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Acute and chronic
inflammation. Repair: cell
growth and regeneration.
Wound healing.
2011
Acute inflammation
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is early, immediate, response of vascularized
living tissue to local injury, non-specific
its purpose is
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1) to destroy injurious agent
2) to reconstitute a damaged tissue (healing)
repair already begins during early phases of
inflammation
injured tissue is replaced by regeneration of
parenchymal cells
by connective tissue formation - scarring
Causes of inflammation
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microbial infections: bacteria, viruses, fungi, etc.
hypersensitivity reactions
physical agents: burns, UV light, radiation,
trauma
chemical agents: acids, alkalis, oxidising agents,
toxins, endotoxins, even toxic catabolites
derived from endogenous processes, such as in
uraemia, etc.
tissue necrosis: ischemia
Main clinical signs and
symptoms of inflammation
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Acute inflammation is characterised by five
major signs described by Celsus and Virchow
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rubor = redness from dilatation of blood vessels
calor = increased heat and fever- redness and heat due to an increased rate and volume of blood flow
because of vasodilatation, release of pyrogens
tumor = swelling from edema
dolor = pain form oedema and histamine release,
pain is said to be due to an accumulation of acid
metabolites that stimulate nerve endings
functio laesa = loss of function form pain and
swelling
Morphologic and functional
changes in acute inflammation
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microcirculatory response
cellular response
CELLS OF THE INFLAMMATORY
RESPONSE
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Neutrophilic leukocytes
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Eosinophilic leukocytes
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leukocytes are the first cells to appear at the site of acute
inflammation
is to degrade cell debris and to ingest and kill microbesphagocytosis
associated with hypersensitivity responses
Basophils and mast cells
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mast cells are usually seen in tissues in type I hypersensitivity
reactions mediated by IgE
binding of IgE to the receptor on mast cells and basophils leads
to degranulation of granules and release of the granule
contents (heparin, histamine, and enzymes, such as acid
hydrolase) into the tissues
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Monocytes and macrophages
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macrophages are major scavenger cells of the body
enzymes, such as lysozyme and hydrogen peroxide- degrade
particulate material including micro-organisms
they control many of the cellular, vascular and reparative
responses of inflammation by releasing chemotactic factors,
cytokines (tumour necrosis factor) and growth factors (PDGF)
and transforming growth factor beta (TGF-beta)
Lymphocytes and plasma cells
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these are principal cells of specific immune responses- produce
antibodies
Microcirculatory response
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increased blood flow and permeability of blood vessels
 Vasodilatation leads to hyperaemia (= increased
amount of blood in infl. area )- heat and redness
 increased permeability of blood vessels- associated
with slowing of the circulation- called stasis
increased passage of fluid out of microcirculation
because of increased permeability in acute inflammation
= exudation of fluid
vascular leakage- loss of protein-rich fluid from blood
vessels
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reduction of osmotic pressure within blood vessels
increase in interstitium- accumulation of fluid out of blood
vessels
inflammatory oedema- major feature of acute inflammation
Formation of transudate and exudate
The major local manifestations of
acute inflammation, compared
to normal.
(1) Vascular dilation
(2) extravasation of plasma fluid
and proteins (edema)
(3) leukocyte emigration
Composition of inflammatory
exudate
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exudate is fluid
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rich in plasma proteins (albumins, immunoglobulins, fibrinogen)
converted into fibrin by tissue tromboplastin
Fibrin can be recognised microscopically-pink fibres or
clumps, macroscopically- most easily seen on acute infl.
of serosal surfaces-acute fibrinous pericarditis- „bread
and butter„ appearance.
