INFLAMMATION.
Inflammatory processes are part of the body´s natural defences.
ACUTE INFLAMMATION
injury
-is early, immediate, response of vascularized living tissue to local
- is nonspecific, may be evoked by all types of cell injury
-its purpose is to localise and eliminate the injurious agent and then
to restore the tissue to normal function and to normal structure
 SIGNIFICANCE OF INFLAMMATION
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
-acute inflammatory response is beneficial but it may also be harmful,
associated with tissue damage
examples: - inflammation has a beneficial effects by localising and
walling off an infection, but on the other hand, the process of
inflammation may cause extensive tissue damage
- swelling of the brain caused by infl. response against viral
infection may lead to death by increased intracranial pressure or
-infl. reactions underlie genesis of autoimmune diseases
(rheumatoid arthritis, fatal acute and chronic glomerulonephritis, that
may lead to renal failure)
-reparatory reactions may cause hypertrophic scars, or may
result in an intestinal obstructions, immobilize joints (use of antiinflammatory drugs )
 CAUSES OF INFLAMMATION
almost all possible causes of cell injury may stimulate inflammatory
response
-microbial infections: bacteria, viruses, fungi, etc
-hypersensitivity reactions
-physical agents: burns, UV light, radition, trauma
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-chemical agents: acids, alkalis, oxidising agents, toxins, endotoxins,
even toxic catabolites derived from endogenous processes, such as in
uremia, etc
- tissue necrosis: ischemia
 MAIN CLINICAL SIGNS AND SYMPTOMS OF INFLAMMATION
Acute inflammation is characterized 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
-tumor =swelling from edema
-dolor =pain form edema and histamine release, pain is said to be
due to an accumulation of acid metabolits that stimulate nerve endings
-functio laesa = loss of function form pain and swelling
These signs are manifested in acute inflammation if this occurs on the
body surface, not always in inflammation of internal organs
CELLS OF THE INFLAMMATORY RESPONSE
 Neutrophilic leukocytes
-leukocytes are the first cells to appear at the site of acute inflammation
-their function - is to degrade cell debris and to ingest and kill microbesphagocytosis
-neutrophils contain bactericidal intracellular enzymes in lysosomes, such
as myeloperoxidase, lysozyme, and acid hydrolase
-lysosomes fuse with the vacuole containing the ingested materialincluding microbes, release enzymes, and destroy the contents
 Eosinophilic leukocytes
- are associated with hypersensitivity responses and allergic reactions
-they produce histaminase, aryl sulphatase and phospholipase which
degrade anaphylactic chemical mediators particularly those produced by
mast cells
 Basophils and mast cells
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-mast cells are usually seen in tissues in type I hypersensitivity reactions
mediated by IgE
-mast cells have specific surface receptors for IgE
-both mast cells and basophils have cytoplasmic granules which contain
heparin and histamine and enzymes, such as acid hydrolase
-binding of IgE to the receptor leads to degranulation and release of the
granule contents into the tissues
 Monocytes and macrophages
macrophages are major scavenger cells of the body
-derived of blood monocytes
-are attracted to sites of inflammation by chemotactic factors
-appear 12-24 hours later than leukocytes
-are long-living phagocytic cells
-contain strong intracellular enzymes, such as lysozyme and hydrogen
peroxide- degrade particulate material including microorganisms
-they control many of the cellular, vascular and reparative responses of
inflammation by releasing chemotactic factors, cytokines ( tumor 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
INFLAMMATION
FUNCTIONAL
CHANGES
IN
ACUTE
-acute inflammation is defined as the early inflammatory response
to an injurious agent which is characterized by the presence of
neutrophils, and later macrophages
-acute infl. last for a few hours or days
-the early acute response is characterized by the presence of edema
fluid, fibrin, and neutrophilic leukocytes
-this is caused by:
-arteriolar dilatation and opening up of capillary channels
-increased vascular permeability (exudate formation)
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-emigration of neutrophils from vessels
-two main processes invovlved in acute infl. response are:
-microcirculatory response (vascular)
-cellular response
1 - microcirculatory response
-vascular response is characterized by an increased blood flow in an
affected area, and an increased permeability of blood vessels
 active vasodilatation=hyperemia
-first step in microcirculation in infl. area is transient vasocontriction,
that is rapidly followed by marked active vasodilatation of capillaries,
small arteries and venules. Vasodilatation leads to hyperemia (= increased
amount of blood in infl. area )- heat and redness
 increased permeability of blood vessels- next event typical of acute
inflammation- associated with slowing of the circulation- called stasis
in normal tissuue - blood vessel walls permeability is a function of the
intercellular junctions between endothelial cells - these small gaps-pores
normally permit passage of only small molecules
in acute infl.- immediate increase of permeability of venules and
capillaries (caused by active contraction of actin microfilaments in
endothelial cells) - results in widening of pores (intercellular junctions)followed by an increase of amount of fluid and high-molecular-weight
proteins can pass through abnormally permeable vessels into the
extravascular space
 increased passage of fluid out of microcirculation because of increased
permeability in acute inflammation –results in formation of
inflammatory exudate- 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 vesselspassage of large amounts of fluid from capillaries into the interstitium is
associated with inflammatory edema- 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
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Fibrin can be recognized microscopically-pink fibers or clumps,
macroscopically- most easily seen on acute infl. of serosal surfaces-acute
fibrinous pericarditis- „bread and butter„ appearance.
 in contrast Transudation= increased passage of fluids (very low level
of plasma proteins, and no cells) through blood vessels with normal
permeability- cause either 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, and acute inflammation is complicated by
-acute inflammation of lymphatics= lymphangitis
-acute inflammation of lymph nodes= lymphadenitis
2 - cellular response
Acute inflammation is characterized by an active emigration of
inflammatory cells from the blood into the area of injury.
