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INFLAMMATION collagen

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INFLAMMATION collagen

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									                          INFLAMMATION.
Acute inflammation
       -is early, immediate, response of vascularized living tissue to
local injury, non-specific
-its purpose is
       1) to destroy injurious agent
       2) to reconstitute a damaged tissue (= healing), repair already
begins during early phases of inflammation, during repair the injured
tissue is replaced by regeneration of parenchymal cells, by filling
defects with fibroblastic scar tissue = scarring
Causes of inflammation
       -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
       -Acute inflammation is characterised by five major signs
described by Celsus and Virchow
       -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
       -tumour = 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

CELLS OF THE INFLAMMATORY RESPONSE
Neutrophilic leukocytes
      -leukocytes are the first cells to appear at the site of acute
inflammation
      - is to degrade cell debris and to ingest and kill microbes-
phagocytosis
Eosinophilic leukocytes-
      - associated with hypersensitivity responses
Basophils and mast cells
      -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
Monocytes and macrophages
      macrophages are major scavenger cells of the body



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-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
-these are principal cells of specific immune responses- produce
antibodies
    morphologic and functional changes in acute inflammation
-two main processes involved in acute infl. response are:
       -microcirculatory response
       -cellular response
1 - microcirculatory response
       - 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 results
in a reduction of osmotic pressure within blood vessels and in and
increase within the interstitium- accumulation of fluid out of blood
vessels-passage of large amounts of fluid from capillaries into the
interstitium is associated with inflammatory oedema- major feature of
acute inflammation
Composition of inflammatory exudate
=exudate is a fluid rich in plasma proteins, such as albumins,
immunoglobulins,        parts    of   complement,       fibrinogen-when
extracapillary it is rapidly 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
Exudation 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 (helps to remove
agents out of area)- lymphatic drainage may be however harmful,
helps to spread infectious agents.
       -acute inflammation of lymphatics= lymphangitis
       -acute inflammation of lymph nodes= lymphadenitis
2 - cellular response



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Acute inflammation is characterised by an active emigration of
inflammatory cells from the blood into the area of injury.

        1.) NEUTROPHILIC LEUKOCYTES 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
2.) MACROPHAGES and 3.) LYMPHOCYTES -movements of these cells
are similar to that of neutrophils- chemotactic mediators for
macrophages- complement factor C5 and lymphokines (secreted by
lymphocytes)
different process - 4.) ERYTHROCYTES enter extracellular space
passively - 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
PHAGOCYTOSIS
= major mechanism by which leukocytes and macrophages inactivate
noxious agents
Major events in phagocytosis
        - 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 vacuoles-degranulation 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
MORPHOLOGIC PATTERNS IN ACUTE INFLAMMATION
        -Basic patterns of acute inflammatory response depend on
severity of noxious agent, severity of reaction, type of tissue involved,
site, local circumstances, composition of exudate etc.
Serous inflammation
        -is characterised by abundant serous fluid (exudate) that is
derived either from the blood stream or from the secretory activity of
mesothelial cells lining peritoneal, pleural or pericardial cavities,
serous exudate is easily removed- complete regeneration
Fibrinous inflammation
        -with more serious injuries, the permeability of blood vessel is
greater and more proteins including large molecules of fibrinogen pass
the vascular wall.
        -Fibrinous exsudate may be removed- resolution. When
fibrinous exsudate is not removed-fibrin may stimulate the ingrowth
of fibroblasts into the blood vessel wall, thus leading to scarring- this
process is called organization.


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Suppurative or purulent inflammation
       -is characterized by production of large amounts of purulent
exsudate (= pus ).
       -Abscess= localized collection of purulent exudate
       -Ulcer = is a local defect in the tissue, mainly in the mucosal or
cutaneous surfaces
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.