Transudation= increased passage of fluids (very low
level of plasma proteins, and no cells) through blood
vessels with normal permeability- increased hydrostatic
pressure or decreased plasma osmotic pressure composition similar to ultrafiltrate of plasma
Significance of the process of
exudation
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Exudation
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helps to destroy infectious agent by its diluting
by flooding the area with blood rich in
immunoglobulins and other important defensive
proteins
by increasing lymphatic flow -lymphatic drainage may
to spread infectious agents
acute inflammation of lymphatics= lymphangitis
acute inflammation of lymph nodes=
lymphadenitis
Cellular response
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NEUTROPHILIC LEUKOCYTES
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MACROPHAGES
LYMPHOCYTES
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remain predominant cell type for several days in acute inflammation.
emigration of neutrophils -leukocytes actively leave the blood vessel by
moving through dilated intercellular junctions, pass through basement
membrane and reach the extracellular space
movements of these cells are similar to that of neutrophils- chemotactic
mediators for macrophages- complement factor C5 and lymphokines
(secreted by lymphocytes)
ERYTHROCYTES enter extracellular space passively –
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RBCs are pushed out from the blood vessel by hydrostatic pressure- the
process is called erythrodiapedesis
when large numbers of erythrocytes enter the inflamed area =
haemorrhagic inflammation
Major events in phagocytosis
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recognition and attachment of bacteria by the phagocytic
cells - either directly (large inactive particles) or after
opsonization (antigen is coated by opsonins)
engulfment - extensions of cytoplasm (pseudopods) flow
around the particles - formation of phagocytic vacuole,
this vacuole fuses with membrane of lysosomal vacuolesdegranulation of leukocytes
bacterial killing and degradation-killing of bacterial
organisms is accomplished by activities of reactive
oxygen species
Failure of oxidative metabolism during phagocytosis leads to a severe disorder of immunity = in chronic
granulomatous disease of childhood
Phagocytosis of a particle (e.g., a bacterium) involves:
MORPHOLOGIC PATTERNS IN
ACUTE INFLAMMATION
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Serous inflammation
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is characterised by abundant serous exudate
derived either from the blood stream or from
the secretory activity of mesothelial cells
pleural or pericardial cavities, skin, mucosal
surfaces
serous exudate is easily removed- complete
regeneration
Acute inflammation
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Serous
Serous inflammation
Fibrinous inflammation
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Caused by more serious injuries
permeability of blood vessel is greater
 and more proteins including large molecules of
fibrinogen pass the vascular wall
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Fibrinous exsudate can be removed-process
called resolution
when fibrinous exsudate is not removed
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fibrin may stimulate the ingrowth of fibroblasts
into the blood vessel wall, thus leading to
scarring- this process is called organization
Acute inflammation
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Fibrinous
Fibrinous inflammation
Suppurative or purulent
inflammation
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is characterized by production of large
amounts of purulent exsudate (pus)
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Abscess localized collection of purulent
exudate
Ulcer = is a local defect in the tissue, mainly
in the mucosal or cutaneous surfaces
Acute inflammation
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Purulent
(suppurative)
Purulent-suppurative
inflammation
Bronchopneumonia
Purulent inflammation
Acute inflammation
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Purulent (suppurative) peritonitis
Ulcerative,
pseudomembranous
inflammation
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acute ulcer- intense leukocyte infiltrate
and vascular dilatation in the margins
chronic ulcer -more developed fibroblastic
reaction, scarring and infiltration of
lymphocytes, macrophages and plasma
cells
Fibrinopurulent and pseudomebranous
Pseudomembranous colitis
SYSTEMIC CLINICAL SIGNS OF
ACUTE INFLAMMATION
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fever
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changes in the peripheral white blood cells
leucocytosis- the total number of neutrophils in the peripheral
blood is increased
 is common feature especially in bacterial infections
 „ shift to the left“ means an increased number of immature
neutrophils in peripheral blood
Leukocyte count-may reach levels of about 15 or 20 thousands cells
per mm3- extreme levels (more than 40 thousand)- referred to as
leukemoid reaction
 viral infections tend to produce neutropenia (decreased number
of leukocytes) with lymphocytosis (excess of lymphocytes in the
blood)
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results either of direct activity of cytokines or through local
activity of prostaglandins
CHRONIC INFLAMMATION
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acute inflammation usually disappears after a few days
and tissue returns to normal
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Complete resolution -means total restoration and regeneration of
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Healing by scarring -occurs after tissue destruction, in case of
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Progression to chronic inflammation
injured area.