Two most important cellular events in acute inflammatory response are:
1-active emigration to inflammed area
2-phagocytosis
 1- ACTIVE EMIGRATION OF CELLS FROM THE BLOOD
-early phase (first 24 hours): neutrophilic leukocytes
-later phase (after first 24-48 hours): macrophages, lymphocytes and
plasma cells
1. ) LEUCOCYTES:
Neutrophilic leukocytes remain predominant cell type for several
days in acute inflammation.
Major events affecting leukocytes in inflammation
-margination of neutrophils - in normal blood stream, the leukocytes are
mostly confined to axial stream (separated from the endothelial surface
by plasma)
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in dilated vessel in inflammation- the rate of blood flow decreaseserytrocytes form aggregates that displace leucocytes from the centre of
axial stream, in combination with a decrease of amount of plasma due to
exudation- leukocytes adhere to endothelial surface
-pavementing of neutrophils -dilated vessels in acute inflammation are
lined by numerous adherent leukocytes (increased adhesiveness of
endothelial cells in inflammation)- probably due to activity of chemical
mediators of inflammation-process of leukocyte-endothelial cell adhesion
is followed by
-emigration of neutrophils -leukocytes actively leave the blood vessel by
moving through dilated intercellular junctions, pass through basement
membrane and reach the extracellular space
 chemotactic factors- process of active emigrating of leukocytes is
governed by chemotactic factors (including C5 complement and various
bacterial products), leukocytes have cell surface receptors for
chemotactic factors
movements of other cells:
emigration of 2.) MACROPHAGES and 3.) LYMPHOCYTES is similar to
that of neutrophils- chemotactic mediators for macrophagescomplement 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 inflammed area=
hemorrhagic inflammation
 2- 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)
- opsonins-Fc fragment of IgG
-C3b fragment of complement -for both molecules there are specific
receptors on the surface of leukocytes
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-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
 CONTROL OF RECRUITMENT OF INFLAMMATORY CELLS TO SITES
OF INFLAMMATION.
- it is now known that interactions can occur between different cells and
between cell and connective tissue components - by CAMs- cell adhesion
molecules
-CAMs are involved in inflammation, cell locomotion, tumor spread, and
immune processes
-in inflammation- CAMs are within the endothelial cells- can bind to
neutrophils and monocytes- some CAMs are present before an
inflammatory response, the others are newly produced
-in addition monocytes and macrophages and neutrophils have surface
adhesion molecules - integrins
 CHEMICAL MEDIATORS OF INFLAMMATION
1.- mediators originate from plasma or from cells
plasma-derived mediators: are present in plasma in precursor forms and
must be activated to acquire their biologic activity
cell-derived mediators: are normally within intracellular granules
(histamine in mast cells) and must be secreted or even synthesized de
novo - due to response to specific stimulus
2.- when activated or released from the cell, most mediators are
quickly inactivated. Important for balanced and controlled mediator
activity, the activity is rapid, specific but short
3.- almost all mediators perform their biologic activities by binding
to specific receptor on specific cells
MAJOR CLASSES OF MEDIATORS OF INFLAMMATION
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- can be divided to the following groups according to their
activities
1- Vasoactive mediators: histamine and serotonine
2- Plasma proteases: kinin system (bradykinin-kalikrein), complement
systém, and coagulation-fibrinolytic system
3- So called AA metabolites (arachidonic acid metabolites): include
endoperoxidases, prostaglandins, thromboxane
4- Lysosomal components ( proteases)
5- Oxygen-derived free radicals
6- Platelet activating factors (PAFs)
7- Cytokines
8- Growth factors
Vasoactive mediators: „H-substances“
Histamine and serotonin are believed to mediate an immediate active
phase of an increase of vessel permeability. In human, histamine is widely
distributed (stored in granules of mast cells and blood basophils, in
platelets).
Different agents can release histamine from mast cells:
-physical agents- such as cold, trauma
-immunologic reactions, through well known mechanism involving the
receptors on the mast cell for IgE
-fragments of complement that can induce icrease of permeability
of blood vessels (anaphylatoxins)
-histamine-releasing
interleukin-1
factors
of
leukocytes
and
platelet,
Function of vasoactive substances:
-Histamine- causes dilation of arterioles and in increase of
permeability of venules
histamine -is rapidly inactivated by histaminase, thus histamine is
important mainly in early inflammatory response and in immediate IgE mediated hypersensitivity
-Serotonin- second vasoactive mediator, main source of serotoninplatelets, release of serotonin from platelets is stimulated when platelets
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aggregate after their contact with complex antigen-antibody, with
collagen etc.
