INFLAMMATION

1. Inflammation. Deffinition.
2. Signts of inflammation.
3. Etiological factors of inflammation.
4. Stages of inflammation.
5. Alteration. Mediators of inflammation.
6. Exudation. Mechanisms.
7. Phagocytosis. Disorders of phagocytosis.
8. Prolliferation.
9. Significance of inflammation.
The survival of all organisms requires that they eliminate foreign invaders,
such as infectious pathogens, and damaged tissues. These functions are
mediated by a complex host response called inflammation.
Inflammation is a protective response intended to eliminate the initial
cause of cell injury as well as the necrotic cells and tissues resulting
from the original insult. Inflammation accomplishes its protective
mission by diluting, destroying, or otherwise neutralizing harmful agents
(e.g., microbes and toxins). It then sets into motion the events that
eventually heal and repair the sites of injury.
Without inflammation, infections would go unchecked and wounds
would never heal. In the context of infections, inflammation is part of a
broader protective response that immunologists refer to as innate
immunity.
Inflammatory conditions are named by adding the suffix -itis to the
affected organ or system. For example, appendicitis refers to
inflammation of the appendix, pericarditis to inflammation of the
pericardium, and neuritis to inflammation of a nerve.
 Inflammation
(inflammatio from Latin)

It is a typical pathological
process, which arises after damage
of tissues and consists of three
main vessel-tissues components:
alteration, violation of
microcirculation with exudation
and emigration of leucocytes and
proliferation.
 Inflammations classify:
1) By clinical course: Neutrophil
a) acute,
b) subacute,
c) chronic.
Lymphocyte
2) By reason:
a) uninfectious origin (banal or unspecific) caused uninfectious factors;
b) infectious origin which includes for itself specific inflammations
(tuberculosis, syphilis, lepra, scleroma, glanders).
3) By character of predominating phase of inflammation:
a) alterative
b) exudative,
c) proliferative inflammation.
4) In dependence on reactivity of organism of inflammation can be:
a) normoergic - adequate after the displays of factor which caused it;
b) hyperergic - is stormy (violent) course of inflammation, for example, on a
background (against a background) sensitizing;
c) hypoergic with insignificant displays (for the children of 1th month of life,
in senile age, at considerable exhaustion of organism).
 - allows inflammatory cells, plasma proteins

Inflammation
(e.g., complement), and fluid to exit blood
vessels and enter the interstitial space

Immediate
Characterized by the Arises in response to infection
(to eliminate pathogen) or response with
presence of edema
tissue necrosis (to clear limited specificity
and neutrophils in
necrotic debris) (innate immunity)
tissue
Fibrose
Acute Inflammation Chronique Inflammation
Cicatrisation

Phase Phase
vasculaire cellulaire
 Etiology of an inflammation
The external causes of an inflammation are classified as
follows:
Physical factors (foreign bodies, strong pressure on a
tissue, high and low temperature, ionizing and ultra-
violet rays, high and low barometric pressure, electrical
current);
Chemical factors (acid, alkali, salts of heavy metals);

Biological factors (microorganisms bacteria, viruses,

fungi; animal organisms worms, insects).

The internal factors are the factors, which arise in
organism, as the result of any other diseases, for example
cholic acids, complex antigen-antibody and others.
 Local external signs of inflammation
The Roman Celsus in 1st century
A.D. named the famous four
cardinal signs of inflammation.
The fifth sign added later
by Virchow.
1) slight swelling tumor
2) reddening rubor
3) increase of temperature
(heat) calor
4) pain dolor
5) loss of function functio laesa.
 Rubor (redness) and calor (heat)
histamine-mediated vasodilatation of arterioles
 histamine-mediated in permeability of venules

Synonyms with edema - fluid in the interstitial space

Prostaglandin (Pg) E2 - sensitizes

specialized nerve endings to the
effects of BRADYKININ and other
pain mediators
 Pyrogens
(e.g., LPS from
bacteria)

macrophages

IL-1 and
perivascular
TNF
cells of the
hypothalamus
cyclooxygenase
activity

PGE2

temperature
set point
 Pathogenesis of inflammation
The inflammation, as typical pathological
process, consists of three stages:
1st is the alteration stage;
2nd is violation of microcirculation with
exudation and emigration of
leucocytes in the center of an
inflammation
3rd proliferation.
 Alteration is the first component of
inflammation, which is characterized by the
injury of structurally-functional unit of an
organ. primary
Alteration is divided on secondary

