CHRONIC INFLAMMATION. MORPHOLOGIC PATTERNS OF CHRONIC
INFLAMMATION.
- acute inflammation usually disappears after a few days and tissue returns
to normal
1.- complete resolution
2.- healing by scarring
3.- progression to chronic inflammation
 1.-Complete resolution
-means total restoration and regeneration of previously injured area.
For many reasons- the complete resolution is often impossible.
The injury must be short in duration, limited in strength, of little tissue
destruction.
Resolution- includes total removal of edema fluid, removal of leukocytes
and other cells of inflammatory infiltrate, removal of cell debris
Key role in resolution has phagocytosis
 2.-Healing by scarring
-occurs after tissue destruction, in case of tissue defects, with abundant
fibrin leakage, secondary infection, etc
 3.-Progression to chronic inflammation
-chronic inflammatory response follows an acute inflammation that failed to
destroy injurious agent or may be chronic in type from the onset (it may
occur without a clinically apparent acute phase)
-chronic inflammation is the sum of the responses developed
by tissues against a persistent injurious agent (bacterial, viral, chemical,
immunological)
Causes of chronic inflammation
1- persistent infection - caused by distinctive infectious agents, for
example- mycobacteria, treponema pallidum,some fungi, organisms of low
toxicity -intracellular organisms
-often the injurious agents are less toxic than those leading to acute
inflammation
2- prolonged exposure to undegradable material, for example silica
particles which, after being inhaled, set up a chronic inflammatory response
in lungs called silicosis
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.
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-chronic inflammation is an inflammatory response characterized by
the presence of lymphocytes, plasma cells and macrophages
-it may result of unresolved acute infl. or de novo
-it is distinguished from acute inflammation by the absence of
cardinal signs such as rubor, calor, dolor, tumor
-active hyperemia, fluid exsudation 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 and proliferation of
small blood vessels, together known as formation of granulation tissue
-most cases of chronic inflammation are acompanied by an increase in
amount of connective tissue, referred to as fibrosis, or production of scar
 CHRONIC INFLAMMATORY CELLS
 1) MACROPHAGES - play central role in chronic inflammatory infiltrate
macrophage activation - multiple-step process governed by mediators
of inflammation, such as lymphokins produced by activated T-lymphocytes,
bacterial toxins, by various chemicals, fibronectin, etc.
morphologic changes in activated macrophages: process of activation
results in -increase in the size, increased level of lysosomal enzymes, more
active metabolism, greater activity in phagocytosis, more ability in killing
microbes.
following activation-macrophages produce biologically active products, such
as:
-enzymes - neutral and acid proteases - some of them may also play a
role in immediate inflammatory response- collagenases, elastase which
degrade connective tissue components
-chemotactic factors for leukocytes
-growth factors and promoting factors for fibroblasts and blood
vessells- thus macrophages may modulate a formation of nonspecific
granulation tissue
-cytokines, such as interleukin I and TNF (tumor necrosis factor)
ets.
-macrophages are the most effective phagocytic cells in acute and chronic
inflammatory response
major functions of macrophages: -enzymatic degradation and phagocytic
activity
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 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.
The granules of eosinophils contain major basic protein (MBP) which
is highly toxic for parasites but also may cause lysis of host epithelial cells,
thus eosinophils may contribute to tissue damage particularly in
hypersensitivity states
 5) NEUTROPHILIC LEUKOCYTES- dominate in acute inflammatory
response but have an important role in many forms of chronic
inflammation too
in chronic inflammation of bone marrow (osteomyelitits)- 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
 6) FIBROBLASTS- fibroproduction and accumulation of extracellular
proteins - characteristic features of chronic inflammatory response
 MORPHOLOGIC TYPES OF CHRONIC INFLAMMATORY RESPONSE.
