Inflammation
• Inflammation is defined as the local
response of living mammalian tissues to
injury due to any agent.
• It is a body defense reaction in order to
eliminate or limit the spread of injurious
agent as well as to remove the
consequent necrosed cells and tissues.
The agents causing inflammation may be
as under:
• Physical agents like heat, cold, radiation,
mechanical trauma.
• Chemical agents like organic and
inorganic poisons.
• Infective agents like bacteria, viruses and
their toxins.
• Immunological agents like cell-mediated
and antigen-antibody reactions.
Acute inflammation has three major
components:
• Alterations in tissue structure and vascular
caliber that lead to injury and increase in blood
flow
• Exudation Structural changes in the
microvasculature that permit the plasma proteins
and leukocytes to leave the circulation to produce
an inflammatory exudate and emigration of the
leukocytes from the microcirculation and their
accumulation in the focus of injury
• Cellular Proliferation
Interaction between alteration,
exudation and proliferation
alteration exudation proliferation
Phlogogenic agent
• SIGNS OF INFLAMMATION.
• The Roman writer Celsus in 1st century
A.D. named the famous 4 cardinal signs of
inflammation as:
• rubor (redness);
• tumor (swelling);
• calor (heat); and
• dolor (pain).
To these, fifth sign functio laesa (loss of
function) was later added by Virchow.
Alteration
• Primery alteration – destruction of cells
and tissues by cause factor
• Secondary alteration - destruction of cells
and tissues by factors, which release and
activeted in organism
CHEMICAL MEDIATORS OF
INFLAMMATION
• CHEMICAL MEDIATORS OF INFLAMMATION
derived either from plasma or from cells . Most
perform their biologic activity by binding initially
to specific receptors on target cells, although
some have direct enzymatic activity (e.g.,
proteases), and others mediate oxidative
damage (e.g., oxygen metabolites). One
mediator can stimulate the release of other
mediators by the target cells themselves,
providing a mechanism for amplification or in
certain instances counteracting the initial
mediator action.
• Vasoactive Amines
• Histamine and serotonin are available from preformed
cellular stores and are among the first mediators to be
released during inflammation. They are found in mast
cells, basophils, and platelets and cause vasodilation
and increased vascular permeability. Release from mast
cells is caused by
• Physical agents (e.g., trauma, heat)
• Immunologic reactions involving binding of IgE
antibodies to mast cells
• Complement fragments C3a and C5a (anaphylatoxins)
• Neuropeptides (substance P)
• Cytokines (IL-1 and IL-8)
• Histamine-releasing factors derived from leukocytes
• serotonin (enterochromaffin cells,
thrombocytes, eosinophiles) aggregation
of thrombocytes, bronchospasm,
expansion of arterioles, increase of
permeability, spasm of damaged vessels,
stimulation of steroidogenesis.
• adrenaline, noradrenaline
(thrombocytes) - vasospasm, reduction of
permeability, aggregation of thrombocytes.
• Plasma Proteases
• There are three interrelated plasma-
derived mediators that play key roles in
inflammatory responses:
• Complement system
• Kinin system
• Clotting factor system
• COMPLEMENT SYSTEM
• Activation of complement functions in host defense
against microbial agents, culminating in the assembly of
the membrane attack complex (MAC) and lysis of the
offending agent. In the process, complement
components are generated that cause increased
vascular permeability, chemotaxis, and opsonization.
Activation of complement occurs via two general
mechanisms:
• The classic pathway, initiated by antigen-antibody
complexes.
• The alternate complement pathway, activated by
endotoxin,complex polysaccharides, and aggregated
globulins.
• KININ SYSTEM
• The kinin system generates vasoactive peptides from
plasma proteins called kininogens by specific proteases
called kallikreins, ultimately resulting in the production of
bradykinin. Surface activation of Hageman factor (factor
XII) produces clotting factor Xlla, which converts plasma
prekallikrein into kallikrein; the latter cleaves high-
molecular-weight kininogen to produce bradykinin, a
potent stimulator of increased vascular permeability.