Primary alteration is the result of the influence

of the pathological (flogogenic) agent on a
tissue. Metabolic and structural changes arise
therefore.
Secondary alteration is the self-injury which
takes place under the action of biological
active substances (BAS) which are produced in
consequence of primary alteration.
 The signs of cells damage are the follows:
the 2;
limitation or termination of 2 consumption by cells;
the of and D and the of the inorganic
phosphorus concentration;
the intensification of glycolysis, which cause the
accumulation of lactic acid and piruvate acid;
the of cells .

The of concentration:
reduces the activity of ionic pumps of cells membranes,
the parity of Na, K, Ca and Mg in cytoplasm is violated,
the activity of biochemical systems of cells is violated
too.
Then content of water in cells changes, the synthesis of
protein , the density of cytoplasm raises, the amount
of + , the outlines of the cell change.
These changes are reversible!
 Mediators of inflammation it is
biologically active substances, which
appear in the place of inflammation and
determine the pathogenesis of
inflammation.
Distinguish two main groups of mediators
from their origin:
Cellular origin Plasmatic origin
appear and activated in appear in cells, but activated in
different cells plasma of blood

Proinflammatory Antiinflammatory

Mediators
 Toll-like receptors (TLRs)
1. Present on cells of the innate immune system :
macrophages;
dendritic cells.
2. Activated by pathogen-associated molecular patterns (PAMPs) that
are commonly shared by microbes
CD14 (a TLR) on macrophages recognizes lipopolysaccharide (a
PAMP) on the outer membrane of gram-negative bacteria.

3. TLR activation results in upregulation of

NF-kB, a nuclear transcription factor that
activates immune response genes leading
to production of multiple immune
mediators.
4. TLRs are also present on cells of
adaptive immunity (e.g., lymphocytes)
and, hence, play an important role in
mediating chronic inflammation.
 Cellular mediators:
1) Lysosomal factors
2) Products of degranulation of tissue basophiles
(biogenic amine: histamine, serotonin)
3) Derivatives of arachidonic acid
4) Peptide and proteins (leukokines, cytokines,
enzymes)
5) Neuropeptides, neuromediators (adrenalin,
noradrenaline (norepinephrine), acetylcholine).
6) Oxygen-Derived free Radicals (O2-, HO-,
H2O2). These metabolites increased vascular
permeability, injured of cells.
7) Nitric Oxyde (NO) the endothelium-derived
relaxation factor. Also it caused damage of the
foreign and hosts cells.
 Mediators of Humoral (plasmatic)
origin
includes 3 groups:
Products of activating of
Products of coagulative and
kallikrein- fibrinolytic systems of
blood, biogenic amines
kinin system
(histamine,
serotonine)
Products of activating
of complements
system

Humoral mediators are characterized by the widespread

effects; spectrum of their influence is very wide.
The effects of cellular mediators are local.
 Products of tissue basophiles
degranulation
Vasoactive amines
Histamine:
Arterial vasodilatation and venular endothelial cell
contraction, junctional widening;
Released by mast cells, basophils, platelets in
response to injury (trauma, heat), immune reactions
(IgE-mast cell FcR), anaphylatoxins (C3a, C5a
fragments), cytokines (IL-1, IL-8), neuropeptides,
leukocyte-derived histamine-releasing peptides
Serotonin:
vasodilatation effects similar to those of histamine;
platelet dense-body granules;
release triggered by platelet aggregation
The inflammatory cellsneutrophils and monocytes, contain lysosomal granules
which on release elaborate a variety of mediators of inflammation. These are as
under:
1) Granules of neutrophils. Neutrophils have 3 types of granules:

Primary or azurophil Secondary or Tertiary

granules are large specific granules granules or
azurophil granules contain: C particles
which contain functionally - alkaline phosphatase, contain:
active enzymes. These are: - lactoferrin, - gelatinase,
- myeloperoxidase, - gelatinase, - acid hydrolases.
- acid hydrolases, - collagenase,
- acid phosphatase, - lysozyme,
- lysozyme, - vitamin-B12 binding
- defensin (cationic protein), proteins,
- phospholipase, - plasminogen activator.
- cathepsin G,
- elastase,
- protease.
2) Granules of monocytes and tissue
macrophages.
These cells on degranulation also release
mediators of inflammation like:

- acid proteases,
- collagenase,
- elastase,
- plasminogen activator.