-depends on type of injurious agent
-vast majority of cases of chronic inflammations occur in response to an
injurious agent that is antigenic, less commonly -inflammatory response due
to non-antigenic stimuli
-immune response is started when antigen enters the body and is
reinforced by an subsequent accumulation of antigen
-local persistence of antigen - leads to accumulation of activated Tlymphocytes, plasma cells and macrophages (these cells are also called
chronic inflammatory cells)
-the immune response takes several days to develop because nonsensitized
lymphocytes must pass through several cell division cycles before increased
number of effector lymphocytes becomes apparent in the tissue
 there are two different types of chronic inflammation in response to
antigenic stimuli
-granulomatous inflammatory response
-nongranulomatous inflammatory response
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 GRANULOMATOUS CHRONIC INFLAMMATION
-is characterized by formation of epithelioid granulomas
granuloma- is defined as an aggregate of macrophages
two types of granulomas are recognized generally
1) epithelioid granuloma- which represents an immune response in which
macrophages are activated by T-lymphocytes
2) foreign body giant cell granuloma- which represents nonimmune
phagocytosis of foreign bodies and particles by nonactivated macrophages
„epithelioid cell„ are activated macrophages - large cells with abundant pale
foamy cytoplasm - seperficial resemblance to epithelial cells
-macrophages aggregation is a function of lymphokines produced by
T-lymphocytes
- typical feature of epithelioid granulomas is formation of Langhanstype giant cells- are derived from macrophages
-gama- interferon plays a key role in transformation macrophages
into epithelioid cells and giant cells
Epithelioid granulomas occur in several different diseases
 1) infection due to intracellular organisms
1/ Tuberculosis (Mycobacterium tuberculosis)- typical granulomatous
inflammation
2/ Leprosy (Mycobacterium leprae)-tissue granulomas composed of
epithelioid macrophages with phagocytosized bacili
3/ Syphilis (Treponema pallidum)- gumma-foci of necrosis
surrounded by histiocytes and plasma cell infiltrate
4/ Cat-scratch disease (Gram negative bacilus)-rounded or stllate
granulomas usually within lymph nodes containing the central granular
debris and leukocytes
5/ Several parasitic and fungal infections (schistosomiasis,
cryptococcus)
6/ Sarcoidosis (Mycobacterium)- noncaseating granulomas composed
of giant cells of Langhans type, epithelioid cells, occassional Schaumann
bodies or asteroid inclusions in giant cells
 2) disorders due to chemical agents such as beryllium (berylliosis), silical
particles (silicosis)
 3) disease of uncertain nature, such as Crohn disease
 NONGRANULOMATOUS CHRONIC INFLAMMATION
- is characterized by the accumulation of sensitized lymphocytes (activated
specifically by the antigen), plasma cells and macrophages in the affected
area
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these cells are scatered diffusely and do not form granulomas
nongranulomatous chronic inflammation occurs for example
 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-lyphocytes or
by cytotoxic antibodies
 2) in chronic autoimmune diseases
-immune response is also mediated by killer- T-lyphocytes or by cytotoxic
antibodies
the antigen is a host cell molecule which is recognized as foreign by immune
system
pathologic result is cell necrosis, resulting in fibrosis and lymphocytic and
plasmacytic inflitration
 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 inlitration is slight, dominating feature is
fibrosis
 4) chronic nonviral bacterial infections in which the causative agents
accumulate in cells
 CHRONIC INFLAMMATION IN RESPONSE TO NONANTIGENIC
AGENTS
when foreign material enters tissue, it can either be phagocytosed by
single macrophage
-or induces formation of foreign body granuloma
- macrophages aggregate around these inert foreign particles (refractile
particles if viewed under polarized light)- foreign body granuloma indicates
the presence of nondigestible foreign material (talc particles, sutures, atc)
FUNCTION OF CHRONIC INFLAMMATION
-chronic inflammatory response serves to remove injurious agent which is
not easily eradicated by the body
-destruction of agent is dependent on immune response which is activated either by direct killing by activated T- lymphocytes or by interaction with
antibodies produced by plasma cells
- chronic inflammation is characterized by tissue fibrosis which may
represent a serious side effect of chronic inflammation (for example-
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pulmonary fibrosis due to chronic interstitial inflammation may cause
respiratory failure)
REPAIR. CELL GROWTH AND REGENERATION. WOUND HEALING.
-tissue injuries associated with inflammation are followed by healing
-proper healing needs previous removal of inflammatory and necrotic cell
debris
-if injurious agent was rapidly inactivated (transitory injury) - rapid
healing follows resolution -removal of debris associated with a complete restoration
of the tissue to preinjury state
regeneration - complete replacement necrotic parenchymal cell by
new parenchymal cells after removal of debris
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 organization= 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.
 RESOLUTION
-inflammatory exudate and necrotic debris are digested by lysosomal
enzymes (mostly from leukocytes), then removed by lymphatics. Remaining
particles are phagocytosed by macrophages.
