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Dr. Saevan Saad Al-Mahmood
Chapter Three
INFLAMMATION
Inflammation
is a
local response (reaction) of living vasculaized tissues
to endogenous and exogenous stimuli
. The term inflammation derived from
the Latin word
inflammare
that mean
to burn
.
The main function of inflammation to localize and eliminate the causative
agent and to limit tissue injury.
Thus, inflammation is a physiologic (protective) response to injury, an
observation made by Sir John Hunter in 1794 concluded: “inflammation is itself
not to be considered as a disease but as a salutary operation consequent either to
some violence or to some diseases”.
3-1: Causes of Inflammation:
1-Physical agents:
included mechanical injuries, alteration in temperatures
and pressure, radiation injuries.
2-Chemical agents:
including the ever-increasing lists of drugs and toxins such
as concentrate acid and alkaline solutions.
3-Biologic agents (infectious):
included bacteria, viruses, fungi and parasites.
4-Immunologic disorders:
included hypersensitivity reactions, autoimmunity,
immunodeficiency states etc.
5-Genetic/metabolic disorders:
examples gout, diabetes mellitus.
3-2: Nomenclature of Inflammation:
The nomenclatures of inflammation usually indicated by the suffix
itis
.
Inflammation of the appendix called
appendicitis
and that of meninges as
meningitis
. However, like any rule it has own exceptions examples
pneumonia
,
typhoid fever
.
3-3: Classification of Inflammation:
Inflammation classified crudely based on [1] duration of the lesion and
[2] histologic appearances into:
[a]
Acute inflammation
or
[b]
Chronic inflammation
.
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Dr. Saevan Saad Al-Mahmood
3-4:
ACUTE INFLAMMATION (
Exudative Inflammation
)
Acute inflammation is an immediate and early response to an injurious
agent and it is relatively of short duration, lasting for minutes to several hours or
few days. Acute inflammation characterized by exudation of fluids and plasma
proteins and the emigration of predominantly neutrophilic leucocytes to the site
of injury.
3-4-1: Cardinal Signs of Acute Inflammation:
-
Redness
(
rubor
), which is due to dilation of small blood vessels within
damaged tissue with vein construction (as it occurs in cellulitis).
-
Heat
(
calor
), which results from increased blood flow (hyperemia) due to
regional vascular dilation.
-
Swelling
(
tumor
), which is due to accumulation of fluid in the extravascular
space that due to increased vascular permeability.
- Pain (dolor), which results from stretching and destruction of tissues due to
inflammatory edema, also from pus that produce pressure on nerve ending.
Some chemicals of acute inflammation like bradykinins, prostaglandins and
serotonin induce pain.
-
Loss of function
(
loss of funcito
), the inflamed area loss its function due to
pain, also severe swelling may also physically immobilize the tissue.
3-4-2: Events of Acute Inflammation:
Acute inflammation is categorized into an early vascular and a late cellular
responses.
1-
Vascular Response
has the following steps:
a- Immediate (momentary) vasoconstriction in seconds due to neurogenic or
chemical stimuli that produced from damaged tissues.
b- Vasodilatation of arterioles and venules resulting in increased blood flow.
c- After the phase of increased blood flow there is a slowing of blood flow and
stasis due to increased vascular permeability that most remarkably seen in
the post-capillary venules. The increased vascular permeability oozes
protein-rich fluid into extra- vascular tissues. Due to this, the already
dilated blood vessels packed with red blood cells resulting in stasis. The
protein-rich fluid which is now found in the extravascular space is called
exudate
. The presence of the exudates clinically appears as swelling.
The chemical mediators are mediate vascular events of acute inflammation.
2-
Cellular Response
The cellular response has the following stages:
a- Migration, rolling, pavementing and adhesion of leukocytes,
b- Transmigration of leukocytes,
c- Chemotaxis and
d- Phagocytosis.
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Normally blood cells particularly erythrocytes in venules found to central
(axial) zone and plasma assumes the peripheral zone. Because of increased
vascular permeability more neutrophils accumulate to the endothelial surfaces
(peripheral zone).
a- Migration, rolling, pavementing, and adhesion of leukocytes:
Margination is a peripheral positioning of white cells along the endothelial
cells. Subsequently, rows of leukocytes tumble slowly along the endothelium in
a process known as rolling. In time, the endothelium can be virtually lined by
white cells, this appearance termed as pavementing.