However, they are more active in chronic

inflammation than acting as mediators of acute
inflammation.
Monocytes and macrophages
 Derivatives of Arachidonic Acid
Arachidonic acid metabolites
CORTICOSTEROIDS
(eicosanoids)
Cyclooxygenase produces
prostaglandins (PG).
NSAIDs a. PGI2, PGD2 and PGE2 mediate

vasodilation and increased vascular
permeability.
b. PGE2 also mediates pain.
Lipoxygenase produces
leukotrienes (LT).
a. LTB4, attracts and activates
neutrophils.
PAF (platelet activating factor) b. LTC4, LTD4, and LTE4 (slow
Derived also from cell membrane reacting substances of anaphylaxis)
phospholipid, causes vasodilation, mediate vasoconstriction,
increased vascular permeability, bronchospasm, and increased
increases leukocyte adhesion vascular permeability.
(integrin conformation) COX blocked by aspirin and NSAIDS
 CYCLOOXYGENASE

LIPOOXYGENASE
 Peptide and Proteins
Cytokines are polypeptide substances produced by activated
lymphocytes (lymphokines) and activated monocytes (monokines).
IL-1, TNF- (formed by activated macrophages) and

TNF-, IFN- (produced by activated T cells) are especially important in

inflammation.
The actions of various cytokines as mediator of inflammation are as under:
1) IL-1 and TNF-, TNF- induce endothelial effects in the form of
increased leucocyte adherence, thrombogenicity, elaboration of other
cytokines, fibroblastic proliferation and acute phase reactions.
2) IFN- causes activation of macrophages and neutrophils and is
associated with synthesis of nitric acid synthase.
3) Chemokines are a family of chemoattractants for inflammatory
cells (as discussed above) and include:
IL-8 chemotactic for neutrophils;
platelet factor-4 chemotactic for neutrophils, monocytes and eosinophils;
MCP-1 chemotactic for monocytes;
eotaxin chemotactic for eosinophils.
 Neuropeptides
Another class of vasoactive amines is
tachykinin neuropeptides, such as:
substance P,
neurokinin A,
vasoactive intestinal polypeptide(VIP),
somatostatin.
These small peptides are produced in the central and
peripheral nervous systems.
The major proinflammatory actions of these
neuropeptides is as follows:
a) Increased vascular permeability.
b) Transmission of pain stimuli.
c) Mast cell degranulation.
 Nitric Oxide (NO)
short-acting soluble free-radical gas
with many functions
Produced by endothelial cells,
macrophages, causes:
Vascular smooth
muscle relaxation
and vasodilation

Kills microbes in
activated
macrophages

Counteracts
platelet adhesion,
aggregation, and
degranulation
 Humoral Mediators
There are three most important blood systems, which play
main role during inflammation: kinines,
hemostasis/fibrinolysis and complements systems.
The II factor of blood coagulation activates derivation
such kinines as the bradykinine and kallidine.
Their main effects are:
pain,
dilatation of vessels,
rise of vascular wall permeability,
activation of hemostasic and fibrinolysis systems.
The system of hemostasis and fibrinolysis directly participate
in the generation of highly active mediators.
The appearance of fibrinopeptides promotes the increase of
microvessels permeability, activation of chemotaxis.
Plasmine plays the main role in the system of fibrinolysis; it
promotes the derivation of biological active substances,
which increase of vessels permeability.
1. Inactive proinflammatory protein produced in
liver
2. Activated upon exposure to subendothelial or
tissue collagen; in turn, activates:
I. Coagulation and fibrinolytic systems

