Inflammation is characterized by cardinal signs such as redness, swelling, heat, and pain. It involves a complex series of events including increased blood flow, vascular permeability, and migration of leukocytes. Mediators like histamine, cytokines, prostaglandins, and leukotrienes are released from cells to induce and propagate the inflammatory response through effects on blood vessels and immune cells. Acute inflammation resolves within days while chronic inflammation persists long-term and can cause tissue damage.

1. INFLAMMATION

2. Inflammation is a typical
pathological process, which
is characterized by a
complex of morphological,
biochemical and functional
changes, the reaction of
microcirculation and
connective tissue in
response to the tissue
damage.

4. Cardinal Signs ( local )
•rubor (redness),
•tumor (swelling),
•calor (heat),
•dolor (pain),
•functio laesa, or loss of
function

5. Cardinal Signs ( systemic signs )
• Fever: cytokines (TNF, IL-1) stimulate production of
prostaglandins in hypothalamus
• Production of acute-phase proteins: C-reactive protein, others;
• Leukocytosis: cytokines (CSFs) stimulate production of
leukocytes from precursors in the bone marrow
• In some severe infections, septic shock

6. Classification of Inflammation
By clinical course:
a) acute,
b) subacute,
c) chronic.
By character of predominating phase of inflammation:
a) alterative
b) exudative,
c) proliferative
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 of sensitizing;
c) hypoergic – with insignificant displays(for the children of 1th month of life).

7. Etiology of an inflammation
Exogenous flogogens Endogenous flogogens

8. 8
Characteristics of acute inflammation:
- Rapid onset of action (typically minutes).
- Short in duration (lasts for hours or a few days).
- Exudation of fluid and plasma proteins (edema).
- Emigration of leukocytes (mainly neutrophils) to the site
of injury.
Characteristics of chronic inflammation:
- May follow acute inflammation or be insidious in onset.
- Long in duration.
- Associated with the presence of lymphocytes and
macrophages.
- Angiogenesis, fibrosis and tissue destruction may occur.

9. Pathogenesis of inflammation
Inflammation has three stages :
1. Alteration
2. Disorder of microcirculation,
exudation, emigration of
leukocytes into focus of
inflammation, and phagocytosis
3. Proliferation and regeneration.

10. ALTERATION
Primary alteration is a
damage of tissue by
flogogenic factors. This
effect may be very short-
termed, but the local
damage of tissue is not
finished.
Secondary alteration is an
additional damage of tissue
by BAS (mediators of
inflammation) that are
produced in consequence
of primary alteration.

11. Mediators of the inflammation
1) Cellular origin (appear and
activated in different cells)
2) Plasmatic origin (appear in cells,
but activated in blood plasma).
3) Proinflammatory
4) Antiinflammatory

12. Mediator Principal Sources Actions
CELL-DERIVED
Histamine Mast cells, basophils,
platelets
Vasodilation, increased vascular permeability, endothelial activation
Serotonin Platelets Vasodilation, increased vascular permeability
Prostaglandins Mast cells, leukocytes Vasodilation, pain, fever
Leukotrienes Mast cells, leukocytes Increased vascular permeability, chemotaxis, leukocyte adhesion and activation
Platelet-activating factor Leukocytes, mast cells Vasodilation, increased vascular permeability, leukocyte adhesion, chemotaxis, degranulation,
oxidative burst
Reactive oxygen species Leukocytes Killing of microbes, tissue damage
Nitric oxide Endothelium, macrophages Vascular smooth muscle relaxation, killing of microbes
Cytokines (TNF, IL-1) Macrophages, endothelial
cells, mast cells
Local endothelial activation (expression of adhesion molecules),
fever/pain/anorexia/hypotension, decreased vascular resistance (shock)
Chemokines Leukocytes, activated
macrophages
Chemotaxis, leukocyte activation
PLASMA PROTEIN–DERIVED
Complement products
(C5a, C3a, C4a)
Plasma (produced in liver)
Kinins Plasma (produced in liver)
Proteases activated during
coagulation
Plasma (produced in liver)

13. Cell-Derived Mediators
Vasoactive amines
(histamine, serotonin)
Arachidonic acid
metabolites
Cytokines
ROS
Nitric Oxide
Lysosomal enzymes

14. Mediators of Humoral (plasmatic) origin
Complement proteins
Coagulation proteins: Activated
factor XII triggers the clotting,
kinin, and complement
cascades and activates the
fibrinolytic system.
Kinins

15. Produced by mast cells in response to:
injury (heat,trauma), immune
reactions, anaphylatoxins (C3a
and C5a fragments ), cytokines
(IL-1, IL-8).
Effects: ( mainly via H1 receptors )
• arteriolar dilation
• increasement of the permeability
of venules
• venular endothelial contraction
• formation of interendothelial gaps
in postcapillary venules.
Histamine