tissue defects, with abundant fibrin leakage, secondary infection,
chronic inflammatory response may follow acute
inflammation that failed to destroy injurious agent or
may be chronic from the onset (without a clinically
apparent acute phase)
Outcomes of acute inflammation: resolution,
healing by scarring, or chronic inflammation
Causes of chronic inflammation
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persistent infection - caused by distinctive infectious
agents, such as mycobacterium, treponema pallidum,
some fungi, by organisms of lower toxicity, by
intracellular organisms
prolonged exposure to undegradable material, such as
silica particles, carbon particles which, after being
inhaled, set up a chronic inflammatory response in lungs
autoimmune diseases= immune reaction set up against
own tissues or cells - reveal a chronic inflammatory
pattern- for example rheumatoid arthritis
MORPHOLOGIC FEATURES AND
CLINICAL SIGNS OF CHRONIC
INFLAMMATION
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chronic inflammation is an inflammatory response
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it is distinguished from acute inflammation
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characterized by the presence of lymphocytes, plasma cells
and macrophages
by the absence of cardinal signs such as rubor, calor,
dolor, tumor
active hyperemia, fluid exudation and neutrophilic emigration are
absent
it is distinguished from acute inflammation by its long
duration, which permits a manifestation of immune
response
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Often associated with scarring, fibroproliferation
chronic
acute
Histologic hallmarks of chronic
inflammation
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infiltration by macrophages, lymphocytes and
plasma cells
proliferation of fibroblasts and myofibroblasts
and proliferation of small blood vessels, together
known as formation of granulation tissue
in most cases, the process of chronic
inflammation is accompanied by a proliferation
of connective tissue (deposition of collagen
fibres), referred to as fibrosis
usually marked tissue destruction
Granulation tissue
Reparation component of inflammation is
represented by granulation tissue composed of
budding capillaries, fibroblasts and occasional
inflammatory cells
CHRONIC INFLAMMATORY
CELLS
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MACROPHAGES
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play central role in chronic inflammatory infiltrate-macrophages
are the most effective phagocytic cells in acute and chronic
inflammatory response
enzymatic degradation and phagocytic activity
following activation-macrophages produce biologically
active products, such as:
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enzymes - neutral and acid proteases
chemotactic factors for leukocytes
growth factors and promoting factors for fibroblasts and blood
vessels- thus macrophages may modulate a formation of nonspecific granulation tissue
cytokines, such as interleukin I , TNF,etc.
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PLASMA CELLS
 produce antibodies directed against persistent
antigens or against altered tissue components
LYMPHOCYTES
 when activated by the contact with antigen,
lymphocytes release lymphokines- many of them
stimulate macrophages
 on the other hand, lymphocytes may be stimulated by
cytokines released by activated macrophages
EOSINOPHILS
 are characteristic of immunologic reaction mediated
by IgE and of parasitic infections
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NEUTROPHILIC LEUKOCYTES
 in chronic inflammation of bone marrow
(osteomyelitis)- large numbers of neutrophils may
persists for months
 also chronic inflammation of fallopian tube may have
the pattern of chronic suppuration with large numbers
of neutrophils
FIBROBLASTS
 fibroproduction and accumulation of extracellular
proteins- characteristic features of chronic
inflammatory response
MORPHOLOGIC TYPES OF
CHRONIC INFLAMMATORY
RESPONSE
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GRANULOMATOUS CHRONIC INFLAMMATION
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is characterized by formation of epithelioid granulomas
granuloma- is defined as an aggregate of macrophages, two
types of granulomas are recognised
epithelioid granuloma- represents immune response
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macrophages are activated by T-lymphocytes
„ epithelioid cell“ are activated macrophages - large cells with
abundant pale foamy cytoplasm - superficial resemblance to
epithelial cells
typical feature of epithelioid granulomas is formation of
Langhans-type giant cells- are derived from macrophages
Chronic granulomatous
inflammation
Langhans cell
Epithelioid
histiocytes
Granuloma (also called „specific granulation tissue“) is composed of modified
macrophages)
Epithelioid granulomas occur in
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infection due to intracellular organisms
 Tuberculosis (Mycobacterium Tuberculosis)
 Leprosy (Mycobacterium leprae)
 Syphilis (Treponema pallidum)
 Cat-scratch disease (Gram negative bacillus)-rounded
or stellate granulomas usually within lymph nodes
containing the central granular debris and leukocytes
Several parasitic and fungal infections
(schistosomiasis, cryptococcus)
Sarcoidosis (Mycobacterium)
disorders due to chemical agents such as beryllium
(berylliosis)
Crohn disease
Tuberculosis
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Tuberculosis
is characterized by specific granulomas, caseous
necrosis and finding of Mycobacterium
tuberculosis (Ziehl-Nielsen stain)
Chronic granulomatous
inflammation
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Sarcoidosis
?allergic reaction to the presence of non-virulent
mycobacteria?