II. Complement

III. Kinin system Kinin cleaves high-

molecular-weight kininogen (HMWK) to
bradykinin, which mediates vasodilation and
increased vascular permeability (similar to
histamine), as well as pain.
 Kinin system
Leads to formation of bradykinin from
cleavage of precursor
Vascular permeability
Arteriolar dilation
Non-vascular smooth muscle contraction
(e.g., bronchial smooth muscle)
Causes pain
Rapidly inactivated (kininases)
 Complement system
The system of complement is a group of 20 plasma proteins
(C1-C9).
Components C1-C9 present in inactive form.
Their main function is the destruction of alien and own
changed cells.
Activated via classic (C1) or alternative (C3) pathways to
generate MAC (C5 C9) that punch holes in microbe
membranes
Activated 2 operates as kinines;
3 raises vascular permeability and stimulates the motion of
phagocytes;
5 has properties of 3 (but is more active) and stimulates
the selection of leucocytes of lysosomic enzymes;
5 stimulates the splitting of arachidonic acid and the
synthesis of leucotriens, promotes the forming of oxygen
radicals and hydroperoxides of lipids;
5b-9 (MAC) is provided by the reactions of alien and own
cells lysis.
 C3a, C5a anaphylatoxins vascular permeability/vasodilation
(via histamine), mast cell degranulation
C5a chemotactic for PMN, monocytes, basophils, increase
adhesion to endothelium (activates WBC), increases integrin avidity
C3b, C3bi as an opsonin, increases phagocytosis
 Disturbance of the microcirculation in
the inflammation area
Y. Kongame has described the stages of disturbance of the
microcirculation in the inflammation area.

The first stage is the short-term spasm of vessels (arterioles),

the second is the arterial hyperemia,
the third stage is the venous hyperemia,
the fourth stage is the prestasis, and the stasis is the fifth stage.

1. 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 re-established in 3-5 seconds while with more severe
injury
2. 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 the
vasoconstriction may last for about 5 minutes.
 3. 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.
4. Slowing or stasis of microcirculation follows which causes
increased concentration of red cells, and thus, raised blood viscosity.
5. Stasis or slowing is followed by leukocytic margination or
peripheral orientation of leukocytes (mainly neutrophils) along the
vascular endothelium. The leukocytes stick to the vascular endothelium
briefly, and then move and migrate through the gaps between the
endothelial cells into the extravascular space. This process is known as
emigration (discussed later in detail).
 Fluid interchange between blood
and extracellular fluid (ECF).
(HP = hydrostatic pressure, OP = osmotic
pressure).
The appearance of inflammatory
oedema due to increased vascular
permeability of microvascular bed is
explained on the basis of Starlings
hypothesis. In normal
circumstances, the fluid balance is
maintained by two opposing sets of
forces:
1) Forces that cause outward
movement of fluid from
microcirculation are intravascular
hydrostatic pressure and colloid osmotic
pressure of interstitial fluid.
2) Forces that cause inward
movement of interstitial fluid into
circulation are intravascular colloid
osmotic pressure and hydrostatic
pressure of interstitial fluid.
 Mechanism Microvasculature Response Type Pathogenesis Examples

Endothelial cell Immediate transient Histamine,

1 Venules Mild thermal injury
contraction (15-30 min) bradykinin, others

Somewhat delayed (in

Endothelial cell
2 Venules 4-6 hrs) prolonged (for IL-1, TNF- In vitro only
retraction
24 hrs or more)

