glomerulonephritis

ii-Bronchopneumonia

Hepatitis

Subacute Severe Locally extensive Fibrinous Splenitis

Chronic Diffuse Suppurative ect

Chronic active hemorrhagic

Lymphocytic

Allergic

DURATION: How long has the process been underway?

Determination of duration can also be very subjective and the morphologic changes

associated with an inflammatory process may not correlate with the onset of clinical signs. For

example, due to the high functional reserve of the liver and kidney it is common to find severe

chronic lesions in these organs in animals that die suddenly.

i-PERACUTE INFLAMMATION: Definition: very acute.

Usually caused by a potent stimulus.

Usually the animal has no time to respond morphologically to a disease process.

Less common than acute disease processes

General Features: (eg: bee sting)

Time: 0-4 hours

Vascular involvement: hyperemia, slight edema, hemorrhage

Inflammatory cells: not usually numerous, few leukocytes

Clinical signs: shock, sudden death

ii-ACUTE INFLAMMATION:

Definition: having a short and relatively severe course.

Time: It begins within 4-6 hours can last for 3-5 days

Vascular involvement: -Local active hyperemia,

-Edema (due to endothelial damage)

-Occasional fibrin thrombi within vessels.

Inflammatory cells: Leukocyte infiltration is variable.

In general, neutrophils, eosinophils and lymphocytes are present.

Clinical signs: Most associated to the vascular changes: warm, red, swollen, painful,

loss of function.

Lymphatics: Lymphatic vessels have a role in moving away the exudate. The

transportation of the exudate (i.e., inflammatory cells and necrotic debris) can

lead to acute regional lymphadenitis and lymphangitis.

iii-SUBACUTE INFLAMMATION:

Definition: Transition period separating acute and chronic inflammation. Evidence of

hyperemia and edema is regressing but evidence of repair such as fibroplasia and

angiogenesis is lacking.

Time: varies from a few days to a few weeks.

Vascular involvement: There is a decline in the magnitude of vascular changes,

compared to acute inflammation (less hemorrhage, hyperemia and edema).

Inflammatory cells: characterized by a “mixed inflammatory infiltrates”.

Lymphatics: lymphatic drainage endothelial damage repaired

iv-CHRONIC INFLAMMATION:

Definition: Inflammation which persists over a period of time.

Features: -Chronic inflammation is often the result of a persistent inflammatory stimulus

in which the host has failed to completely eliminate the causative agent.

-Inflammatory response usually is accompanied by an immune response.

-Chronic inflammation is characterized by evidence of host tissue response in

terms of repair

-Formation of scar and regeneration of damaged tissue

Histology: mononuclear inflammatory cells, fibroblasts and collagen with proliferating

vasculature.

Cause: May follow an acute inflammatory phase. May develop as an insidious, low-

grade, subclinical process without history of a prior acute episode.

Time: Variable

Vascular involvement: Proliferations of capillaries and small blood vessel (angiogenesis/

neovascularization) resulting in edema, hemorrhage and congestion.

Host involvement: Parenchymal regeneration or repair by fibrosis (scarring).

Inflammatory cells: Macrophages, epithelioid and giant cells besides plasma cells and

fibroblasts

Lymphatics: involvement variable +/- proliferation and activation.

Clinical Signs: Primary dependent upon duration of the illness and inflammatory lesions.

NB: Many changes represented in chronic inflammation are also seen in areas of repair. EXTENT/SEVERITY:

The severity of the process must be evaluated. However, it is important to recognize that

determining the degree of severity is often very subjective.

Extent of injury Tissue damage Inflammatory cells Vascular Involvement

Mild Absent - minimal Few Slight

Moderate Some present Evident Moderate edema and Hgs.

Severe Substantial Abundant Massive edema and Hgs.

NB: In addition to mild, moderate, severe; other modifiers can also be used, as minimal, extensive, etc.

DISTRIBUTION: What is the location of the lesion within an organ?

i-FOCAL:

Definition: Single abnormality or inflamed area within a tissue.

Size: Varies from 1 mm to several centimeters in diameter

ii-MULTIFOCAL:

Definition: Arising from many foci (several foci separated from one another).

Size: Variable.

NB: Each focus of inflammation is separated from other inflamed foci by an intervening zone of

relatively normal tissue.

iii-LOCALLY EXTENSIVE ( Focally extensive):

Definition: Involvement of considerable area within an organ.