16. Arachidonic acid metabolites

17. Arachidonic acid metabolites
The prostaglandins are
synthesized from arachidonic acid
through the cyclooxygenase
metabolic pathway.
PGE1 and PGE2 induce inflammation
and potentiate the effects of
histamine.
The thromboxane A2 promotes
platelet aggregation and
vasoconstriction.
Aspirin and the nonsteroidal anti-
inflammatory drugs (NSAIDs)
reduce inflammation by inactivating
the first enzyme in the
Leukotrienes are formed
from arachidonic acid
through the lipoxygenase
pathway.
LTB4 – potent chemotactic
agent for neutrophils
LTD4 and LTE4 cause
bronchoconstriction and
increased vascular
permeability

18. Cytokines

19. Cytokines are polypeptide products that
mediate and regulate immune and
inflammatory reactions. The major cytokines in
acute inflammation are TNF, IL-1, IL-6.
The actions of TNF and IL-1:
• Endothelial activation. Increased expression
of endothelial adhesion molecules, mostly E-
and P-selectins and ligands for leukocyte
integrins;
• Activation of leukocytes and other cells
• Systemic acute-phase response (fever)
• TNF regulates energy balance by promoting
lipid and protein catabolism and by suppressing
appetite

21. Nitric Oxide
NO is as a microbicidal (cytotoxic)
agent in activated macrophages.
• NO plays other roles in
vasodilation,
• antagonism of all stages of platelet
activation (adhesion, aggregation,
and degranulation),
• reduction of leukocyte recruitment
at inflammatory sites.

22. Lysosomal Enzymes of Leukocytes
The lysosomal granules of neutrophils and monocytes
contain enzymes that destroy phagocytosed substances.
Acid proteases are active only in low-pH environment of
phagolysosomes;
Neutral proteases (elastase, collagenase are active in
extracellular locations).
The potentially damaging effects of lysosomal enzymes
are limited by antiproteases present in the plasma (α1-
antitrypsin and α2-macroglobulin).

23. Reactive Oxygen Species
When ROS are produced within lysosomes, they destroy
phagocytosed microbes.
When secreted at low levels, ROS can increase chemokine,
cytokine, and adhesion molecule expression, thus amplifying the
cascade of inflammatory mediators.
At higher levels, these mediators are responsible for tissue injury
by :
(1) endothelial damage and increased permeability;
(2) protease activation and antiprotease inactivation, with a net
increase in breakdown of the ECM;
(3) direct injury to other cell types (tumor cells, red cells).

24. Coagulation and Kinin Systems
Hageman factor (factor XII of the intrinsic coagulation
cascade) is synthesized by the liver that circulates in an
inactive form until it encounters collagen, basement
membrane, or platelets (at a site of endothelial injury).
Activated Hageman factor initiates four systems that may
contribute to the inflammatory response:
(1) the kinin system, producing vasoactive kinins;
(2) the clotting system, inducing the activation of
thrombin, fibrinopeptides, and factor X;
(3) The fibrinolytic system, producing plasmin;
(4) the complement system, producing C3a and C5a.
Kinin system activation leads to the formation of bradykinin
which causes increased vascular permeability, arteriolar
dilation, and bronchial smooth muscle contraction. It also
causes pain when injected into the skin.

25. The complement system consists of plasma
proteins that play an important role in host
defense.
Vascular effects.C3a and C5a increase vascular
permeability and cause vasodilation by inducing
mast cells to release histamine.
Leukocyte activation, adhesion, and
chemotaxis.C5a, C3a and C4a, activate leukocytes,
increasing their adhesion to endothelium, and is a
potent chemotactic agent.
Phagocytosis. C3b and its cleavage product iC3b
(inactive C3b), when fixed to a microbial cell wall,
act as opsonins and promote phagocytosis by
neutrophils and macrophages, which bear cell
surface receptors for these complement
fragments.
• Cell lysis The MAC, which is made up of multiple
copies of the final component C9, kills some
bacteria by creating pores that disrupt osmotic
balance.

26. Disturbance of the microcirculation in the inflammation area
1.Short-term spasm of arterial vessels
2. Arterial hyperemia
3. Venous hyperemia
4. Stasis.

27. Short-Term Spasm
It is an unspecific initial reaction of vessels to
any damage and has protective value.
Catecholamines stimulate ά-adrenoreceptors
and promote the contraction of smooth
muscles of vascular wall.
Arterial Hyperemia
Vasodilation is induced by the action of
histamine. Vasodilation first involves the
arterioles and then leads to the opening of new
capillaries. The result is increased blood flow,
which is the cause of heat and redness
(erythema) at the site of inflammation.
Vasodilation is quickly followed by increased
permeability of the microvasculature, with the
outpouring of protein-rich fluid (an exudate) into
the extravascular tissues.