Thereafter, the binding of leukocytes with endothelial cells is
facilitated by cell adhesion molecules such as selectins, immunoglobulins and
integrins, which result in adhesion of leukocytes with the endothelium.
b- Transmigration of leukocytes
Leukocytes escape from venules and small veins but only occasionally
from capillaries. The movement of leukocytes by extending pseudopodia
through the vascular wall occurs by a process called diapedesis. The most
important mechanism of leukocyte emigration is via widening of inter-
endothelial junctions after endothelial cells contractions. The basement
membrane disrupted and resealed thereafter immediately.
c- Chemotaxis:
chemotaxis define as unidirectional attraction of leukocytes from vascular
channels towards the site of inflammation within the tissue space guided by
chemical gradients (including bacteria and cellular debris). The most important
chemotactic factors for neutrophils are
[1]
components of the complement
system (C
5a
),
[ 2 ]
bacterial and mitochondrial products of arachidonic acid
metabolism (such as leukotriene B
4
and cytokines IL-8). All granulocytes,
monocytes and to lesser extent lymphocytes respond to chemotactic stimuli.
How do leukocytes "see" or "smell" the chemotactic agent
? This is
because receptors on cell membrane of the leukocytes react with the
chemoattractants resulting in the activation of
phospholipase C
that ultimately
leads to release of
cytocolic calcium ions
and these ions trigger cell movement
towards the stimulus.
d- Phagocytosis
Phagocytosis is the process of engulfment and internalization by specialized
cells of particulate material, which includes invading microorganisms, damaged
cells, and tissue debris. These phagocytic cells include polymorphonuclear
leukocytes (particularly neutrophiles), monocytes and tissue macrophages.
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3-4-3: Phagocytosis involves three distinct but interrelated steps:
1-
Recognition and attachment of the particle to be ingested by the
leukocytes:
Phagocytosis is enhanced if the material to be phagocytosed is
coated with certain plasma proteins called
opsonins
. These opsonins promote
the adhesion between the particulate material and the phagocyte’s cell
membrane. The three major opsonins are:
(1)
The Fc fragment of the
immunoglobulin
,
(2)
Components of the complement system C
3b
and C
3bi
,
and the
(3)
Carbohydrate-binding proteins – lectins
. Thus, IgG binds to
receptors for the Fc piece of the immunoglobulin (FcR) whereas C
3cb
and
C
3bi
are ligands for complement receptors CR
1
and CR
2
respectively.
2-
Engulfment:
During engulfment, extension of the cytoplasm (pseudopods)
flow around the object to be engulfed, eventually resulting in complete
enclosure of the particle within the
phagosome
created by the cytoplasmic
membrane of the phagocytic cell. As a result of fusion between the
phagosome and lysosome, a
phagolysosome
is formed and the engulfed
particle is exposed to the
degradative lysosomal enzymes
.
3-
Killing or degradation:
The ultimate step in phagocytosis of bacteria is
killing and degradation. There are two forms of bacterial killing:
a-
Oxygen- independent mechanism:
This is mediate by some of the
constituents
of
the
primary
and
secondary
granules
of
polymorphonuclear leukocytes. These
include:
(1)
Bactericidal
permeability increasing protein (BPI) Lysozymes
(2)
Lactoferrin
(3)
Major
basic protein
(4)
Defenses
. It is probable that bacterial killing by
lysosomal enzymes is inefficient and relatively unimportant compared
with the oxygen dependent mechanisms. The lysosomal enzymes are,
essential for the degradation of dead organisms within phagosomes.
b-
Oxygen- dependent mechanism:
There are two types of oxygen-
dependent killing mechanisms:
i-
Non- myeloperoxidase dependent:
The oxygen - dependent killing of
microorganisms is due to formation of reactive oxygen species such as
hydrogen peroxide (H
2
O
2
), super oxide (O2) and hydroxyl ion (HO-)
and possibly single oxygen (1O
2
). These species have single unpaired
electrons in their outer orbits that react with molecules in cell
membrane or nucleus to cause damages.
The destructive effects of H
2
O
2
in the body are gauged by the action of the glutathione peroxidase and
catalase.
ii-
Myloperoxidase– dependent:
The bactericidal activity of H
2
O
2
involves the
lysosomal enzyme myeloperoxidase
, which in the
presence of halide ions converts H
2
O
2
to hypochlorous acid (HOCI).
This H
2
O
2
– halide - myecloperoxidease system is the most efficient
bactericidal system in neutrophils. A similar mechanism is also
effective against fungi, viruses, protozoa and helminthes.
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3-4-4: Chemical mediators of inflammation
Chemical mediators account for the events of inflammation. The
Inflammation has the following sequence: Cell injury lead to release Chemical
mediators which lead to initiate inflammatory response (i.e. the vascular and
cellular events). The sources of mediators of inflammation can be derived from
plasma or cells.
