inflammation
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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
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