Kallikrein in an autocatalytic loop is a potent activator of
Hageman factor, has chemotactic activity, and causes
neutrophil aggregation. Thus, kallikrein can, by feedback,
activate Hageman factor, resulting in profound
amplification of the effects of the initial contact.
Kinin system
Prekallikrein Kallikrein
Kininogen Bradikinin
Effects: vasodilation, increase permeability,
pain
• Cytokines are proteins produced principally by
activated lymphocytes and macrophages that
modulate the function of other cell types.
• Monokines Cytokines generated by mononuclear
phagocytes.
• Lymphokines Cytokines generated by activated
lymphocytes.
• Colony-stimulating factors Cytokines produced by
monocytes and macrophages that stimulate the growth of
immature leukocytes in the bone marrow.
• Interleukins Broad family of cytokines that are made by
hematopoietic cells and act primarily on leukocytes.
• Chemokines Cytokines that share the ability to stimulate
leukocyte movement (chemokinesis) and directed movement
(chemotaxis) and are particularly important in inflammation.
• General properties and classes of cytokines are as
follows:
• Cytokines are produced during immune and
inflammatory responses, and secretion of these
mediators is transient and closely regulated.
• Many cell types produce multiple cytokines.
• Cytokine effects are often redundant, and these proteins
can influence the synthesis or action of other cytokines.
• Cytokines are multifunctional in that an individual
cytokine may have both positive and negative regulatory
actions.
• Cytokines mediate their effects by binding to specific
receptors on target cells, and the expression of cytokine
receptors can be regulated by a variety of exogenous
and endogenous signals.
FUNCTIONS OF CYTOKINES
• Cytokines can be grouped into five classes,
depending on their major function or on the
nature of the target cell:
• Cytokines that regulate lymphocyte
function
• Cytokines involved with natural immunity
• Cytokines that activate inflammatory cells
• Chemokines
• Cytokines that stimulate hematopoiesis
• Cytokines that regulate lymphocyte
function. These cytokines regulate
lymphocyte activation, growth, and
differentiation (e.g.,IL-2 and IL-4, which
favor lymphocyte growth; IL-10 and
transforming growth factor, which are
negative regulators of immune
responses).
• Cytokines involved with natural immunity.
This group includes the inflammatory
cytokines (e.g., TNF-a and IL-1), the type
I interferons (IFN), and IL-6.
• Cytokines that activate inflammatory
cells.
These cytokines activate macrophages
during cell-mediated immune responses
(e.g., IFN, TNF-a, IL-5, IL-10, and IL-12).
• Chemokines. This group of cytokines is
characterized by chemotactic activity for
various leukocytes (e.g., IL-8).
• Cytokines that stimulate hematopoiesis.
These cytokines mediate immature
leukocyte growth and differentiation (e.g.,
IL-3, IL-7, granulocyte-macrophage
colony stimulating factor [GM-CSF],
macrophage-CSF [M-CSF], granulocyte-
CSF [G-CSF], and stem cell factor).
• IL - 1 (interleukine) (macrophages, endothelium,
keratinocytes, microglia, B-lymphocytes, fibroblasts,
dendritic cells) - pro-inflammatory effects, induction of
аdhesive molecules, endopyrogen, reason of prodromal
syndrome, trigger of the reaction of an acute phase of
inflammation, the main mediator of the immune reaction to
alien substances, stimulator of stress.
• IL - 6 (Т and B cells, macrophages, fibroblasts,
endothelium, thymus epithelium) - pro-inflammatory
effects, inductor of the reaction of an acute phase,
endopyrogen, stimulator of аntibody production.
• IL - 8 (fibroblasts, monocytes, macrophages)-initiation of
inflammation and reaction of an acute phase,
hemoattractant and activator of degranulation of
granulocytes and Т lymphocytes, factor of lymphocyte
growth.