1-
Plasma- derived mediators:
a-
Complement activation:
the complement activation lead to increases vascular
permeability (C
3a
,C
5a
), activates chemotaxis (C
5a
) and opsoninization
(C
3b
,C
3bi
).
b-
Factor XII (Hegman factor) activation
: Its activation results in recruitment
of four systems: the kinin, the clotting, the fibrinolytic and the compliment
systems.
2-
Cell- derived chemical mediators:
Cell-derived chemical mediators include agents as in the following table
Cellular mediators
Cells of origin
Functions
1
Histamine
Mast cells, basophiles
Vascular leakage and platelets
2
Serotonine
Platelets
Vascular leakage
3
Lysosomal enzymes
Neutrophiles
Bacterial and tissue destruction
macrophages
4
Prostaglandines
All leukocytes
Vasodilatation, pain, fever
5
Leukotriens
All leukocytes
LB4
Chemoattractant
LC4,
LCD4, and LE4 Broncho and
vasoconstriction
6
Platelet activating factor
All leukocytes
Bronchoconstriction and WBC
priming
7
Activated oxygen species
All leukocytes
Endothelial and tissue damage
8
Nitric oxide
Macrophages
Leukocyte activation
9
Cytokines
Lymphocytes, macrophages Leukocyte activation
Most mediators perform their biologic activities by initially binding to
specific receptors on target cells. Once activated and released from the cells,
most of these mediators are short lived. Most mediators have the potential to
cause harmful effects.
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3-4-5: Morphology of acute inflammation
Characteristically, the acute inflammatory response involves production of
exudates. An exudate is an edema fluid with high protein concentration,
which frequently contains inflammatory cells. A transudate is simply a non-
inflammatory edema caused by cardiac, renal, undernutritional, and other
disorders.
The differences between an exudate and a transudate are
Features
EXUDATE
TRANSUDATE
Cause
inflammation
Non-inflammatory
Appearance
Colored, turbid, hemorrhagic
disorders Clear, translucent or
pale yellow
Specific gravity
Greater than or equal to 1.020
Much less
Coagulation
Yes
No
Protein
> 3gm %
< 3gm %
Cells
Abundant WBC, RBC, and Cell
debris usually present
Only few mesothelial cells
Bacteria
Present
Absent
3-4-6: Types of acute inflammation:
1-Serous inflammation
Either an outpouring of a thin fluid that derived from the blood serum or
secretion of mesothelial cells lining the peritoneal, pleural, and pericardial
cavities characterizes this. It resolves without inflammatory reactions.
2-Fibrinous inflammation
More severe injuries result in greater vascular permeability that ultimately
leads to exudation of larger molecules such as fibrinogens through the vascular
barrier. Fibrinous exudate is characteristic of inflammation in serous body
cavities such as the pericardium (butter and bread appearance) and pleura.
Course of fibrinous inflammation include
(1)
the Resolution by fibrinolysis
(2)
Scar formation between parietal and visceral surfaces, i.e. the exudates get
organized and
(3)
Fibrous strand formation that bridges the pericardial space.
3) Suppurative (Purulent) inflammation
This type of inflammation characterized by the production of a large
amount of pus. Pus is a thick creamy or liquid, yellowish or blood stained in
colour and composed of
(1)
A large number of living or dead leukocytes (pus
cells)
(2)
Necrotic tissue debris
(3)
Living and dead bacteria
(4)
Edema fluid. There
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are two types of suppurative iflammation:
a-
Localized suppurative inflammation (Abscess formation):
An abscess is a
circumscribed accumulation of pus in a living tissue. It encapsulated by
pyogenic membrane, which consists of layers of fibrin, inflammatory cells
and granulation tissue.
b-
Diffuse suppurative (phlegmonous) inflammation:
characterized by diffuse
spread of the exudate through tissue spaces. It is caused by virulent bacteria
(e.g. Streptococci spp. cause cellulitis in palmar spaces).
4) Catarrhal inflammation
This is a mild and superficial inflammation of the mucous membrane. It is
commonly seen in the upper respiratory tract following viral infections where
mucous secreting glands are present in large numbers, e.g. Rhinitis.
5) Pseudomembranous inflammation
The basic elements of pseudomembranous inflammation are extensive
necrosis of the surface epithelium of an inflamed mucosa and severe acute
inflammation of the underlying tissues. The fibrinogens in the inflamed tissue
coagulate within the necrotic epithelium. Then
(1)
Fibrinogen,
(2)
Necrotic
epithelium,
(3)
Neutrophilic polymorphs,
(4)
Red blood cells,
(5)
Bacteria and
(6)
tissue debris form a
false (pseudo) membrane
, which forms a white or colored
layer over the surface of inflamed mucosa.
Pseudomembranous inflammation exemplified by dipthetric infection of
the pharynx or larynx, also on Clostridium difficille infection in the large bowel
following certain antibiotic use.