28. Venous Hyperemia
Venous hyperemia follows the arterial one. The
blood stream slows down, and leukocytes
occupy boundary position near the wall. The
adhesive proteins, which are formed in
endothelium, make the surface of
endoteliocytes and leukocytes more “sticky”.
Stasis
As stasis develops, leukocytes accumulate along
the vascular endothelial surface. At the same
time endothelial cells are activated by mediators
and express increased levels of adhesion
molecules. Leukocytes then adhere to the
endothelium, and soon afterward they migrate
through the vascular wall into the interstitial
tissue.

29. Increased Vascular Permeability
Increasing vascular permeability
leads to the movement of
protein-rich fluid and blood cells
into the extravascular tissues.
As a result, the osmotic
pressure of the interstitial fluid
increases, leading to more
outflow of water from the blood
into the tissues. The resulting
protein-rich
fluid accumulation is called an
exudate.

30. 30
• An exudate is an extravascular fluid that has
a high protein concentration, contains cellular
debris, and has a high specific gravity.
• A transudate is a fluid with low protein
content (most of which is albumin), little or no
cellular material, and low specific gravity.

31. Mechanisms of penetration of fluid through the vessel wall
(exudation) :
• Endothelial cell contraction (after
binding of histamine, bradykinin)
leading to intercellular gaps in
postcapillary venules.
• Endothelial injury results in
vascular leakage by causing
endothelial cell necrosis and
detachment.
• Increased transcytosis of proteins
by way of an intracellular vesicular
pathway augments venular
permeability, especially after
exposure to vascular endothelial
growth factor (VEGF). Transcytosis
occurs through channels formed by
fusion of intracellular vesicles.

32. Mechanisms of leukocyte migration through blood vessels

34. Leukocyte Recruitment to Sites of Inflammation
(1) margination and rolling along the vessel wall
endothelium (mediated by selectins);
(2) firm adhesion to the endothelium (mediated
by integrins)
(3) Transmigration between endothelial cells;
(4) migration in interstitial tissues toward a
chemotactic stimulus
• Various cytokines promote expression of
selectins and integrin ligands on endothelium
(TNF, IL-1), increase the avidity of integrins for
their ligands (chemokines), and promote
directional migration of leukocytes (also
chemokines);
• Neutrophils predominate in the early
inflammatory infiltrate and are later replaced by
macrophages

36. Leukocyte Activation
Once leukocytes have been recruited to the site
of infection, they must be activated to perform:
• Phagocytosis of particles
• Intracellular destruction of phagocytosed
microbes and dead cells by substances
produced in phagosomes, including ROS and
RNS and lysosomal enzymes
• Liberation of substances that destroy
extracellular microbes
• Production of mediators that amplify the
inflammatory reaction, by recruiting and
activating more leukocytes.

37. Recognition of Pathogen
Toll-like receptors (TLRs) located in
plasma membranes and endosomes,
so they are able to detect extracellular
and ingested microbes. TLRs
recognize motifs common to many
microbes called pathogen associated
molecular patterns (PAMPs) which
stimulate cytokine production.
Also cells have cytosolic receptors
that recognize molecules that are
liberated after cell damage, and called
damage-associated molecular patterns
(DAMPs). These molecules include uric
acid, ATP, DNA and activate
inflammasome (a protein complex
)that induces the secretion IL-1.
Toll-like receptor 3 (TLR3) ectodomain
bound to double-stranded RNA
inflammasome

40. Phagocytosis is defined as the process of
engulfment of solid particulate material by
by phagocytes :
• Polymorphonuclear neutrophils (PMNs)
which appear early in acute inflammatory
response
• Circulating monocytes and fixed tissue
mononuclear phagocytes, commonly called
as macrophages.
Phagocytosis consists of three steps :
(1) recognition and attachment
(2) engulfment, with formation of a phagocytic vacuole;
(3) killing and degradation of the ingested material.

42. 1. RECOGNITION AND ATTACHMENT
Phagocytosis is initiated by the expression
of surface receptors on macrophages.
Some of receptors recognize
components of the microbes and dead
cells and other receptors recognize
host proteins, called opsonins, that
coat microbes and target them for
phagocytosis (opsonization). The main
opsonins are:
i) IgG opsonin is the Fc fragment of
immunoglobulin G
ii) C3b opsonin is the fragment generated
by activation of complement pathway.
It is strongly chemotactic for attracting
PMNs to bacteria.
iii) Lectins are carbohydrate-binding
proteins in the plasma which bind to
bacterial cell wall.

43. 2. ENGULFMENT
The opsonised particle bound to the
surface of phagocyte is ready to be
engulfed. This is accomplished by
formation of cytoplasmic pseudopods
around the particle.
Eventually, the plasma membrane
enclosing the particle breaks from the cell
surface so that membrane lined phagocytic
vacuole or phagosome lies internalised and
free in the cell cytoplasm. The phagosome
fuses with one or more lysosomes and
form bigger vacuole called phagolysosome.