Possible origin:

1-Severe local reactions that spread into adjacent tissue

2-Coalescence of foci in a multifocal reaction

Example:

-Pulmonary lesion of pneumonic Mannheimiosis in cattle.

-The cranioventral aspects of the lungs are involved while the dorsal portions usually

are spared.

iv-DIFFUSE:

-Involve all the tissue or organ in which the inflammation is present.

-Variations in severity may exist.

Example: Interstitial pneumonia. Diffuse lesions are often viral or toxic in etiology.

Acute Inflammation The acute inflammation is characterized by:

I-Macroscopically: swollen (thickened) and congested affected tissue.

II-Microscopically: dilated blood vessels, leukocytic infiltration and plasma leakage.

Classification of the inflammation according to the predominant constituents of the exudate:

1-Serous inflammation

Mild Inflammation

2-Catarrhal inflammation

3-Fibrinous inflammation

4-Suppurative inflammation Severe Inflammation

5-Hemorrhagic inflammation

6-Lymphocytic inflammation

Moderate Inflammation

7-Allergic inflammation

Serous Inflammation Definition: It is a mild inflammation of serous and mucous membranes, where the predominant

constituent of exudate is albumin (serous fluid).

Occurrence: It occurs within organs or on surfaces as in case of:

i-Serous pneumonia, lymphadenitis,.

ii-Serous rhinitis, gastritis..

iii-Serous pleuritis, peritonitis,

Causes: Mild irritants such as sun-rays, blisters on skin, burns,

Macroscopic Pictures:

i-The affected area is swollen and congested (red) Cardinal Signs.

ii-Cut sections oozed watery fluid (lymph).

iii-the serous membranes lose their shiny appearance because the inflammatory cells and

few fibrin threads may adhere to it.

Microscopic Pictures:

i-Dilated blood vessels (Active hyperemia).

ii-Leukocytic infiltrations.

iii-Fine granular or homogenous eosinophilic material within the tissue spaces (albumin).

Significance:

i-It indicates that the cause is mild and the prognosis is favorable if the cause removed.

ii-If the cause is not removed change into another type.

iii-The exudate either absorbed or become organized by fibrous tissue.

Catarrhal Inflammation

Mucous Inflammation

Cellular Inflammation Definition: It is a relatively mild inflammation of mucous membranes where the predominant

constituent of exudate is mucus (mucin in water).

Occurrence: It occurs on the mucous membrane of tubular respiratory, reproductive and

digestive tracts, where the goblet cells are numerous as catarrhal rhinitis, laryngitis, tracheitis,

enteritis, gastritis, endometritis, cystitis, ….

Causes: Mild irritants such as

i-Chemicals as formaldehyde and cresol in high concentration.

ii-Inhaled dusts, cold air or foreign proteins.

iii-Infection as in some viral and bacterial diseases.

iv-Ingestion of spoiled or moldy or irritating food.

Macroscopic Pictures:

i-The affected m.m. are swollen and congested (red) Cardinal Signs.

ii-Clear transparent or gray, yellow opaque material is sticky on hyperemic m.m.

Microscopic Pictures:

i-Dilated blood vessels (Active hyperemia).

ii-Leukocytic infiltrations.

iii-Hyperplasia and desquamation of the lining epithelium in the lumen.

iv-Numerous columnar epithelium changed into goblet cells (metaplasia).

v-Homogenous basophilic material (mucus) in the lumen.

vi-The mucus is stained red by mucicarmine stain.

Significance:

i-It indicates that the cause is mild and the prognosis is good if the cause removed.

ii-If the cause persists for a long period, it change into another type.

NB: Sloughing: It is a loss or separation of mass of tissue as testis or ear concha.

Desquamation: It is a loss or separation of sheet of the lining epithelium from its m.m.

Fibrinous Inflammation Definition: It is a severe inflammation where the predominant constituent of the exudate is

fibrin.

Occurrence: It occurs on the serosal and mucosal surfaces and is predominant on the intestinal

mucosa, peritoneum, pleura, synovial membrane, and meninges and in the lungs.

Causes: It is so severe cause to be escape of fibrinogen (largest molecule of plasma protein)

through the wall of blood vessels.

i-Viral diseases as in feline enteritis.

ii-Bacterial diseases as in salmonellosis and necrobacillosis.

iii-Inhalation of hot gases during barn fires.