3-4-7: Effects of acute inflammation:
1- Beneficial effects:
a-
Dilution of toxins
: The concentration of chemical and bacterial toxins at the
site of inflammation diluted via exudate, then remove from site by flow
of exudates from the venules through the tissue to the lymphatics.
b-
Protective antibodies:
Exudation results in the presence of plasma proteins
including antibodies at the site of inflammation. Thus, antibodies directed
against the causative organisms will react and promote microbial
destruction by phagocytosis or complement- mediated cell lysis.
c-
Fibrin formation:
fibrin formation will prevents bacterial spread and
enhances phagocytosis by leukocytes.
d-
Plasma mediator systems provisions:
The complement, coagulation,
fibrinolytic, and kinin systems provided to the area of injury by the process
of inflammation.
e-
Cell nutrition:
The flow of inflammatory exudates brings with it glucose,
oxygen and other nutrients to meet the metabolic requirements of the
greatly increased number of cells. It also removes their solute waste
products via lymphatic channels.
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f-
Promotion of immunity:
Microorganisms and their toxins carried by the
exudates either free or in phagocytes, along the lymphaics to local lymph
nodes where they stimulate an immune response to generate antibodies and
cellular immune mechanisms of defense.
2- Harmful effects:
a-
Tissue destruction:
Inflammation may result in tissue necrosis and the
tissue necrosis may in turn incite inflammation.
b-
Swelling:
swelling caused by inflammation may have serious mechanical
effects at certain locations. Examples include acute epiglottitis with
interference in breathing; acute meningitis and encephalitis with effects of
increased intracranial pressure.
c-
Inappropriate
response:
The inflammatory seen in hypersensitivity
reactions is inappropriate (i.e. exaggerated).
3-4-8: Course of acute inflammation
Acute inflammation may end up in:
1-
Resolution:
by complete restitution of normal structure and function of the
tissue, e.g. lobar pneumonia.
2-
Healing by fibrosis (scar formation).
3-
Abscess formation:
When abscess formed, it should drain all abscesses.
However, if it is left untouched, it may result in:
a-
Sinus formation:
when an abscess cavities makes contact with each other.
b-
Fistula formation:
when an abscess tract connects two epithelial surface.
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3-5:
CHRONIC INFLAMMATION
(
Proliferative Inflammation
)
Chronic inflammation is prolonged inflammatory process or reaction
(weeks or months) where an active inflammation, tissue destruction and
attempts at repair are proceeding simultaneously.
3-5-1: Causes of chronic inflammation:
1-
Persistent infections:
Certain microorganisms associated with intracellular
infection such as tuberculosis, leprosy, certain fungi that are characteristically
cause chronic inflammation. These organisms are of low toxicity and evoke
delayed hypersensitivity reactions.
2-
Prolonged exposure to non-degradable but partially toxic substances
either
endogenous lipid components which result in atherosclerosis or exogenous
substances such as silica, asbestos.
3-
Progression from acute inflammation:
Acute inflammation almost always
progresses to chronic inflammation following persistent suppuration as a
result of uncollapsed abscess cavities, foreign body materials (dirt, cloth,
wool), sequesterum in osteomylitis, or a sinus/fistula from chronic abscesses.
4-
Autoimmuniy:
Autoimmune diseases such as rheumatoid arthritis and
systemic lupus erythematosis are chronic inflammation
s
from the outset.
3-5-2: Cells of chronic inflammation:
1-
Monocytes and Macrophages:
are the prima dona (primary cells) in chronic
inflammation. Macrophages arise from the common precursor cells in the
bone marrow, which give rise to blood monocytes. These cells are then
diffusely scattered in various parts of the body, in the liver (Kuffer cells),
spleen, lymph nodes (histiocytes), lungs (alveolar macrophages), bone
marrow, brain (microglia), skin (Langerhan’s cells). These cells constitute the
mononuclear- phagocytic system. Macrophages are scavenger cells of the
body.
2-
T-Lymphocytes:
are primarily involved in cellular immunity with lymphokine
production, and they are the key regulator and effector cells of the immune
system.
3-
B-lymphocytes and Plasma cells:
produce antibody directed either against
persistent antigen in the inflammatory site or against altered tissue
components.
4-
Mast cells and eosinophil:
appear predominantly in response to parasitic
infestations and allergic reactions.
Though neutrophils are hallmarks of acute inflammatory reactions, large
numbers of neutrophils may be seen in some forms of chronic inflammation,
notably chronic osteomylitis, actinomycosis and choric lung diseases induced by
smoking and other stimuli.
