Victor Babe University of Medicine and Pharmacy

Timisoara

Department of Pathophysiology

PATHOPHYSIOLOGY
OF INFLAMMATION

LECTURE

OUTLINE
Acute inflammation
I. Definition, etiology
II. Manifestations
1. Local
2. Systemic
III. Pathogenesis of acute inflammation
1. Activation of initiation and control systems of
inflammatory reaction mediators of inflammatory
reaction
2. Vascular reaction inflammatory exudate
formation
3. Cellular reaction inflammatory cellular infiltrate
formation
4. Healing
IV. Clinical forms of acute inflammation

Learning objectives
At the end of this lecture, the student should be able to:
- Define the acute inflammation
- List the causes and manifestations of acute inflammation.
- Discuss the roles of various chemical mediators of acute
inflammation.
- Discuss and describe the sequence of vascular and cellular
events in the evolution of acute inflammation.
- List the possible outcomes of acute inflammation and
characterize the healing process.
- Describe the clinical forms of acute inflammation.

OUTLINE
Acute inflammation
I. Definition and etiology
II. Manifestations
1. Local
2. Systemic
III. Pathogenesis of acute inflammation
1. Activation of initiation and control systems of
inflammatory reaction mediators of inflammatory
reaction
2. Vascular reaction inflammatory exudate
formation
3. Cellular reaction inflammatory cellular infiltrate
formation
4. Healing
IV. Clinical forms of acute inflammation

MECHANISMS OF DEFENSE

1st line of defense

2nd line of
defense

3rd line of
defense

IMMUNITY AND INFLAMMATION ARE

COMPLEMENTARY

Inflammation
fast
no memory
non-specific

Immunity
slower
memory
specific

ACUTE INFLAMMATION
Definition:

the immediate and early response to injury or necrosis that

occurs in a vascularized tissue

Latin inflammare = to set on fire

Nomenclature:
The term used to describe inflammation in different tissues employs
the tissue name and the suffix -itis
E.g.: pulpitis = inflammation of dental pulp tissue:
- dental caries;
- bacterial infections;
- trauma (repeated dental procedures)

gingivitis = inflammation of the gum tissue:

- bacterial infections of the plaque

ACUTE INFLAMMATION
Roles:
Acute inflammation is the most important normal nonspecific (innate) defense reaction aimed at:

Removing the cause (microorganisms, foreign

bodies)
Repairing / limiting the damage to a certain area
Clearing debris and prepare the area of injury for
healing
Interacting with components of the specific
immune system

ACUTE INFLAMMATION
Etiology:
I. Non-specific factors:
1. Microorganisms: bacteria, viruses, fungi, parasites
2. Foreign bodies
3. Tissue destruction with formation of tissue debris through:
Mechanical damage: cuts, stubs, scratches
Chemical compounds: acids, alkali
Physical agents: cold, heat, radiation (UV, X-rays)
Endogenous causes: tumour cells, crystals of
substances precipitated in the body
II. Specific factors

Hypersensitivity reactions (when your immune system

overreacts !)
Autoimmune diseases (when your immune system mistakenly
attacks your own healthy cells !)

OUTLINE
Acute inflammation
I. Definition and etiology
II. Manifestations
1. Local
2. Systemic
III. Pathogenesis of acute inflammation
1. Activation of initiation and control systems of
inflammatory reaction mediators of inflammatory
reaction
2. Vascular reaction inflammatory exudate
formation
3. Cellular reaction inflammatory cellular infiltrate
formation
4. Healing
IV. Clinical forms of acute inflammation

ACUTE INFLAMMATION

Manifestations:
1. Local Effects: 5 cardinal signs

- Calor (heat)
- Dolor (pain)
- Rubor (redness)
- Tumor (swelling)
Functio Laesa (loss of function)

changes in microenvironment interfere with

function

ACUTE INFLAMMATION
Manifestations (cont.):
2. Systemic Effects: the acute phase reaction
Clinic: fatigue, loss of
appetite, weight loss
(adrenocorticotropic hormone)

plasma level:
up to 1000fold

30.000 /mm3 with:

Neutrophilia (bacterial infections, ischemic
damage)
Lymphocytosis (viral infections)
Eosynophilia (parasitic infections, allergic
reactions)

OUTLINE
Acute inflammation
I. Definition and etiology
II. Manifestations
1. Local
2. Systemic
III. Pathogenesis of acute inflammation
1. Activation of initiation and control systems
of inflammatory reaction mediators of
inflammatory reaction
2. Vascular reaction inflammatory exudate
formation
3. Cellular reaction inflammatory cellular infiltrate
formation
4. Healing
IV. Clinical forms of acute inflammation

Cells of inflammatory response

Name

Neutrophil
(Microphag
e)

Monocyte
(Macrophage
)

T
Lymphocyte

Platelets

Mast cells

Plasma cell
(Plasmocyt
e)

Function

Phagositic
1st defense
element:
small
eaters

Phagocytic
2nd defense
element: big
eaters
- engulf
bacteria,
dead cells,
debris &
dead
neutrophils
(pus cells)

Determine
the
specificity
of the
immune
response to
infectious
microorgani
sand other
foreign
substances.