Macroscopic Pictures:

i-The affected m.m. appear opaque dull and covered with whitish fuzzy material.

ii-The early lesion on a serosal surface gives a roughened ground-glass appearance. It is

easily overlooked.

iii-When it present in large quantities, it takes “a bread and butter” appearance.

iv-The affected membrane is congested (when remove the fibrin membrane).

Microscopic Pictures:

i-Dilated blood vessels (Active hyperemia).

ii-Leukocytic infiltrations.

iii-Pink fibrin network adhered to the affected surface, entrapped the leukocytes.

iv-Coagulative necrosis is only seen with diphtheritic type.

Significance:

i-The fibrinous inflammation indicates severe cause.

ii-The fibrin act as physical barrier to confined the irritants and prevent its spreading by

occlusion of blood vessels and lymphatics.

iii-The fibrin helps the phagocytosis and healing.

iv-The fibrinous exudate is either absorbed, sloughed or organized by fibrous tissue.

a-permanent adhesions in serous membrane as in case of.

Pericardium heart block.

Pleura suffocation.

Peritoneum adhesions between different organs leading to impair

intestinal motility and the circulation of the area

b-The organized portion of the lung becomes permanently converted into fibrous

tissue (lung carnification=fleshy).

The fibrin membrane (pseudomembrane) is 2 types:

i-Croupous membrane: It is one type of pseudomembrane can be removed from the affected

surface without causing to the surface (there is no necrosis).

ii-Diphtheritic membrane: It is one type of pseudomembrane when be removed leave the

affected surface eroded and damaged (there is coagulative necrosis).

Suppurative Inflammation

Purulent Inflammation

Definition: It is a severe inflammation where the predominant constituent of exudate is

“neutrophils”. It occurs in all body tissue.

Causes:

i-Pyogenic bacteria as staph, strept, coryne (pyo=pus * genic-produce).

ii-Some chemicals as turpentine oil (if injected in tissue).

Macroscopic Pictures:

i-The affected area show swelling and redness Cardinal Signs.

ii-Cut section oozed pus with different colors and consistency.

A-Color: according to species of bacteria.

o Staph and strept white to yellow pus.

o Corynebacterium greenish pus.

o Presence of RBCs red pus.

o Saprophytic (produce H2S) turn the pus into black (hoof injury).

B-Consistency: according to animal species and neutrophil-lymphocyte ratio.

Animal species Neutrophil-lymphocyte ratio Consistency of pus

Dog 3.5 : 1 Thin and watery

Cat 2 : 1 Liquid

Horse 1.5 : 1 Slightly viscid

Bovine 0.5 : 1 Viscid

Chickens No neutrophils (heterophils) Dry and caseous

Microscopic Pictures:

i-Dilated blood vessels (Active hyperemia).

ii-Considerable numbers of neutrophils infiltrations (living or dead).

iii-Homogenous basophilic material (pus) is seen.

iv-Line of defense (pyogenic membrane) separate the inflamed tissue from the adjacent.

It consist of dilated capillaries, fibrin threads and leukocytes infiltrations.

v-Few numbers of lymphocytes, macrophages and plasma cells may be seen.

NB: The pus consists of

i-Living neutrophils. ii-Dead neutrophils.

i-Liquefied necrotic tissue. iii-The causative agents (bacteria).

Significance and Results:

i-The suppurative inflammation indicates presence of pyogenic bacteria.

ii-Pus is healthy signs.

iii-Pyemia and death or localized as abscess surrounded by fibrous tissue capsule.

iv-Abscess may become sterile where the body defenses may kill all the causative agents

and the pus slowly absorbed or organized.

Types of Suppurative inflammation:

NB: presence of large number of neutrophils means rich in the proteolytic enzyme that liquefy the

tissue into pus (watery); while the decreased numbers (poor in the proteolytic enzyme) the

liquefaction is not efficient to become watery where the consistency is viscid.

In birds: The pus is dry and caseous due to presence of “antitryptic enzyme”. The neutrophil is

called heterophil so there is suppurative inflammation and no liquefactive necrosis.

Abscess: It is a local suppurative inflammation. It has different names according to its sites.

Pustule: It is a small abscess in the malpighian layer of the epidermis.

Furuncle or Boil: It is a small abscess in the hair follicle or sebaceous gland.