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Differentiation points between acute and chronic inflammation
s
include:
Characteristics
Acute inflammation
Chronic inflammation
Duration
Short
Relatively long
Pattern
Stereotyped
Varied
Predominant cell
Neutrophils
Lymphocytes
Macrophages,
plasma cells
Tissue destruction
Mild to moderate
Marked
Fibrosis
Absent
Present
Inflammatory reaction
Exudative
Productive
3-5-3: Classification of chronic inflammation:
Chronic inflammation classified into the following two types based on
histologic features:
1-
Nonspecific chronic inflammation:
This type of inflammation involves a
diffuse accumulation of macrophages and lymphocytes at site of injury that
is usually productive with new fibrous tissue formations, e.g. Chronic
cholecystitis.
2-
Specific inflammation (granulomatous inflammation):
Granulomatous
inflammation characterized by the presence of
granuloma
. A granuloma is a
microscopic aggregate of epithelioid cells with fibrous tissue surrounding.
Epithelioid cell is an activated macrophage, with a modified epithelial cell-
like appearance (hence the name epithelioid). The epithelioid cells can fuse
with each other and form multinucleated giant cells. So, even though, a
granuloma basically a collection of epithelioid cells, it also usually contains
multinucleated giant cell (
Giant cells formed by fusion of macrophages by
concerted attempt of two or more cells to engulf a single particle
) and is
usually surrounded by a cuff of lymphocytes and occasional plasma cells.
There are two types of giant cells:
a-
Foreign body-type giant cells:
which have irregularly scattered nuclei
in presence of indigestible materials.
b-
Langhans giant cells:
in which the nuclei are arranged peripherally in a
horse -shoe pattern which is seen typically in tuberculosis, sarcoidosis.
3-5-4: Pathogenesis of granuloma type:
There are two types of granulomas, which differ in their pathogenesis.
1-
Foreign body granuloma:
Inert foreign bodies such as talc, sutures (non-
absorbable) initiate these granulomas, fibers that are large enough to
preclude phagocytosis by a single macrophage and do not incite an immune
response.
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2-
Immune granulomas:
Antigen presenting cells (macrophages) engulf a
poorly soluble inciting agent. Then, the macrophage processes and presents
part of the antigen (in association with MHC type2 molecules) to CD
4
+
T
helper 1 cells, which become activated. The activated CD
4
+
T-cells produce
cytokines (IL-2 and interferon gamma).The IL-2 activates other CD
4
+
T
helper cells and perpetuates the response. The IFN-γ is important in
transforming macrophages into epitheloid cells and multinucleated giant
cells. The cytokines implicated not only in the formation but also in the
maintenance of granuloma. Macrophage inhibitory factor helps to
localize activated macrophages and epitheloid cells.
3-5-5: Causes of granuloma:
1-
Bacterial
: Tuberculosis, Leprosy, Syphilis, Cat scratch disease, Yersiniosis.
2-
Fungal:
Histoplasmosis, Cryptococcosis, Coccidioidomycosis, Blastomycosis.
3-
Helminthic:
Schistosomiasis.
4-
Protozoal:
Leishmaniasis, Toxoplasmosis.
5-
Chlamydia:
Lymphogranuloma venerum.
6-
Inorganic material:
Berrylliosis.
7-
Idiopathic:
Acidosis, Cohn’s disease, Primary biliary cirrhosis.
3-6: SYSTEMIC EFFECTS OF INFLAMMATIONS
The systemic effects of inflammation include:
1-
Fever:
is the most important systemic manifestation of inflammation. It is
coordinated by the hypothalamus and by cytokines (IL -1, IL-6, TNF-α)
released from macrophages and other cells.
2-
Endocrine and metabolic responses
: include liver secrets acute phase proteins
such as
[1]
C-reactive proteins,
[2]
Serum Amyloid A,
[3]
Complement and
coagulation proteins,
[4]
Increased Glucocorticoids,
[5]
Decreased Vasopressin.
3-
Autonomic responses
: include
[1]
Redirection of blood flow from the
cutaneous to the deep vascular bed.
[2]
Increased Pulse rate and blood pressure
[3]
Decreased Sweating.
4-
Behavioral responses
: include Rigor, chills, anoroxia, somnolence, and
malaise.
5-
Leucocytosis:
a common feature of inflammation, especially in bacterial
infections. Its usual count is 15,000 to 20,000 cells/mm3. Most bacterial
infections induce
neutrophilia
. Some viral infections such as infectious
mononucleosis, and mumps cause
lymphocytosis
. Parasitic infection and
allergic reactions (bronchial asthma) and hay fever induce
eosinophilia
.
6-
Leukopenia:
a feature of typhoid fever and some parasitic infections.