44. 3. KILLING AND DEGRADATION
The microorganisms after being killed by
antibacterial substances are degraded by
hydrolytic enzymes. However, this
mechanism fails to kill and degrade some
bacteria like tubercle bacilli.
A. Intracellular mechanisms:
i) Oxidative bactericidal mechanism by oxygen free radicals
a) MPO-dependent
b) MPO-independent
ii) Oxidative bactericidal mechanism by lysosomal granules
iii) Non-oxidative bactericidal mechanism
B. Extracellular mechanisms ( granules, immune
mechanisms)
Disposal of microorganisms can proceed by
following mechanisms:
Neutrophil extracellular traps

45. MORPHOLOGIC PATTERNS OF ACUTE INFLAMMATION
Fibrinous inflammation occurs as
a consequence of more severe
injuries, resulting in greater
vascular permeability that allows
large molecules (such as
fibrinogen) to pass the endothelial
barrier. A fibrinous exudate is
characteristic of inflammation in
the lining of body cavities, such as
the meninges, pericardium, and
pleura. (pseudomembranous inflammation in
diphtheria), consisting of fibrin mixed with
necrotic cells in mucosa

46. Serous inflammation is characterized by
relatively protein-poor fluid that,
depending on the site of injury, derives
either from the plasma or from the
secretions of mesothelial cells lining the
peritoneal, pleural, and pericardial
cavities.
skin blister

47. Suppurative (purulent)
inflammation is
manifested by the
collection of large
amounts of purulent
exudate (pus) consisting of
neutrophils, necrotic cells,
and edema fluid. purulent inflammation, multiple abscesses in lung,
abscess contains neutrophils, cellular debris, congested
blood vessels

48. 48
• Complete resolution
- injury is limited or short lived
- little tissue destruction, and
- parenchymal cells can regenerate
Removal of cellular debris and microbes
Resorption of edema fluid by lymphatics
• Healing by connective tissue replacement (fibrosis).
- substantial tissue destruction
- tissue involved is incapable of regeneration
- abundant fibrin exudation in tissues or serous cavities
Outcomes of acute inflammation

50. Regeneration
Regeneration involves replacement of the
injured tissue with cells of the same
parenchymal type, leaving little or no
evidence of the previous injury.
Body cells are divided into three types
according to their ability to undergo
regeneration:
• Labile cells continue to divide and
replicate throughout life, replacing cells
that are continually being destroyed.
• Stable cells are those that normally stop
dividing when growth ceases.
• Permanent cells cannot undergo mitotic
division. The fixed cells include nerve
cells, skeletal muscle cells, and cardiac
muscle cells.

51. Growth Factors
Most growth factors are proteins that stimulate
proliferation of particular cells, and may also
promote migration, differentiation, and other
cellular responses.
They induce cell proliferation by binding to
specific receptors.
Many of the growth factors that are involved in
repair are produced by macrophages and
lymphocytes.
Other growth factors are produced by
connective tissue cells in response to cell injury.

52. Role of the Extracellular Matrix in Tissue Repair
The ECM consists of the interstitial matrix
between cells, made up of collagens and
glycoproteins, and basement membranes
underlying epithelia and surrounding vessels,
made up of nonfibrillar collagen and laminin.
• It provides mechanical support to tissues
• It acts as a substrate for cell growth and the
formation of tissue microenvironments.
• It regulates cell proliferation and differentiation;
proteoglycans bind growth factors and display
them at high concentration, and fibronectin and
laminin stimulate cells through cellular integrin
receptors.
• An intact ECM is required for tissue
regeneration, and if the ECM is damaged, repair
can be accomplished only by scar formation.

53. SCAR FORMATION
If tissue injury is severe or chronic
and results in damage to parenchymal
cells and epithelia or if nondividing
cells are injured, repair occurs by
replacement of the nonregenerated
cells with connective tissue, leading to
the formation of a scar.

54. Repair by connective tissue
deposition consists of :
• Formation of new blood vessels
(angiogenesis)
• Migration and proliferation of
fibroblasts and deposition of
connective tissue, which, together
with abundant vessels and
interspersed leukocytes is called
granulation tissue
• Maturation and reorganization of
the fibrous tissue (remodeling) to
produce the stable fibrous scar.

55. Chronic inflammation is inflammation
of prolonged duration (weeks to years)
in which continuing inflammation,
tissue injury, and healing, often by
fibrosis, proceed simultaneously.
Mediated by cytokines produced by
macrophages and lymphocytes
(notably T lymphocytes), with a
tendency to an amplified and
prolonged inflammatory response
owing to bidirectional interactions
between these cells.
The macrophages are the
dominant cells in chronic
inflammation (predominates
within 48 hrs).