Plasma -derived mediators:
a variety of phenomena in acute inflammatory response are mediated by
three interrelated systems- kinins, complement, and the clotting system
-kinin system -activation of kinin system leads to a release of
bradykinin-causes arterial dilatation and increase of permeability of
venules, rapidly inactivated by kinases
there is multi-step pathway to activate kinin system-system of activation
is related to clotting systeme, key role of Hagemann factor XII of
coagulation
-complement system -consists of several plasma proteins and plays
a role both in inflammation and immunity.
Complement components ( C1-C9 ) are present in plasma in inactive form
„complement cascade“- most important is C3
activation may start either complex antigen-antibody (IgG and IgM)=
classic pathway
or bacterial polysaccharids and endotoxins= alternative pathway
complement system influences:
-vascular changes in inflammation
-chemotactic effect for monocytes, neutrophils
-acts as opsonin-helps in phagocytosis
clotting system (coagulation cascade )
coagulation is iniciated by activation of factor XII- Hagemann factor XII
- cause activation of series of plasma proteins - the final step is change
of fibrinogen to fibrin
Platelet-activating factor (PAF)
-is a mediator derived from antigen-stimulated basophils that had
been sensitized by IgE and cause aggregation of plateles and release of
their active constituents, such as histamine and serotonin
PAFs are not stored, they are rapidly generated after cell stimulation
PAF causes - increase of vessel permeability, increase of leukocyte
aggregation and adhesion to endothelium
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PAFs appear to act directly on target cells but they can also stimulate
the synthesis of other mediators, particularly prostaglandins and
leukotriens
Cytokines-are certain polypeptide products of activated lymphocytes and
macrophages refered to as lymphokines and monokines
-are involved in cellular response in immune processes, such as lymphocyte
proliferation - it has been known for long time, but recently it has become
clear that cytokines are involved also in inflammatory response
the most important cytokines in inflammation are
interleukin I
tumor necrosis factor (TNF) = cachectin
-because it is thought to be involved also in the cachexia in chronic
inflammation and cancer
their most important actions in inflammation are
-1) local effects on endothelium, such as stimulation of increased
adhesion of leukocytes and lymphocytes to endothelium and stimulation of
synthesis of PAFs
-2) induce the systemic acute inflammatory responses, such as
induction of fever, release of ACTH and corticosteroids, release of
neutrophils to the circulation, etc.
 MORPHOLOGIC PATTERNS OF 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 exsudate etc.
 Serous inflammation
-is characterized 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.
 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.
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Fibrinous inflammation develops if highly permeable wall let pass the
fibrinogen- lots of fibrin in the inflammatory fluid.
Fibrin- histologically-eosinophilic meshwork or it may be amorphous.
Fibrinous exsudate may be removed-this process is called 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.
Fibrinous exsudate may have more serious consequencies than the serous
exsudate.
 Suppurative or purulent inflammation
-is characterized by production of large amounts of purulent
exsudate (= pus ).
Localized suppuration- caused mainly by staphylococci- pyogenic bacteria
acute suppurative appendicitis- common example of purulent inflammation.
-Abscess= localized collections of purulent exsudate
pyogenic inflammation in the skin-folliculitis (furuncle)
-Ulcer = is a local defect in the tissue, mainly in the mucosal or
cutaneous surfaces
examples: include inflammatory necrosis in mouth, stomach intestines,
genitourinary tract or, peptic ulcer of stomach or duodenum, ulcers of
the lower extremites due to vascular disorders
acute ulcer- intense leukocyte infiltrate and vascular dilatation in the
margins
chronic ulcer-more developed fibroblastic reaction,
infiltration of lymphocytes, macrophages and plasma cells.
scarring
and
 SYSTEMIC CLINICAL SIGNS OF ACUTE INFLAMMATION
1) fever- is one of the most prominent features of acute inflammation
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
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-under these circumstances, peripheral blood leukocytes tend to be of
the less mature forms with fewer nuclear lobes ( so called „ band forms“)
and they often contain large cytoplasmic granules ( so called „ toxic
granulation“)
the term „ shift to the left“ means the change to 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
Leukocytosis occurs initially because of accelerated release from bone
marrow, later proliferation of precursors in bone marrow appears, caused
by stimulation by cytokines (colony-stimulating factors)
on the other hand- viral infections tend to produce neutropenia
(decreased number of leukocytes) with lymphocytosis- excess of
lymphocytes in the blood
3) changes in plasma protein levels
elevated levels of acute phase reactants, including C-reactive protein,
alfa-1-antitrypsin, fibrinogen, ceruloplasmin, etc.
incresed erythrocyte sedimentation rate
 DIAGNOSIS OF ACUTE INFLAMMATION:
1) local cardinal signs of acute inflammation (rubor, calor, dolor, tumor)enable a correct diagnosis when process involves surface structures (skin,
mouth mucosa, etc)
2) acute inflammation of internal organs, such as lungs, kidney, liver may
first manifest with systemic changes, such as fever, blood cell changes,
etc.
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