7-
Weight loss:
thought to be due to the action of IL-1 and TNF-α which
increase catabolism in skeletal muscle, adipose tissue and the liver with
resultant negative nitrogen balance.
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Chapter Four
TISSUE HEALING
The word healing, used in a pathological context, refers to the body’s
replacement of destroyed tissue by living tissue.
4-1:
Processes of Healing:
The healing process involves two distinct processes:
1-
Regeneration
, replacement of lost tissue by tissues similar in type.
2-
Repair
(healing by scaring), replacement of lost tissue by granulation tissue
that matures to form scar tissue. Healing by fibrosis is inevitable when the
surrounding specialized cells do not possess the capacity to proliferate.
Whether healing takes place by regeneration or by repair (scarring) is
determined partly by the type of cells in the damaged organ and partly by the
destruction or the intactness of the stromal framework of the organ. Hence, it
is important to know the types of cells in the body.
4-2:
Types of Cells:
Based on their proliferative capacity there are three types of cells.
1-
Labile cells
These are cells have a continuous turn over (new cells) by programmed
division of stem cells. They found in the surface epithelium of the
gastrointestinal tract, urinary tract or the skin. The cells of lymphoid and
haemopoietic systems are further examples of labile cells. The chances of
regeneration are excellent.
2-
Stable cells
Tissues that have such type of cells have normally a much lower level of
replication. However, the cells of such tissues can undergo rapid division in
response to injury. For example, mesenchymal cells such as smooth muscle
cells, fibroblasts, osteoblasts and endothelial cells are stable cells that can
proliferate. Liver, endocrine glands and renal tubular epithelium has also such
type of cells, which can regenerate. Their chances of regeneration are good.
3-
Permanent cells
These are non-dividing cells. If lost, permanent cells cannot replaced,
because they do not have the capacity to proliferate, e.g. adult neurons, striated
muscle cells, and cells of the lens, and when these cells e lost they replaced by
less specialized cells like fibrocytes.
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4-3:
Type of Tissue Healing:
1-
Healing
(
by Regeneration-same tissue
)
Regeneration (generare=bring to life) is the renewal of a lost tissue in
which the lost cells are replaced by identical ones. Labile and stable cells can
regenerate in one condition the stromal framework are intact. Regeneration
involves two processes:
1-
Proliferation of surviving cells to replace lost tissue.
2-
Migration of surviving cells into the vacant space.
The capacity of a tissue for regeneration depends on its
1-
Proliferative ability,
2-
Degree of damage to stromal framework and
3- T
ype and severity of the damage.
2-
Repair
(
by connective tissue-scar tissue
)
Repair is the orderly process by which lost tissue eventually replaced by
less specialized tissue termed scar tissue. A wound in which only the lining
epithelium is affected heals exclusively by regeneration. In contrast, wounds
that extend through the basement membrane to the connective tissue (dermis in
the skin or the sub-mucosa in the gastrointestinal tract) lead to the formation of
granulation tissue and eventual scarring (scar tissue). Tissues containing
differentiated (permanent) cells such as neurons and skeletal muscle cells
cannot heal by regeneration but heal by formation of granulation tissue. In
granulation-tissue formation, three phases may be observed:
a-
Inflammatory Phase:
At this phase, inflammatory exudate containing
polymorphs cells is seen in the area of tissue injury with platelet aggregation
and fibrin deposition.
b-
Demolition Phase:
The dead cells liberate their autolytic and proteolytic
enzyme which secreted from disintegrating polymorphs cells. There is
infiltration of macrophage to ingest particulate matter, either digesting or
removing it.
c-
Ingrowth of granulation tissue:
This is characterized by proliferation of
fibroblasts and an growth of newly blood vessels (
angiogenesis
) into the area
of injury with a variable number of inflammatory cells.
Event occurs at Ingrowth of granulation tissue
Fibroblasts synthesize and secrete extracellular matrix components,
including fibronectin, proteoglycans, and collagen types I and III. The
fibronectin and proteoglycans form the ‘scaffolding’ for rebuilding of the
matrix. Fibronectin binds to fibrin and acts as a chemotactic factor for the
recruitment of more fibroblasts and macrophages.
The synthesis of collagen by fibroblasts begins within 24 hours of the
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injury although its deposition in the tissue is not apparent until 4 days. By day
5, collagen type III is the predominant matrix protein being produced; but by
day 7 to 8, type I is prominent, and it eventually becomes the major collagen of
mature scar tissue. This type I collagen is responsible for providing the tensile
strength of the matrix in a scar.
At same time of fibroblast proliferation there is
angiogenesis
(neovascularization),
a proliferation and formation of new small blood vessels
.
Vascular proliferation starts 48 to 72 hours after injury and lasts for several days.