SYSTEMIC CLINICAL SIGNS OF ACUTE INFLAMMATION
1) fever
       - results either of direct activity of cytokines or through local
activity of prostaglandins
2) 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)

      CHRONIC INFLAMMATION. MORPHOLOGIC PATTERNS OF
      CHRONIC INFLAMMATION. MIXED ACUTE AND CHRONIC
                      INFLAMMATORY RESPONSE.
       -acute inflammation usually disappears after a few days and
tissue returns to normal
1.-Complete resolution -means total restoration and regeneration of
injured area.
2.-Healing by scarring -occurs after tissue destruction, in case of
tissue defects, with abundant fibrin leakage, secondary infection,
3.-Progression to chronic inflammation
-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 )
Causes of chronic inflammation
       1- persistent infection - caused by distinctive infectious agents,
such as mycobacterium, treponema pallidum, some fungi, by
organisms of lower toxicity, by intracellular organisms
       2- prolonged exposure to undegradable material, such as silica
particles, carbon particles which, after being inhaled, set up a chronic
inflammatory response in lungs



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       3- 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
-chronic inflammation is an inflammatory response characterized by
the presence of lymphocytes, plasma cells and macrophages
-it is distinguished from acute inflammation by the absence of
cardinal signs such as rubor, calor, dolor, tumor
-active hyperaemia, fluid exudation and neutrophilic emigration are
absent
-it is distinguished from acute inflammation by its long duration,
which permits a manifestation of immune response
Histologic hallmarks of chronic inflammation are:
       -infiltration of affected tissue 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
CHRONIC INFLAMMATORY CELLS
1) MACROPHAGES - 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:
       -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 non-specific
granulation tissue
       -cytokines, such as interleukin I and TNF (tumour necrosis
factor ) etc.
2) PLASMA CELLS- produce antibodies directed against persistent
antigens or against altered tissue components
3) 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
4) EOSINOPHILS -are characteristic of immunologic reaction mediated
by IgE and of parasitic infections.
5) NEUTROPHILIC LEUKOCYTES-
       -in chronic inflammation of bone marrow (osteomyelitis)- large
numbers of neutrophils may persists for months


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      -also chronic inflammation of fallopian tube may have the
pattern of chronic suppuration with large numbers of neutrophils
6) FIBROBLASTS- fibroproduction and accumulation of extracellular
proteins- characteristic features of chronic inflammatory response

MORPHOLOGIC TYPES OF CHRONIC INFLAMMATORY RESPONSE
there are two different types of chronic inflammation in response to
antigenic stimuli
GRANULOMATOUS CHRONIC INFLAMMATION
        -is characterized by formation of epithelioid granulomas
granuloma- is defined as an aggregate of macrophages
two types of granulomas are recognised
        1)- foreign body giant cell granuloma- which represents
nonimmune phagocytosis of foreign bodies and particles by
inactivated macrophages
        2)- epithelioid granuloma- which represents an immune
response in which macrophages are activated by T-lymphocytes
„ epithelioid cell“ are activated macrophages - large cells with
abundant pale foamy cytoplasm - superficial resemblance to epithelial
cells
        -a typical feature of epithelioid granulomas is formation of
Langhans-type giant cells- are derived from macrophages
Epithelioid granulomas occur in:
1) infection due to intracellular organisms
        1/ Tuberculosis (Mycobacterium Tuberculosis)
        2/ Leprosy (Mycobacterium leprae)
        3/ Syphilis (Treponema pallidum)
        4/ Cat-scratch disease (Gram negative bacillus)-rounded or
stellate granulomas usually within lymph nodes containing the central
granular debris and leukocytes
        5/ Several parasitic and fungal infections ( schistosomiasis,
cryptococcus )
        6/ Sarcoidosis (Mycobacterium)- noncaseous granulomas
composed of giant cells of Langhans type, epithelioid cells, occasional
Schaumann bodies or asteroid inclusions in giant cells
2) disorders due to chemical agents such as beryllium (berylliosis),
silica particles (silicosis )
3) disease of uncertain nature, such as Crohn disease
foreign body giant cell granuloma
        -when foreign material enters tissue, it can either be
phagocytosed by single macrophage
-or it may initiate immune response
-or if inert it induces formation of foreign body granuloma
- macrophages aggregate around these inert foreign particles
(refractile particles if viewed under polarised light)- foreign body
granuloma indicates the presence of nondigestible foreign material (
talc particles, sutures, etc.)