Carbuncle: It is a subcutaneous abscess with several opening to the surface of the skin (sinus).

Pyorrhea: It is a deep suppurative inflammation of the gum.

Empyema: It is an accumulation of pus in the body cavity.

Phlegmon or Cellulitis: It is acute diffuse suppurative inflammation in subcutaneous loose

connective tissue. It is caused by Streptococcus hemolyticum which produces:

a-Streptokinase (fibrinolysin): dissolve and prevent fibrin formation.

b-Hyaluronidase: break tissue cement substance helping spread of bacteria and its toxins.

Ulcer: It is discontinuation of the epithelial lining, where the base lies in the lamina propria

(lining epithelium) or the dermis (covering epithelium).

Erosion: It is loss of the superficial layer of the epithelium with intact basement membrane.

Sinus: It is the formation of tract lined by FCT connects between cavity and surface.

Fistula: It is a tract between 2 cavities.

Cold Abscess: It is a chronic abscess in the internal organs as liver and lungs.

NB: Pathogenesis of Abscess Formation:

i-The pyogenic microorganisms produce toxin which induce coagulative necrosis.

ii-The damaged tissue produce chemical mediators (leukotaxine) chemotaxis to neutrophils.

iii-Many neutrophils died during the process (pus cells) proteolytic enzymes which liquefy

the damaged tissue and fibrin threads (liquefactive necrosis).

iv-The resulting fluid is mixed with the other products of the inflammatory process forming

the pus.

v-The adjacent tissue (peripheral zone of the inflamed tissue) called pyogenic membrane

which consists of dilated capillaries, fibrin and leukocytes neutrophils lymphocyte and

macrophages.

Hemorrhagic Inflammation Definition: It is a severe inflammation, where the predominant constituent of exudate is

erythrocytes.

Causes: the injurious agents are usually severe as

i-Bacterial or viral diseases as in blackleg, anthrax, pasteurellosis, cattle plague.

ii-Chemicals as phenol, arsenic, chloroform and phosphorus.

Macroscopic Pictures:

i-Swelling and redness (cardinal signs).

ii-The exudate is red due to presence of RBCs.

iii-In the stomach, the blood becomes black where the Hb is changed into acid hematin

(derived from oxidized Hb).

Microscopic Pictures:

i-Dilated blood vessels (Active hyperemia).

ii-Leukocytic infiltrations.

iii-The RBCs are the main constituent of exudate.

Significance:

i-The hemorrhagic inflammation indicates severe cause and bad prognosis.

ii-The animal is died due to anemia and extensive tissue damage.

iii-Recovery is usually delayed.

Lymphocytic Inflammation Definition: it is a special type of inflammation where the predominant constituent of exudate is

lymphocytes and characterized by absence of cardinal signs of inflammation.

Causes: Cellular exudate (lymphocytes).

i-Viral infections.

ii-Toxins. iii-Protozoal infection.

Macroscopic Pictures:

i-Absence of cardinal signs of inflammation.

ii-Grayish-white spots of irregular shape on the surface of the affected organs.

iii-This type of inflammation mostly seen in parenchymatous organs and brain.

Microscopic Pictures:

i-The dilated blood vessels are absent (not clear).

ii-The exudate is highly cellular (lymphocytes and may few macrophages).

iii-In the brain: the lymphocytes usually accumulate in the Virchow-Robin spaces

forming “perivascular lymphocytic cuffing).

Significance:

i-The indicates viral disease, toxemia or protozoa.

ii- If the cause is removed the healing occur rapidly.

NB: Grayish-white nodules in the liver of birds are due to one of the following:

1-Leukosis 2-Asperigellosis 3-Histomoniasis 4-TB.

Allergic or Eosinophilic Inflammation Definition: it is a special type of inflammation where the predominant constituent of exudate is

eosinophils and usually associated with any types of inflammation (fibrinous, catarrhal,).

Causes: Cellular exudate (lymphocytes).

i-Metazoan parasitism.

ii-Hypersensitivity (allergy). iii-Sodium chloride toxicosis.

Macroscopic Pictures: It is associated with any type of inflammation.

i-Cardinal signs of inflammation.

ii-The exudate may be serous, fibrinous, hemorrhagic, suppurative.

Microscopic Pictures:

i-Dilated blood vessels.

ii-The cellular exudate is mainly eosinophils besides other inflammatory cells.