• TNF (tumor necrosis factor) alpha and beta
(macrophages, mastocytes, lymphocytes, аstrocytes) -
endogenic pyrogen, stimulator оf an acute phase
reaction, inductor of IL-1, IL- 6, stimulator of cytotoxicity,
granulocytes, apoptosis of tumoral and other cells,
cachexia, hypercatabolism, contrinsulin action, induction
of collagenase, procoagulants, FAT (factor of activation
of thrombocytes), fibrogenesis, granulomatosis,
аngoigenesis.
• Interferon alpha, beta, gamma (macrophages, Th1,
NК-cells, fibroblasts)- activator of macrophages, all kinds
of cytotoxicity, inhibites synthesis of cytokines ,
proliferation of thymocytes, endopyrogen, antiviral,
аntiproliferative, antitumoral effects.
LIPID MEDIATORS
Components of eicosanoid system
Lipids
Phospholipase A
Arachidonic acid
Lipoxygenas Cycloxygenas
LEUCOTRIENS PROSTAGLANDINS
thromboxanes prostacyclines
• Cycloxygenasic way of activation:
• PROSTAGLANDINES (PgE 2, PgF2, - various cells, PgD2- tissue
basophiles, PgF1a-endothelium)- expansion of vessels and
increase of permeability (E1, D2), narrowing of skin vessels and
lowering of permeability, suppression of emigration (F2a), spasm of
smooth muscles of bronchi (D2, G2, H2), potentiation of painful
effects of kinines and histamine (E2), activation of phagocytes,
stimulation of adhesion and phagocytosis, chemotaxis of
neutrophils, adhesion and reaction of releasing of thrombocytes
(G2, H2),
• THROMBOXANES (thrombocytes, endothelium, macrophage)-
vasoconstriction, chemotaxis and margination of neutrophils,
adhesion, aggregation, reaction of thrombocyte release,
bronchospasm.
• PROSTACYCLINES (endothelium) - vasodilatation, stimulation of
collateral blood flow, antithrombotic, antiadhesive,anticoagulative
action, stimulation of fibrinolysis, antiatherogenic effect.
Lipoxygenasic way of activation:
• LEUKOTRIENS (various cells, especially neutrophils, mastocytes) -
vasoconstriction and increase of permeability, bronchospasm,
chemotaxis, margination of neutrophils, macrophages, chemotaxis
and inhibition of lymphocyte proliferation, chemotaxis of eosinophils,
degranulation of basophiles.
• FTA (factor of thrombocyte activation) - (basophiles,
neutrophiles, macrophages, mastocytes, eosinophils, endothelium)-
stimulator of adhesion, aggregation and reaction of thrombocyte
release, activator of granulocytes, vaso- and bronchoconstrictor,
promotes production of eicosanoids, in small concentrations
expands vessels, synergist of thromboxanes, stimulates emigration
of neutrophiles and basophiles, a powerful agent raising vascular
permeability (10,000 times is more active than histamine).
• HYDROXYEICOSAPOLYENE ACIDS (neutrophiles, other cells) -
chemotaxis, chemokinesis and activation of neutrophiles,
eosinophiles, macrophages, inhibition of lymphocyte proliferation.
• LIPOXINES (neutrophiles) - pro-inflammatory effects.
• Nitric Oxide
• Also known as endothelium-derived
relaxation factor, nitric oxide acts in a
paracrine manner and causes
vasodilation; inhibits platelet aggregation
and adhesion; and may act as a free
radical, becoming cytotoxic to certain
microbes, tumor cells, and also possibly
other tissue cells. Nitric oxide is
synthesized from arginine, molecular
oxygen, NADPH, and other cofactors by
the enzyme nitric oxide synthase (NOS).
• Nitric oxide acts in the host response to
infection. Interactions occur between
nitric oxide and reactive oxygen species,
leading to the formation of multiple
antimicrobial metabolites Each reactive
form is distinct, but they share
the ability to damage microbes, at the
potential cost of inflammatory
damage to host cells and tissues.
• Lysosomal Constituents of Leukocytes
• Neutrophils and monocytes contain
lysosomal granules, which when released
may contribute to the inflammatory
response and to tissue injury.