Chronic granulomatous
inflammation
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Sarcoidosis
Asteroid inclusions
Schaumann´s
inclusions
Granuloma without caseous
necrosis
Hamazaki –
Wesenberg
inclusions
NONGRANULOMATOUS
CHRONIC INFLAMMATION
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accumulation of sensitised lymphocytes, plasma cells and
macrophages
chronic viral infections
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in chronic autoimmune diseases
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persistent infection of parenchymal cells by viruses evokes an immune
response- the affected tissue shows presence of lymphocytes and
plasmacytes, cytotoxic effect is mediated either by killer- T-lymphocytes
or by cytotoxic antibodies
immune response is also mediated by killer- T-lymphocytes or by
cytotoxic antibodies
the antigen is a host cell molecule which is recognised as foreign by
immune system
pathologic result is cell necrosis, resulting in fibrosis and lymphocytic
and plasmacytic infiltration
in chronic inflammation due to chemical toxic substances
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alcohol produces chronic inflammation – liver, pancreas
cell necrosis - alteration in host molecule - becomes antigenic and
evoke immune response
REPAIR. CELL GROWTH AND
REGENERATION. WOUND
HEALING
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resolution -removal of debris associated with a complete
restoration of the tissue to preinjury state
regeneration - complete replacement of necrotic
parenchymal cells by new parenchymal cells of the same
quality
resolution and regeneration- ideal outcome of healing- is
possible only in the tissues with prevailing labile cells
(cells capable of mitotic division- complete regeneration)
if complete resolution and regeneration is not possible,
necrotic foci may be replaced by collagen
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this process is termed organisation repair by scar formation
REGENERATION
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replacement of lost parenchymal cells is dependent on
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regenerative capacity of the cells
number of surviving cells
maintenance of basement membranes or presence of stem cell
layer
The cells of the body can be divided into 3 groups on the
basis of their regenerative capacity and their relation to
the cell cycle:
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Labile cell (intermitotic)
Stable cell (reversible postmitotic )
Permanent cell (irreversible postmitotic)
Labile cells
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continuously dividing cells- they continue to
proliferate, remain all the time in cell cycle
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Healing in tissues with many labile cells:
injury is followed by rapid and complete regeneration
surgical removal of endometrium by curettage is
followed by complete regeneration from the
basal germinative layer within short time
or destruction of erythrocytes stimulates rapid
erythroid hyperplasia in bone marrow which
results in complete regeneration of erythropoesis
Stable cells-quiescent
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they are considered to be in G0 phase, may undergo
rapid proliferation after appropriate stimuli, they may be
recruited back to the cell cycle
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Healing in tissues with prevailing stable cells:
regeneration in tissues with most stable cell is possible but the
following conditions must be fulfilled:
sufficient amount of viable tissue must remain
intact fibrous interstitial network and original basement
membranes preserved
if complete necrosis involves both parenchyma and
interstitium- no regeneration is possible and necrosis
heals by scar formation
Permanent cells- non-dividing
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cells have no regenerative capacity
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Healing in tissues with permanent cells:
injury to tissue with permanent cells is always
followed by scar formation, no regeneration is
possible
REPAIR BY SCAR FORMATION
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scar=mass of collagen that is the final
result of the process of organization
repair by scar occurs:
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if resolution fails
if the injurious agent continuously causes
injury in chronic inflammation
if parenchymal necrosis cannot be repaired by