Immediate prolonged
Moderate to severe
(hrs to days), or
Direct endothelial Arterioles, venules, Cell necrosis and burns, severe
3 delayed (2-12 hrs)
cell injury capillaries detachment bacterial infection,
prolonged (hrs to
radiation injury
days)
Leukocyte-
Leukocyte Pulmonary venules
4 mediated Venules, capillaries Delayed, prolonged
activation and capillaries
endothelial injury
Angiogenesis,
VEGF (vascular
5 Neovascularisation All levels Any type Healing, tumors
endothelial
growth factor)
Exudative processes
The increase
of vascular
wall
permeability
provokes
exudation
(penetration of
a liquid from
the blood into
the tissue),
emigration of
leucocytes.
The
permeability of
microvessels
increases first
of all
(especially of
venules).
 There are three ways penetration of fluid through the vessel wall
(exudation).
The 1st way is interendotelial (between nearby endotheliocytes).
Histamine promotes contraction of endothelial cells, the slots between
nearby endotheliocytes extend, and basal membrane is exposed.
The 2nd way of exudation is transendotelial (through the
endoteliocytes cytoplasm). Vesicles pinocytosis activity (the catch of
fluid) of the endoteliocytes increases. The blood plasma is inside
vesicles, which move through the cell and some time form channels.
Various substances
can pass without any
control through
channels
(microvesicle
transport).
The 3rd way of
the exudation is the
vessels wall area,
where are injured endoteliocytes.
 The main cause of the exudation is mediators of
inflammation, but amplifying disorder of the
metabolism, the injury cells and leucocytes promotes
other pathological mechanisms, which increase
vascular permeability.
They are lysosomes hydrolytic enzymes of
various phagocytes and parenchimal cells
(collagenase, elastase) and bacterial enzymes
(hyaluronidase), lactic acid and piruvate acid, other
non-oxidated substances, which are the result of
tissues hypoxia, adenosine, + and K+, especially
during the decrease of 2+ level. First of all
albumins, than globulins and fibrinogen, which
promotes the formation of fibrins clots, penetrate
outside the vessels.
Transudate
is no
inflammatory
effusion.
 Exudate kinds
The inflammation is named the exudative if this
component is expressed stronger than others. The
exudate type determines type of an inflammation.
There are next types of the exudates and inflammation:
serous,
fibrinous,
purulent,
decaying,
hemorrhagic
combination.
The serous inflammation develops in mucous and
serous coats, interstitial tissue, skin, and kidneys
glomes capsules. The amount of cells in the serous
exudate is not large.
 The causes of purulent
inflammation are staphylococcus,
streptococcus, gonococcus,
meningococcus, and Frenkels
diplococcus.
Purulent exudate consists of
many viable leukocytes and
purulent bodies (perishing
leukocytes), cells detritus,
microorganisms, plenty of proteins
(especially globulines)
 The hemorrhagic inflammation,
as the form of the serous, the
fibrinous or the purulent
inflammation, is characterized by
erythrocytes impurity to the
exudate (Siberian ulcer, natural
smallpox, influenza).
 The combination
forms of inflammation
are characterized by
connection of one type
of exudate to another.
Any combinations are
possible.
Such forms usually
develop as the result
of connection of a new
infection to the lasting
process. The tissues
damage and the
process of
inflammation cause
the restoring of broken
structure and function
(reparative
regeneration).
Chronic Osteomyelitis
 The unique feature of the
inflammatory process is the
reaction of blood vessels, leading
to the accumulation of fluid and
leukocytes in extravascular
tissues.
 In most cases of acute inflammation neutrophyles
emmigrate the first (that process lasts 6-24 hours).
In 24-48 hours monocytes emigrate most actively.
Lymphocytes emigrate a little bit later.
Lymphocytes emmigrate first time during virus
infection and tuberculosis, and eosinophiles during
allergic reactions.
Leukocytes regulate of the cells cooperation and
delete the alien agents or the detritus of defective
tissues.
The neutrophiles (microphages) destroy pathological
agents due to the following properties:
the absorption of the foreign agent (phagocytosis),
the microbicydity and cytotoxicity (these are the
mechanisms of the foreign agent destroy by such
biooxidants as superoxide anions, hydroxyl- radicals,
singlet oxygen, peroxide),
the intra- and extracellular lysis.
 Step 1 Margination
1. Vasodilation slows blood flow in postcapillary venules.
2. Cells marginate from center of flow to the periphery.
Step 2 Rolling
1. Select in "speed bumps" are upregulated on endothelial cells.
a) P-selectin release from Weibel-Palade bodies is
mediated by histamine.
b) E-selectin is induced by TNF and IL-1.
2. Selectins bind sialylated carbohydrate groups related to the
Lewis X on leukocytes.
3. Interaction results in rolling of leukocytes along vessel wall
 Step 3 Adhesion
1. Cellular adhesion molecules (ICAM and VCAM) are
upregulated on endothelium by TNF and IL-1
2. Integrins are upregulated on leukocytes by C5a and LtB4
3. Interaction between CAMs and integrins results in firm adhesion of
leukocytes to the vessel wall,
4. Leukocyte adhesion deficiency is most commonly due to an autosomal
recessive defect of integrins (CD18 subunit).
LAD type 1 is a deficiency of CD11 a:CD18 (LFA-1 and Mac-1 subunit defects lead
to impaired adhesion)
LAD type 2 is a deficiency of a selectin that binds neutrophils (Absence of sialyl-
Lewis X, and defect in E- and P-selectin sugar epitopes).
Clinical features include:
Delayed separation of the umbilical cord (~1 month), (neutrophil enzymes are
important in cord separation)
Increased circulating neutrophils (due to impaired adhesion of marginated pool of
leukocytes),
recurrent bacterial infections that lack pus formation (severe gingivitis, poor wound
healing)
 Step 4 Transmigration (diapedesis) and Chemotaxis
1. Leukocytes transmigrate across the endothelium of
postcapillary venules and move toward chemical attractants
(chemotaxis).
2. Neutrophils are attracted by bacterial products, IL-8, C5a,
and LtB4.
Step 5 Phagocytosis
1. Consumption of pathogens or necrotic tissue;
2. Phagocytosis is enhanced by
opsonins (IgG and C3b).
3. Pseudopodias extend from
leukocytes to form phagosomes, which
are internalized and merge with
lysosomes to produce
phagolysosomes.
 Phagocytosis and
Degranulation
Once at site of
injury, leukocytes:
Recognize and
attach
Engulf (form
phagocytic vacuole)
Kill (degrade)
1. Adhesion
(chemotaxis)
2. Attachment
3. Engulfment
4. Digestion
 Step 6 Destruction of phagocytosed material
1. O2-dependent killing is the most effective mechanism.
2. HOCl generated by oxidative burst in phagolysosomes
destroys phagocytosed microbes.
1) O2 is converted to O2
by NADPH oxidase
(oxidative burst!).
Positive NBT test (blue).
2) O2 is converted to H2O2
by superoxide dismutase
(SOD).
3) H2O2 is converted to
HOCl (bleach) by
myeloperoxidase (MPO).
 CGD is characterized by poor O2-dependent killing.
1). Due to NADPH oxidase defect ; X-linked or autosomal recessive;
2). Leads to recurrent infection and granuloma formation with catalase-
positive organisms, particularly:
Staphylococcus aureus, Pseudpmonas cepacia,
Serratia marcescens, Nocardia, and Aspergillus
3). Nitrobiue tetrazolium test (NBT) is used to screen for CGD. Leukocytes
are incubated with NBT dye, which turns blue if NADPH oxidase can
convert O2 to O2, but remains colorless if NADPH oxidase is detective.
 Results in defective
conversion of H2O2, to HOCI.
1). risk for Candida
infections (most patients are
asymptomatic).
2). NBT is normal; respiratory
burst (O2 to H2O2 is intact. O2-independent killing
O2-independent killing is less effective than O2-dependent
killing and occurs via enzymes present in leukocyte secondary
granules (e.g., lysozyme in macrophages and major basic
protein in eosinophils).
Step 7 Resolution
Neutrophils undergo apoptosis and disappear within 24 hours
after resolution of the inflammatory stimulus.
 1) return to normal vascular
permeability;
2) drainage of edema fluid
and proteins into lymphatics
or
3) by pinocytosis into
macrophages;
4) phagocytosis of apoptotic
neutrophils
5) phagocytosis of necrotic
debris;
6) disposal of macrophages.
Macrophages also produce
growth factors that initiate
the subsequent process of
repair.
Note the central role of
macrophages in resolution.
 The inflammation proliferative phase
The inflammation proliferative phase is simultaneously a phase
of the reparatory regeneration. The restoring of the damaged
tissues structure depends on the interaction of connective
tissues cells among themselves (fibroblasts, macrophages,
labrocytes, lymphocytes, endotheliocytes), on the interaction of
connective tissues cells with the intercellular matrix (collagen,
proteoglicans, fibronectine), on the interaction of connective
tissue cells with blood cells and parenchymal ones.
Reparation and regeneration
WOUND HEALING