• Lysosomal constituents can potentiate
further increases in vascular permeability
and chemotaxis and cause tissue damage.
These harmful proteases, however, are
held in check by a system of antiproteases
in the serum and tissue fluids.
• Oxygen-Derived Free Radicals
• Oxygen-derived free radicals are metabolites that may
be released extracellularly from leukocytes after
exposure to chemotactic agents, immune complexes, or
a phagocytic challenge. These include O2', H2O2, and
hydroxyl radical (OH'), and these metabolites can
combine with nitric oxide to form other reactive nitrogen
intermediates, which cause:
• Endothelial cell damage with resultant increased
vascular permeability
• Inactivation of antiproteases, thus leading to unopposed
protease activity
• Injury to a variety of cell types (e.g., tumor cells, red
cells,parenchymal cells)
Haemodynamic Changes
• transient vasoconstriction
• persistent progressive vasodilatation
• elevate the
local hydrostatic pressure
• Slowing or stasis
CHANGES IN VASCULAR FLOW AND CALIBER
Changes in vascular flow and caliber constitute one of
the three major components of the inflammatory
response. They begin immediately after injury and
develop at various rates depending on the severity of the
injury.
• Initially, transient vasoconstriction of arterioles occurs.
• Vasodilation follows, causing increased flow; it accounts
for the heat and redness.
• Eventual slowing of the circulation occurs as a result of
increased vascular permeability, leading to stasis. The
increased permeability is the cause of edema.
• With slowing, the larger white cells fall out of the axial
stream, and leukocytic margination appears, a prelude to
the cellular events .
• Irrespective of the type of injury,
immediate vascular response is of
transient vasoconstriction of arterioles.
With mild form of injury, the blood flow
may be reestablished in 3-5 seconds
while with more severe injury
the vasoconstriction may last for about 5
minutes.
• Next follows persistent progressive
vasodilatation which involves mainly the
arterioles, but to a lesser extent, affects other
components of the microcirculation like
venules and capillaries. This change is obvious
within half an hour of injury. Vasodilatation
results in increased blood volume in
microvascular bed of the area, which is
responsible for redness and warmth at
the site of acute inflammation.
• Progressive vasodilatation, in turn, may
elevate the local hydrostatic pressure
resulting in transudation of fluid into the
extracellular space. This is responsible
for swelling at the local site of acute
inflammation.
Decrease blood flow depended from:
• - agregation and adhession of the cells
• - increase vessels permeability
• - increase blood coagulation
• - raised blood viscosity
• Slowing or stasis of microcirculation
occurs next.
Slowing is attributed to increased
permeability of microvasculature that
results in increased concentration of
red cells, and thus, raised blood
viscosity.
• Exudation The escape of fluid, proteins, and blood cells
from the vascular system into the interstitial tissue or
body cavities.
• Exudate An inflammatory extravascular fluid that has a
high protein content, specific gravity ( 1.012) and many
cells
• Transudate A fluid with low protein content and a
specific gravity of less than 1.012. It is essentially an
ultrafiltrate of blood plasma and results from hydrostatic
imbalance across the vascular endothelium.
• Edema Denotes an excess of fluid in the interstitial
tissue or serous cavities; it can be either an exudate or a
transudate.
• There are six possible mechanisms of
increased endothelial permeability:
• Endothelial cell contraction in venules
• Endothelial retraction
• Increased transcytosis
• Leakage from regenerating capillaries
• Direct endothelial injury
• Leukocyte-mediated endothelial injury
• Type of Exudation
• The appearance of escaped plasma determines the
morphologic type of inflammation. These are:
• Serous, when the fluid exudate resembles serum or is
watery e.g. pleural effusion in tuberculosis, blister
formation in burns.
• Fibrinous, when the fibrin content of the fluid exudate is
high e.g. in pneumococcal and rheumatic pericarditis.