With further healing, there is an increase in extracellular constituents,
mostly collagen, with a decrease in the number of active fibroblasts and new
vessels. Despite an increased collagenase activity in the wound (responsible for
removal of built collagen), collagen accumulates at a steady rate, usually
reaching a maximum 2 to 3 months after the injury.
The tensile strength of the
wound continues to increase many months after the collagen content has
reached a maximum
.
As the collagen content of the wound increases, many of the newly
formed vessels disappear. This vascular involution which takes place in a few
weeks, dramatically transforms a richly vascularized tissue in to a pale,
avascular scar tissue.
4-4:
Wound contraction
Wound contraction is a mechanical reduction in the size of the defect. The
wound is reduced approximately by 70-80% of its original size. Contraction
results in much faster healing since only ⅓ amount of destroyed tissue has to
be replaced. If contraction is prevented healing is slow and a large ugly scar is
formed. The wound contraction occur due to contraction of myofibroblasts.
Myofibroblasts have the features intermediate between those of fibroblasts and
smooth muscle cells. Two to three days after the injury they migrate into the
wound and their active contraction decrease the size of the defect.
4-5:
Molecular control of healing process
Healing involves an orderly sequence of events which includes
regeneration and migration of specialized cells, angiogenesis, proliferation of
fibroblasts and related cells, matrix protein synthesis and finally cessation of
these processes. These processes are mediated and control by a series of low
molecular weight polypeptides referred to as
growth factors
. These growth
factors have the capacity to stimulate cell division and proliferation.
Sources of
Growth Factors are
(1)
Platelets activated after endothelial damage
(2)
Damaged
epithelial cells
(3)
Circulating serum growth factors
(4)
Macrophages
(5)
Lymphocytes recruited to the area of injury.
The healing process ceases when lost tissue has been replaced. The
mechanisms regulating this process are not fully understood. TGF-β acts as a
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growth inhibitor for both epithelial and endothelial cells and regulates their
regeneration.
4-6:
Wound Healing
The two processes of healing (described above) can occur during healing
of a diseased organ or during healing of a wound. A wound can be accidental or
surgical. Healing of a wound demonstrates both epithelial regeneration (healing
of the epidermis) and repair by scarring (healing of the dermis). There are two
patterns of wound healing depending on the amount of tissue damage:
1- Healing by first intention
2- Healing by second intention
4-6-1:
Healing by first intention
Healing of a clean surgical incision is the best example of this type of
healing. The wound edges are approximated by surgical sutures, and healing
occurs with a minimal loss of tissue. Such healing is referred as “primary
union” or “healing by first intention”. The incision causes the death of a limited
number of epithelial cells as well as of dermal adnexa and connective tissue
cells, the incisional space is narrow and immediately fills with clotted blood,
containing fibrin and blood cells, dehydration of the surface clot forms the
well-known scab that covers the wound and seals it from the environment
almost at once.
Event in Healing by First Intention
1- Within 24 hours, neutrophils appear at the margins of the incision moving
toward the fibrin clot. The epidermis at its cut edges thickens as a result of
mitotic activity of basal cells and, within 24 to 48 hours, spurs of epithelial
cells from the edges both migrate and grow along the cut margins of the
dermis and beneath the surface scab to fuse in the midline, thus producing a
continuous but thin epithelial layer.
2- By day 3, the neutrophils have been largely replaced by macrophages.
Granulation tissue progressively invades the incisional space. Collagen fibers
are now present in the margins of the incision, but at first these are vertically
oriented and do not bridge the incision. Epithelial cell proliferation continues,
thickening the epidermal covering layer.
3- By day 5, the incisional space is filled with granulation tissue.
Neovascularization is maximal. Collagen fibrils become more abundant and
begin to bridge the incision. The epidermis recovers its normal thickness and
differentiation of surface cells yields a mature epidermal architecture with
surface keratinization.
4- During the second week, there is continued accumulation of collagen and
proliferation of fibroblasts. Leukocytic infiltrate, edema, and increased
vascularity have largely disappeared. At this time, the long process of
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blanching begins, accomplished by the increased accumulation of collagen
within the incisional scar, accompanied by regression of vascular channels.
5- By the end of the first month, the scar comprises a cellular connective tissue
devoid of inflammatory infiltrate, covered now by an intact epidermis. The
dermal appendages that have been destroyed in the line of the incision are
permanently lost. Tensile strength of the wound increases thereafter, but it may
take months for the wounded area to obtain its maximal strength.
4-6-2:
Healing by second intention
When there is more extensive loss of cells and tissue, such as occurs in
infarction, inflammatory ulceration, abscess formation, and surface wounds that
create large defects, the reparative process is more complicated. The common
denominator in all these situations is a large tissue defect that must be filled.