BASIC PRINCIPLES
I. Healing is initiated
when inflammation
begins.
II. Occurs via a
combination of
regeneration and repair
 The process of cells proliferation is regulated by
substances, which can stimulate (mitogens) or oppress
(keilones) the reproduction of cells.
Cambial cells are the tissues source of regeneratory
material. The damage of tissues causes intensive
proliferation trunk cells.
The reparative stage of inflammation begins when
phagocytes actively swallow the microorganisms or the
tissues detritus.
At that time labrocytes activate interaction with
macrophages, fibroblasts, and intercellular matrix, clotting
blood system and promote the excretion and the synthesis of
substances, which stimulate proliferative processes.
Thrombocytes produce substances, which strengthen the
proliferation and the chemotaxis of fibroblasts to the
injurious area: the thrombocytal growth factor of
fibroblasts, the factor of epidermis and fibroblasts growth,
the peptide, which activates connective tissue etc.
1. Replacement of damaged tissue with native tissue; dependent on
regenerative capacity of tissue
2. Tissues are divided into three types based on regenerative capacity:
labile,
stable, and
permanent.
3. Labile tissues possess stem cells that continuously cycle to regenerate
the tissue.
1). Small and large bowel (stem cells in mucosal crypts)
2). Skin (stem cells in basal layer)
3). Bone marrow (hematopoietic stem cells, CD34+)
4. Stable tissues are comprised of cells that are quiescent, but can reenter
the cell cycle to regenerate tissue when necessary.
Classic example is regeneration of liver by compensatory hyperplasia after
partial resection. Each hepatocyte produces additional cells and then
reenters quiescence.
5. Permanent tissues lack significant regenerative potential
(e.g., myocardium, skeletal muscle, and neurons).
1. Replacement of damaged tissue with fibrous scar
2. Occurs when regenerative stem cells are lost (e.g.,
deep skin cut) or when a tissue lacks regenerative
capacity (e.g., healing after a myocardial infarction)
3. Granulation tissue formation is the initial phase
of repair
Consists of fibroblasts (deposit type III collagen),
capillaries (provide nutrients),
myofibroblasts (contract wound)
4. Eventually results in scar formation, in which type III
collagen is replaced with type I collagen
1). Type III collagen is pliable and
present in granulation tissue,
embryonic tissue, uterus, and
keloids;
2). Type I collagen has high
tensile strength and is present in
skin, bone, tendons, and most
organs;
3). Collagenase removes type III
collagen and requires zinc as a
cofactor.
Tissue granulation
I. Mediated by paracrine signaling via growth factors (e.g.,
macrophages secrete growth factors that target fibroblasts)
II. Interaction of growth factors with receptors
(e.g.. epidermal growth factor with growth factor receptor)
results in gene expression and cellular growth.
III. Examples of mediators include
1. TGFepithelial and fibroblast growth factor