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NONGRANULOMATOUS CHRONIC INFLAMMATION
- is characterized by the accumulation of sensitised lymphocytes
(activated specifically by the antigen), plasma cells and macrophages
in the affected area
       1) in chronic viral infections
-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
       2) in chronic autoimmune diseases
-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
       3) in chronic inflammation due to chemical toxic substances
       -alcohol may produce chronic inflammation notably of the liver
and pancreas
toxic substance can cause cell necrosis that may result in alteration
in host molecule which thus can become antigenic and evoke immune
response
lymphocyte and plasma cell infiltration is slight, dominating feature is
fibrosis
4) chronic nonviral bacterial infections in which the causative agents
accumulate in cells

REPAIR. CELL GROWTH AND REGENERATION. WOUND HEALING.
       -proper healing needs previous removal of inflammatory and
necrotic cell debris
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, this process is termed organisation
repair by scar formation
- mechanism of healing depends on the type of inflammation, the
extent of necrosis, regenerative capacity of damaged cells, rate of
lymphatic flow, amount of fibrin in the inflammatory exudate etc.

REGENERATION
      -replacement of lost parenchymal cells is dependent on
1-regenerative capacity of the cells
2-number of surviving cells
3-maintenance of basement membranes or presence of stem cell layer


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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:
       1.- Labile cell (intermitotic)
       2.- Stable cell (reversible postmitotic )
       3.- Permanent cell (irreversible postmitotic)
1.- Labile cells- continuously dividing cells- they continue to
proliferate, remain all the time in cell cycle
-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
2.-Stable cells-quiescent- they are considered to be in G0 phase,
may undergo rapid proliferation after appropriate stimuli, they may be
recruited back to the cell cycle
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

3.- Permanent cells- non-dividing. cells have no regenerative
capacity
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.
scar=mass of collagen that is the final result of the process of
organization
repair by scar occurs:
      - 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 has several steps:
1- Preparation - the tissue is prepared by removal of the inflammatory
exudate. Debris is liquefied by lysosomal enzymes derived of
neutrophil leukocytes, liquefied material is removed by lymphatics,
residual particle are phagocytosed by macrophages
2- Ingrowth of granulation tissue



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-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
3- Collagenization
-collagens are the major fibrillary extracellular proteins.
Classification of collagens:
       -types I and III collagens - interstitial types of collagen,
ubiquitous, most common in connective tissues, scars, stroma of
tumours, stroma of normal organs
       -type II collagen - major collagen of cartilage
       -type IV collagen - one of major constituents of BMs ( in addition
to laminin, entactin and heparan sulphate )
       type V collagen - collagen of so called anchoring fibrils of BMs of
epithelia
       -collagens types VI- XIII - are minor constituents of either
connective soft tissues or cartilage
       The most important in scar formation are interstitial collagens
type III and I- type III composed of thin fibers, synthesised by young
fibroblasts and myofibroblast in granulation tissue, on the other
hand, type I collagen prevails in mature scar.
4- Maturation of the scar
-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
5- Contraction and strengthening
-contraction decreases the size of scar- allows optimal function of the
remaining tissue

HEALING OF SKIN WOUNDS.
       1-Healing by first intention (primary union)- 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
-within 24 hrs-neutrophils appear, there is an increased proliferation
in basal layer of epidermis at the margins of the wound - epithelial
cells migrate and synthesise basement membrane
-day 3- leukocytes disappear and the are replaced by macrophages -
granulation tissue progressively invades the incision space, collagen
fibres are already present but do not cross completely the incision
space, and the epithelial cells continue to proliferate



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-day 5- the incision space is filled with granulation tissue, collagen
fibres are abundant and begin to bridge the incision, epidermis
recovers to normal thickness, there is a maturation of the epidermis
-2nd week- accumulation of collagen continues, but proliferation of
fibroblasts and leukocytes slow down,
- oedema, fluid, and necrotic cells mostly have disappeared, and there
is a regression of vascular channels
-end of the 1st month- scar covered by intact epidermis is finished
-the scar is composed of mature collagenous connective tissue devoid
of inflammatory infiltrate
2- Healing by second intention ( secondary union )
healing by second intention differs from primary healing in several
aspects:
       -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.
-Cell growth and fibroplasia are the most important aspects in
healing-
-these processes of healing may be modified by pathologic state:
The factors that modify the quality of tissue repair include:
       -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
       -the presence or absence of diabetes mellitus and other
underlying diseases
       -adequate levels of circulating white blood cells
       -type of injured tissue - 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 )
       -large amounts of exudate slows down a healing -
healing of exudate include:
-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


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transformed into fibrous tissue (organization of exudate )- for example
lung carnification in pathologic healing of pneumonia
      -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.




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