Department of Pathology,Faculty of Veterinary Medicine, Zagazig University, Egypt.

INFLAMMATIONBY

Prof. Dr. Mohamed Hamed Mohamedmohamedelariny@yahoo.com

+201224067373

2011

INFLAMMATIONDefinition: 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 (based upon the production of antibodies).

-Cellular systemic defense (leukocytosis).

-Fever

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: 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-Hotness (Calor) 2-Redness (Rubor) 3-Swelling (Tumor or Edema)

4-Pain (Dolar) 5-Loss of Function (Functiolaesa)

1-Redness (Rubor):The inflamed area usually appears red due to a great increase of blood in the

inflamed part due to dilation of capillaries and arterioles with opening of all

collapsed capillaries.

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

arterioles caused by nerve reflex.

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.

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).

In this experiment, 3 cardinal signs of inflammation are evident

*Redness,

*Hotness and

*Swelling .

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:i-Capillaries dilation is mediated by chemical mediators.

ii-Dilation of arterioles is mediated by axon reflex.

iii-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. bradykininsensitizing 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

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

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.

-They 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.

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

- Contain abundant cytoplasmic granules.

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).

Function of Neutrophils in the inflammation:1-PhagocytosisIngest, 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

II-Eosinophils:Characteristics

1-Numerous at inflammatory sites which result from

-Parasites.

-Allergic or Immunologic Disease.

-Some fungi and Salt toxicosis.

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

3-Phagocytic but less so than neutrophils

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), blobbed 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 helminthes and other pathogens

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

iii-Regulator of inflammation - particularly to mast cell products

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

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 subtypes1-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: (granulocyte-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:

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.

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

Explain that the platelets act as inflammatory cells during inflammation?

PLATELETS AS INFLAMMATORY CELLSi-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)