2. TGF important fibroblast growth factor; also inhibits

inflammation;
3. Platelet-derived growth factor (PDGF)growth factor for
endothelium, smooth muscle, and fibroblast growth factor;
4. Fibroblast growth factor (FGF) important for
angiogenesis; also mediates skeletal development
5. Vascular endotheIial growth factor (VEGF) important
for angiogenesis
 I.
Cutaneous healing occurs via primary or secondary
intention.
1. Primary intention wound edges are brought
together (e.g., suturing of a surgical incision); leads
to minimal scar formation.
2. Secondary intention edges are not
approximated.
Granulation tissue fills the defect; myofibroblasts
then contract the wound, forming a scar.
.
 II. Delayed wound healing occurs in:
1. Infection (most common cause
S.aureus is the most common offender)
2. Vitamin C, copper, or zinc deficiency
1) Vitamin C is an important cofactor in the hydroxvlation of
proline and lysine procollagen residues; hvdroxylation is necessary
for eventual collagen cross-linking.
2) Copper is a cofactor for lysyl oxidase, which cross-links lysine
and hydroxy lysine to form stable collagen.
3) Zinc is a cofactor for collagenase, which replaces the type III
collagen of granulation tissue with stronger type I collagen.
3. Other causes include foreign body, ischemia, diabetes, and
malnutrition.
III. Dehiscence is rupture of a wound;
most commonly seen after abdominal surgery
IV. Hypertrophic scar is excess production of scar
tissue that is localized to the wound
V. Keloid is excess production of scar tissue that is
out of proportion to the wound
1. Characterized by excess type III collagen
2. Genetic predisposition (more common in African Americans)
3. Classically affects earlobes, face, and upper extremities
 The influence of endocrine system on the
inflammation is proved by numerous clinical
observations.
Hyperthyroidism amplifies manifestations of
the inflammation and hypothyroidism is
characterized by the insignificant sings.
Mineralocorticoids promote the development
of inflammatory reaction and
glucocorticoids weaken it.
 Glucocorticoids induce synthesis of
proteins, which block
prostaglandines and leucotriens
synthesis.
Mineralocorticoids are capable to
strengthen the exudation, to
accelerate the reproduction of cells,
the derivation of new capillaries, and
synthesis of the connective tissue
 The ability of glucocorticoids to
weaken the inflammation is
constantly used in clinics because
they:
reduce the amount of tissues
basophiles,
increase the activity of histaminase
(enzyme, which destroys histamine),
reduce serotonine formation,
stabilize lysosome membranes and
inactivate their enzymes.
 BASIC PRINCIPLES
I. Characterized by the presence of lymphocytes
and plasma cells in tissue.
II. Delayed response, but more specific (adaptive
immunity) than acute inflammation
III. Stimuli include:
1) persistent infection (most common cause);
2) infection with viruses, mycobacteria, parasites and
fungi;
3) autoimmune disease;
4) foreign material;
5) some cancers.
 GRANULOMATOUS INFLAMMATION