• Purulent or suppurative exudate is formation of
creamy pus as seen in infection with pyogenic bacteria
e.g. abscess, acute appendicitis.
• Haemorrhagic, when there is vascular damage e.g.
acute haemorrhagic pneumonia in influenza.
• Catarrhal, when the surface inflammation of epithelium
produces increased secretion of mucus .
• CELLULAR EVENTS: LEUKOCYTE
EXTRAVASATION AND PHAGOCYTOSIS
A critical function of inflammation is the delivery of
leukocytes to the site of injury. The sequence of
events in this journey, called extravasation, can be
divided into the following steps:
• Margination, rolling, and adhesion of leukocytes in
the lumen
• Transmigration across the endothelium (also called
diapedesis)
• Migration in interstitial tissues toward a chemotactic
stimulus
• Chemotaxis and Leukocyte Activation
• Adherent leukocytes emigrate through
interendothelial junctions, traverse the
basement membrane, and move toward
the site of injury along a gradient of
chemotactic agents. Neutrophils emigrate
first, and monocytes and lymphocytes
follow. Chemotactic agents for neutrophils
include bacterial products, complement
fragments (e.g., C5a), arachidonic acid
metabolites (e.g., leukotriene B4), and
chemokines (e.g., IL-8).
• Chemotactic agents also cause leukocyte
activation, characterized by:
• Degranulation and secretion of enzymes
• Activation of an oxidative burst
• Production of arachidonic acid metabolites
• Modulation of leukocyte adhesion
molecules
• Phagocytosis
• Phagocytosis and the release of enzymes by
neutrophils and macrophages constitute two of
the major benefits derived from the accumulation
of leukocytes at the inflammatory focus.
Phagocytosis involves three steps:
• Recognition and attachment of the particle to
be ingested by the leukocyte.
• Engulfment by pseudopods encircling the
phagocytosed particle, with subsequent
formation of a phagocytic vacuole or
phagosome.
• Killing and degradation of bacteria.
• There are two types of bactericidal
mechanisms:
• Oxygen-dependent mechanisms
• Oxygen-independent mechanisms
• Oxygen-dependent mechanisms.
• Bacterial killing is accomplished largely by oxygen-
dependent mechanisms. This is triggered by activation
of nicotinamide-adenine dinucleotide phosphate
(reduced form) (NADPH) oxidase, in the process
reducing oxygen (O2) to superoxide anion (O2~) and
hence to hydrogen peroxide (H2O2) Myeloperoxidase
(MPO) from lysosomal granules then converts H2O2, in
the presence of a halide such as Cl , to the highly
bactericidal HOCK. Although the H2O2-MPO-halide
system is the most efficient bactericidal mechanism,
the reactive oxygen species produced during an
oxidative burst can kill bacteria directly.
• Oxygen-independent mechanisms.
These include bactericidal
permeability increasing protein,
lysozyme, lactoferrin, major
basic protein (MBP) of eosinophils, and
arginine-rich defensins. Killed organisms
are then degraded by hydrolases and
other enzymes in lysosomes.
Release of Leukocyte Products and Leukocyte-Induced
Tissue Injury
• During phagocytosis, leukocytes release products not
only within the phagolysosome, but also potentially into
the extracellular space. These released products include
• Lysosomal enzymes, by regurgitation during feeding,
reverse endocytosis, or cytotoxic release
• Oxygen-derived active metabolites
• Products of arachidonic acid metabolism, including
prostaglandins and leukotrienes
• These products are powerful mediators of tissue damage
and amplify the effects of the initial inflammatory stimulus.
• OUTCOME OF ACUTE INFLAMMATION
• The process of acute inflammation can be altered by the
nature and intensity of the injury, the site and tissue
affected, and the responsiveness of the host, but generally
the process has one of four outcomes:
• Complete resolution, with regeneration of native cells and
restoration of the site of acute inflammation to normal
• Abscess formation, particularly in infections with pyogenic
organisms
• Healing by connective tissue replacement (fibrosis)
and scarring, which occurs after substantial tissue
destruction, when the inflammation occurs in tissues that
do not regenerate or when there is abundant fibrin
exudation
• Progression to chronic inflammation, as is outlined in
more detail subsequently.