regeneration because of prevalence of
permanent cells
Process of repair by scar formation
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Preparation
 removal of the inflammatory exudate
 Debris is liquefied by lysosomal enzymes derived of neutrophil
leukocytes
 is removed by lymphatics, residual particle are phagocytosed by
macrophages
Ingrowth of granulation tissue
 granulation tissue is highly vascularized connective tissue composed of
newly formed capillaries, proliferating fibroblasts and myofibroblasts,
cell debris and residual inflammatory cells
 major role of the granulation tissue is to occupy the tissue defects lost
by injury
 Grossly granulation tissue is deeply red (because of numerous
capillaries) and soft, with granularity of the surface
Collagenization
 collagens are the major fibrillary extracellular proteins
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Maturation of the scar
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collagen content of granulation tissue progressively
increases with the time, particularly the amount of
type I collagen increases
the scar becomes less cellular and less vascular
the mature scar is composed of hypovascular poorly
cellular collagenous mass- composed mostly of
collagen type I
Contraction and strengthening
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contraction decreases the size of scar- allows optimal
function of the remaining tissue
HEALING OF SKIN WOUNDS
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Healing by first intention (primary union)
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healing of clean uninfected surgical incision
joined by surgical sutures
limited number of dead cells, minor
discontinuity of basement membrane
the incisional space immediately fills with
clotted blood containing fibrin
Healing by second intention
(secondary union)
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differs from primary healing in several aspects:
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large tissue defects, such as large infarctions,
ulcerations, abscesses
large wounds- have always more fibrin in exudate,
thus more intense inflammatory reaction
much greater amount of granulation tissue is formed
final scar is much smaller than original wound due to
wound contraction (mostly results of activities of
myofibroblasts) - tissue retraction
PATHOLOGIC ASPECTS OF
REPAIR
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The factors that modify the quality of tissue
repair include:
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nutrition deficiency, particularly vitamin C deficiency
decreases the ability to heal wounds
glucocorticoids have anti-inflammatory effect
persistent infection is the most important cause of
delayed healing
mechanical factors, as wound dehiscence
low blood supply, presence of foreign bodies
disorders of lymphatic flow may slow down the
removal of necrotic cells and cause delayed healing
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the presence or absence of diabetes mellitus and
other underlying diseases
adequate levels of circulating white blood cells
type of injured tissue
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perfect repair may occur only in tissues built up of
labile and stable cells,
while injuries to permanent cells results in scarring,
such case is myocardial infarction (no regeneration of
specialised heart muscle elements)
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large amounts of exudate slows down a healing healing of exudate include:
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digestion of the exudate initiated by proteolytic enzymes of
leukocytes-resorption of dissolved exudate= process called „
resolution“
the presence of extensive necrosis or large amounts of fibrin in
the exudate or low blood and lymphatic rate
the process of resolution cannot occur and the exudate is
replaced by granulation tissue and transformed into fibrous
tissue -organization of exudate
for example lung carnification in pathologic healing of
pneumonia
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aberration of growth -hyperplastic scarring- if
excessive amounts of collagen accumulate
within the scar= keloid
-keloid formation appears to an individual
predisposition of unknown reasons or excessive
formation of granulation tissue= exuberant
granulation - granulation tissue protrudes over
the surface of the wound and in fact blocks the
reepithelization- granulation tissue must be
removed surgically