I. Subtype of chronic inflammation

II. Characterized by granuloma, which is
a collection of epithelioid histiocytes
(macrophages with abundant pink
cytoplasm), usually surrounded by giant
cells and a rim of lymphocytes
 III. Divided into noncaseating and caseating
subtypes
1. Noncaseating granulomas lack central necrosis.
Common etiologies include reaction to foreign
material, sarcoidosis, beryllium exposure, Crohn
disease, and cat scratch disease,
2. Caseating granulomas exhibit central necrosis and
are characteristic of tuberculosis and fungal
infections,
 IV. Steps involved in granuloma formation
1. Macrophages process and present antigen via
MHC class II to CD4 helper T cells.
2. Interaction leads macrophages to secrete IL-12,
inducing CD4 helper T cells to differentiate intoTh1
subtype.
3. Th1 cells secrete IFN-, which converts
macrophages to epithelioid histiocytes and giant
cells.
 FEATURE ACUTE INFLAMMATION CHRONIC INFLAMMATION
Persistent acule inflammation, foreign
bodies (e.g., silicone, glass), autoimmune
Pathogenesis Microbial pathogens, trauma, burns
disease, certain types of infection (e.g.,
tuberculosis, leprosy)

Monocytes/macrophages (key cells), B and

Primary cells involved Neutrophils
T lymphocytes, plasma cells, fibroblasts

Histamine (key mediator),

Primary mediators Cytokines (e,g., IL-1), growth factors
prostaglandins, leukotrienes
Necrosis Present Less prominent
Scar tissue Absent Present
Onset Immediate Delayed
Duration Few days Weeks, months, years
Complete resolution, progression to
Outcome chronic inflammation, abscess Scar tissue formation, disability, amyloidosis
formation
Main immunoglobulin IgM IgG
Serum protein Polyclonal gammopathy; greater degree of
Mild hypoalbuminemia
electrophoresis effect hypoalbuminemia
Peripheral blood
Neutrophilic leukocytosis Monocytosis
leukocyte response
 Inflammation came on changing of sepsis which
is a general process;
development of necrosis of tissue during
alteration promote stopping of blood stream and
result in limitation of infection spreading;
Exudation:
dilution of toxins;
proteins absorb the toxins;
phagocytosis;
limitation of toxins matters and mediators
spreading in an organism.
Proliferation the regeneration of organ or tissue,
recover of structure and function take place.
 Negative significance of
inflammation:

alteration is the injury

dysfunction of organs;
exudate results in compression
of arterial, venous and
lymphatic vessels hypoxia;
the fibroplasia results in the
organ dysfunction.
 Literature
Handbook of general and clinical pathophysiology.
Edited by prof. A.V. Kubyskin. Simferopol.-2005
General and clinical pathophysiology. Edited by prof.
Gozhesko. Odessa. 2005.
Pathophysiology, N.K. Symeonova. Kyiv, AUS medicine
Publishing, 2010, p 120-125.
1. General and clinical pathophysiology. Workbook for
medical students and practitioners. Odessa. 2001.
2. J.B.Walter I.C.Talbot General pathology. Seventh
edition. 1996.
3. Stephen J. McPhee, William F. Ganong.
Pathophysiology of Disease, 5th edition. 2006.
4. Robbins and Cotran Pathologic Basis of Disease 7th
edition./ Kumar, Abbas, Fauto 2006.
5. . Pathophysiology, Concepts of Altered Health States,
Carol Mattson Porth, Glenn Matfin.- New York,
Milwaukee- 2009 p. 377-390.