• REPAIR
• Repair is the replacement of injured tissue by
fibrous tissue. Two processes are involved in
repair:
• Granulation tissue formation;
• Contraction of wounds.
Repair response takes place by participation of
mesenchymal cells (consisting of connective
tissue stem cells, fibrocytes and histiocytes),
endothelial cells, macrophages, platelets, and
the parenchymal cells of the injured organ.
• REGULATORS OF PROLIFERATION
• 1. GROWTH FACTORS (macrophages, lymphocytes, fibroblasts,
thrombocytes, etc.) - stimulation of proliferation and restriction of
apoptosis.
• 2. КЕILONS -glycoproteid tissue-specific inhibitors of growth.
• 3. ADHESIVE GLYCOPROTEIDS OF INTERCELLULAR
SUBSTANCE.
• 4. FIBRONECTIN -chemoattractant of fibroblasts.
• 5. LAMININ - main adhesive protein of basal membranes.
• 6. SYNDECAN - integral proteoglycane of cellular membranes,
connects collagen, fibronectin and thrombospondin.
• 7. THROMBOSPONDIN is a glycoproteid which forms complexes
with syndecan, collagen and heparin and plays an essential role in
assembly of a bone tissue.
• CHRONIC INFLAMMATION
• Chronic inflammation is defined as prolonged process in which
tissue destruction and inflammation occur at the same time. Chronic
inflammation can be caused by one of the following 3 ways:
• Chronic inflammation following acute inflammation. When the tissue
destruction is extensive, or the bacteria survive and persist in small
numbers at the site of acute inflammation e.g. in osteomyelitis,
pneumonia terminating in lung abscess.
• Recurrent attacks of acute inflammation. When repeated bouts of
acute inflammation culminate in chronicity of the process e.g. in
recurrent urinary tract infection leading to chronic pyelonephritis,
repeated acute infection of gall bladder leading to chronic
cholecystitis.
• Chronic inflammation starting de novo. When the
infection with organisms of low pathogenicity is chronic
from the beginning e.g. infection with Mycobacterium
tuberculosis.
• SYSTEMIC EFFECTS OF INFLAMMATION
• The major systemic manifestations of acute inflammation
involve a wide range of endocrine, autonomic, and
behavioral responses, as follows:
• Endocrine and metabolic: Secretion of acute-phase
proteins by the liver (including C-reactive protein, serum
amyloid A, complement, and coagulation proteins)
• Autonomic: A redirection in blood flow from cutaneous to
deep vascular beds, to minimize heat loss through the
skin; increased pulse and blood pressure; and
decreased sweating
• Behavioral: Rigors (shivering), chills (search for
warmth), anorexia, somnolence, and malaise.
• Other major systemic manifestations are as
follows:
• The principal manifestation of fever is an elevation of
body temperature, usually by 1 to 4°C.
• Leukocytosis (elevation in total white blood cell count)
is a common feature of inflammatory reactions,
especially those induced by bacterial infection.
Extreme elevations are referred to as leukemoid
reactions. The leukocytosis occurs because of
the proliferation of precursors in the bone marrow and
the accelerated release of cells from the bone marrow.
• Most bacterial infections induce neutrophilia (an
increased number of polymorphonuclear leukocytes in
the blood), but some viral infections (e.g.,
mononucleosis, mumps, and German measles) produce
a leukocytosis because of an absolute increase in the
number of lymphocytes (lymphocytosis). In other disor
ders, there is an absolute increase in the number of
eosinophils creating an eosinophilia (e.g., bronchial
asthma, hay fever, and parasitic infestations). Certain
infections (typhoid fever and infections caused by
viruses, rickettsiae, and certain protozoa) are associated
with a decreased number of circulating white cells
(leukopenia). Leukopenia is also encountered in
infections that overwhelm patients debilitated by
disseminated cancer.