Significance:

i-It depends on the cause allergy is severe while parasites are milder.

ii-If the cause is removed recovery occur.

iii-Shock and death may occur due to excess histamine.

Chronic Inflammation

Proliferative or Productive Inflammation Definition: It is an inflammation of prolonged duration in which the body responds by

producing excessive amount of:

NB: Alterative inflammation:

The term alterative refers to the retrogressive alterations e.g. cloudy swelling, fatty change and

necrosis induced in cells with injurious agents which under other circumstances cause inflammation.

i-Connective tissue.

ii-Reticuloendothelial tissue.

iii-Epithelium tissue.

Causes:

i-Follow the acute inflammation when the tissue destruction is extensive or the bacteria

survive and persist in small number at the site of inflammation (fail to eliminate).

Recurrent attacks of acute inflammation leading to develop the chronic one.

ii-Some immune diseases (Type-IV hypersensitivity).

ii-Some specific diseases (can’t be removed by the host defense) as TB, some

retroviruses, dust (silica and carbon).

Macroscopic Pictures:

i-If the inflammation is not severe and the proliferative component is not profound it may

not be noticed grossly.

ii-If the fibrous tissue has yet to develop, the only gross change is paleness of the affected

tissue (white to tan) than normal.

iii-If there is large amount of fibrosis the inflammatory area appear indurated , tan and

feels gritty upon cutting with scalpel (white in color).

Microscopic Pictures: the chronic inflammation is characterized by:

i-Hyperplasia (proliferation):

o Epithelium

o Fibrous connective tissue

o Lymphoid tissue (increase number of lymphocytes at the area).

ii-Metaplasia:

o The fibrous tissue changed into cartilage bone.

o The epithelium changed into another type of epithelium.

iii-Chronic inflammatory cells infiltrations:

o Macrophages or Epithelioid cells (secretory macrophages).

o Plasma cells.

o Giant cells (its presence indicates rapid turn over of macrophages).

Types of Chronic Inflammation: I-Non-Specific: when the irritant substance produces a non-specific chronic

inflammatory reaction with formation of granulation tissue and healing by fibrosis. A-Chronic non-specific inflammation

B- Chronic non-specific interstitial inflammation

II-Specific: when the injurious agent causes a characteristic histological tissue response,

e.g. tuberculosis, leprosy.

NB: The proliferative changes are as a result of necrosis, proliferation of small blood vessels and

fibroblasts is stimulated resulting in formation of “granulation tissue”. There are 4 components of this

process:

Formation of new blood vessels (angiogenesis).

Migration and proliferation of fibroblasts.

Deposition of extracellular matrix.

Maturation and organization of the fibrous tissue (remodeling).

A-Chronic Granulomatous Inflammation. Definition: It is a specific chronic inflammation characterized by formation of granulomas.

Granuloma: It is a chronic inflammatory reaction consisting of macrophages or macrophages

and giant cells.

-The macrophages kill the intracellular microorganisms.

-They produce cytokines and certain degradative enzymes.

-They enhance the phagocytosis

-They can recognize and kill tumor cells.

NB: The word “granuloma” is composed of granule meaning circumscribed granule-like

lesion, and -oma, which is a suffix commonly, used for true tumors.

Types of granulomas: according to the nature of stimulus.

I-High Turnover Granulomas (hypersensitivity granulomas).

II-Low Turnover Granulomas (foreign body granulomas).

I-High Turnover Granulomas:

i-They are characteristic response to TB, fungi, helminthes and their ova, and many

organisms that replicate intracellular e.g. brucella.

ii-They consist of focal collection of macrophages, epithelioid cells and Langhan’s giant

cells besides T-lymphocytes.

iii-The granulomas often become partially or completely surrounded by immature

fibrous connective tissue which is infiltrated with lymphocytes.

II-Low Turnover Granulomas:

i-They are formed in response to agent which fails to stimulate immune response such as

silk suture, splinters or oil.

ii-They consist of collection of macrophages associated with neutrophils surrounding the

foreign objects and that may form foreign body giant cells (no lymphocytes and

epithelioid cells).

NB: Other classification of granulomas:

1-Infectious granuloma.

2-Non-infectious granulomas.

How do endothelial cells become permeable?

Endothelial cell contraction

Junctional retraction

Direct endothelial injury (immediate sustained response)

Leukocyte-dependent endothelial injury

Increased transcytosis of fluid