 REGENERATION
-replacement of lost parenchymal cells is dependent on
1-regenerative capacity of the cells
2-number of surviving cells
3-maintanance 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:
1.- Labile cell ( intermitotic)
2.- Stable cell ( reversible postmitotic )
3.- Permanent cell ( irreversible postmitotic)
 The cell cycle and types of cells
Proliferating cells occupy several functional states between two
mitoses. The cell cycle consists of G1 gap ( presynthetic), S ( DNA
synthesis), G2 gap ( premitotic) and M ( mitotic ) phases.
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The cells may leave cell cycle during G1 and then they either cease
proliferation, differentiate or eventually die or they enter G0 phase,
resting phase from which they can be eventually recruited back to the
cycle.
 1.- Labile cells- continuously dividing cells- they continue to proliferate, remain
all the time in cell cycle
-tissues that contain labile cells
-stratified squamous epithelium of the skin, oral cavity, vagina cervix,
esophagus,
-lining epithelial cell of the gland such as salivary glands, pancreas biliary
tract,
-columnar epithelium of uterus,fallopian tube,
-urinary epithelium
-lymphoid tissue, hematopoetic tissue
 Healing in tissues with many labile cells:
-injury is followed by rapid and complete regeneration
for example-surgical removal of endometrium by curretage 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
-tissues tha contain stable cells
-parenchymal cell of virtually all glandular organs, such as liver, kidney,
pancreas, breast, lung
-mesenchymal cells, such as fibroblasts and smooth muscle cells
-vascular endothelial cells
 Healing in tissues with prevailing stable cells:
-regeneration in tissues with most stable cell is possible but there are
following conditions:
-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. These cells have left cell cycle and cannot
undergo mitotic division. These cells have no regenerative capacity
This group includes:
-nerve cells ( mature neurons)
-skeletal and heart muscle cells.
Healing in tissues with permanent cells:
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-injury to tissue with permanemt 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 continuesly 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
-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
-proliferation of capillaries and fibroblasts in granulation tissue is governed
by variety of growth factors-controled by chemical mediators of
inflammatory response
grossly- granulation tissue is deeply red (because of numerous capillaries)
and soft, with granular of the surface- name
microscopically- granulaiton tissue is composed of thin-wall proliferating
capillaries lined by hyperplastic endothelial cells, of fibroblasts and
myofibroblasts
- both fibroblasts and endothelial cells- very active metabolism
fibronectin - extracellular matrix glycoprotein- that has an important role
in proliferation of granulation tissue
in the early phase- fibronectin is derived of blood plasma
later-it is produced by fibroblasts and endothelial cells of granulation
tissue
-fibronectin is chemotactic for fibroblasts and promotes formation of
capillaries
 3- Collagenization
-collagens are the major fibrillary extracellular proteins.
Classification of collagens:
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-types I and III collagens - interstitial types of collagen, ubiquituous, most
common in connective tissues, scars, stroma of tumors, 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, synthesized by young fibroblasts
and myofibroblast in granulation tissue, on the other hand, type I collagen
prevails in mature scar.
-Collagen is synthesized by fibroblasts in the form of precursor as
tropocollagen, shortly after secretion-terminal nonfibrillary parts of the
polypeptidic chain is removed by collagenase and nonsoluble molecule of
collagen is deposited inextracellular matrix
-Fine collagen fiber (reticulin)- correspond to type III collagen
-fibrous tissue, scar tissue= collagen type I and III
 4- Maturation of the scar
-collagen content of granulation tissue progressively increases with the
time, particularly the amount of type I collagen steadily 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
-strength of scar depends on the amount of collagen type I - fully mature
scar if firm, flexible structure
 HEALING OF SKIN WOUNDS.
-Wound healing is complex phenomen involving number of different
processes, including parenchymal cell regeneration, synthesis of
extracellular matrix proteins, remodeling of connective tissue etc.
 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 synthesize basement membrane
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-day 3- leukocytes disappear and the are replaced by macrophages granulation tissue progressively invades the incision space, collagen fibers
are already present but do not cross completely the incision space, and the
epithelial cells continue to proliferate
-day 5- the incision space is filled with granulation tissue, collagen fibers
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,
- edema, 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
-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 specialized
heart muscle elements)
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-large amounts of exudate slows down a healing
healing of exudate include:
-digestion of the exudate initiated by proteolytic enzymes of leukocytesresorption 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
-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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