Regeneration of parenchymal cells cannot completely reconstitute the original
architecture. Abundant granulation tissue grows in from the margin to complete
the repair. This form of healing is referred to as “secondary union” or “healing
by second intention.”
Secondary healing differs from primary healing in several respects:
1- Inevitably, large tissue defects initially have more fibrin and more necrotic
debris and exudate that must be removed. Consequently, the inflammatory
reaction is more intense.
2- Much larger amounts of granulation tissue are formed. When a large defect
occurs in deeper tissues, such as in a viscus, granulation tissue bears the full
responsibility for its closure, because drainage to the surface cannot occur.
3- Perhaps the feature that most clearly differentiates primary from secondary
healing is the phenomenon of wound contraction, which occurs in large
surface wounds.
4- Healing by second intention takes much longer than when it occurs by first
intention.
4-7:
Factors that influence wound healing
A number of factors can alter the rate and efficiency of healing. These can
be classified in to those which act locally, and those which have systemic
effects. Most of these factors have been established in studies of skin wound
healing but many are likely to be of relevance to healing at other sites.
4-7-1:
Local Factors
1- Type, size, and location of the wound:
A clean, aseptic wound produced by
the surgeon’s scalpel heals faster than a wound produced by blunt trauma,
which exhibits abundant necrosis and irregular edges. Small blunt wounds
heal faster than larger ones. Injuries in richly vascularized areas (the face) heal
faster than those in poorly vascularized ones (the foot). In areas where the skin
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adheres to bony surfaces, as in injuries over the tibia, wound contraction and
adequate apposition of the edges are difficult. Hence, such wounds heal
slowly.
2- Vascular supply:
Wounds with impaired blood supply heal slowly. For
example, the healing of leg wounds in patients with varicose veins is
prolonged. Ischemia due to pressure produces bed sores and then prevents their
healing. Ischemia due to arterial obstruction, often in the lower extremities of
diabetics, also prevents healing.
3- Infection:
Wounds provide a portal of entry for microorganisms infection
delays or prevents healing, promotes the formation of excessive granulation
tissue and may result in large deforming scars.
4- Movement:
Early motion particularly before tensile strength has been
established preventing or retarding healing.
5- Ionizing radiation:
Irradiation leaves vascular lesions that interfere with
blood supply and result in slow wound healing. Acutely, irradiation of a
wound blocks cell proliferation, inhibits contraction, and retards the formation
of granulation tissue.
4-7-2:
Systemic Factors:
1- Circulatory status:
Cardiovascular status which determining the blood
supply to the injured area, is important for wound healing. Poor healing
attributed to old age is often due to impaired circulation.
2- Infection:
Systemic infections delay wound healing.
3- Metabolic status:
Poorly controlled diabetes mellitus is associated with
delayed wound healing. The risk of infection in clean wound approaches
fivefold the risk in non- diabetics. In diabetic patients, there can be impaired
circulation secondary to arteriosclerosis and impaired sensation due to diabetic
neuropathy. The impaired sensation renders the lower extremity blind to every
day hazards. Hence, in diabetic patients, wounds heal in very slowly pattern.
4- Nutritional deficiencies:
Protein deficiency: In protein depletion there is an impairment of granulation
tissue and collagen formation, resulting in a great delay in wound healing.
Vitamin deficiency: Vitamin C is required for collagen synthesis and secretion.
It is required in hydroxylation of proline and lysine in the process of collagen
synthesis. Vitamin C deficiency results in grossly deficient wound healing,
with a lack of vascular proliferation and collagen deposition.
Trace element deficiency: Zinc deficiency will retard healing by preventing
cell proliferation. Zinc is necessary in several DNA and RNA polymerases and
transferases; hence, a deficiency state will inhibit mitosis. Proliferation of
fibroblasts (fibroplasia) is therefore retarded.
5- Hormones:
Corticosteroids impair wound healing, an effect attributed to an
inhibition of collagen synthesis. However, these hormones have many other
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effects, including anti-inflammatory actions and a general depression of
protein synthesis. It also inhibits fibroplasia and neovascularization. Both
epithelialization and contraction are impaired. It is therefore difficult to
attribute their inhibition of wound healing to any one specific mechanism.
Thyroid hormones, androgens, estrogens and growth hormone also influence
wound healing. This effect, however, may be more due to their regulation
of general metabolic status rather than to a specific modification of the healing
process.
6- Anti-inflammatory drugs:
Anti-inflammatory medications do not interfere
with wound healing when administered at the usual daily dosages. Asprin and
indomethalin both inhibit prostaglandin synthesis and thus delay healing.