Release PAF
(platelet
activating
factor) which
in turn
begins call to
action and
release of
chemical
mediators

Release
chemical
mediators
that begin
inflammatio
n

Primary
source of
specific
Antibodies
- Derived
from B cells

CHEMICAL MEDIATORS OF INFLAMMATION

Cell-derived
Preformed (sequestered intracellularly)
Newly formed (synthesized de novo)
Plasma-derived
Circulating precursors
Have to be activated

CELL-DERIVED: PREFORMED
Histamine
- in mast cells and
basophils

- Early released (1/2 h) in response to

stimuli
- Promotes arteriolar dilation and
venular endothelial contraction
- Results in widening of interendothelial cell
junctions with increased vascular
permeability

Serotonin
- in platelets

- Released when platelets aggregate

- Vasoactive effects similar to histamine

Lysosomal
enzymes

- Direct effect: degradation of

extracellular structures
- Indirect effect: activation of
complement and kinin system

in neutrophils and
macrophages

NEWLY SYNTHETISED ARACHIDONIC ACID

MEDIATORS

non-selective inhibitors
- Aspirin
- NSAIDS

housekeeper enzyme

CELL-DERIVED: NEWLY SYNTHETISED

PGD2, PGE2, PGF2

vasodilation

synthesized by neutrophils
and macrophages

vascular permeability

TxA2

vasoconstriction
stimulates adhesion and aggregation
of Thrombocytes

synthesized by thrombocytes

contract the smooth bronchial and

intestinal muscles
PGE2: induce fever and pain

synthesized by endothelial
cells

vasodilatation
inhibits adhesion and aggregation of
Thrombocytes

LTB4

chemotactic factor

PGI2

synthesized by neutrophils
and macrophages
LTC4, LTD4, LTE4

vascular permeability

synthesized by neutrophils
and macrophages

contract the smooth bronchial and

intestinal muscles

CELL-DERIVED: NEWLY SYNTHETISED

PAF
(PLATELET ACTIVATING
FACTOR)

- phospholipid-derived
mediator released by
phospholipases

Cytokines
- polypeptides secreted by
macrophages, lymphocytes,
endothelial cells, fibroblasts

- Induces aggregation of platelets

- Causes bronchoconstriction
- 100 to 1,000 times more potent
than histamine in inducing
vasodilation and vascular
permeability
- Enhances leukocyte adhesion,
chemotaxis, degranulation
- act as a message to other cells.
- IL-1, TNF- are especially
important in inflammation.
- Increase endothelial cell adhesion
molecule expression, activation
and aggregation of PMNs, etc.

PLASMA-DERIVED MEDIATORS

- vd
- increased
capillary
permeability
- pain

may induce increased vascular permeability

PLASMA-DERIVED MEDIATORS:
COMPLEMENT SYSTEM
> 20 proteins that circulate in the blood in an inactive
form
Proteins are activated (in an orderly sequence and where
each step catalyzes the next) via
classic/alternative/lectin pathways
All the pathways converge on C3
In acute inflammation
As an opsonin, increases phagocytosis (C3b)
Vasodilation, vascular permeability, mast cell degranulation
(C3a, C5a = anaphylatoxins)
to generate MAC membrane attack complex (C5 C9) that
punch holes in microbe membranes

QUIZ

1. Which of the following represent

systemic events in an acute inflammation:
A. Fever
B. Oedema
C. Leukocytosis with neutrophilia
D. Functio laesa
E. Fatigue

QUIZ

2. Which of the followings are cellular

preformed mediators in acute
inflammation:
A. Histamine
B. Prostaglandins
C. Anaphylatoxins C3a, C5a
D. Serotonin
E. PAF

QUIZ

3. Which of the following plasma-derived

mediators are inducing vasodilation:
A. Histamine
B. Prostaglandins
C. Anaphylatoxins C3a, C5a
D. Serotonin
E. Bradykinin

OUTLINE
Acute inflammation
I. Definition, etiology, general characteristics
II. Manifestations
1. Local
2. Systemic
III. Pathogenesis of acute inflammation
1. Activation of initiation and control systems of
inflammatory reaction mediators of
inflammatory reaction
2. Vascular reaction inflammatory exudate
formation
3. Cellular reaction inflammatory cellular
infiltrate formation
4. Healing
IV. Clinical forms of acute inflammation

THE VASCULAR EVENTS

1. Vasodilation, leads to
increased blood flow causing
redness and warmth (RUBOR
and CALOR)
2. Increased Permeability,
leads to exudation of protein
rich fluid into the
extravascular space causing
edema (TUMOR)
- Mediated by:
Histamine
PGD2, PGE2, PGF2
Complement components
(C3a, C5a)
Bradikinine

INTERMEZZO
Exudate
result of inflammation
high protein and cell debris content
Role of inflammatory exudates
1-Dilute the invading microorganism and its toxins.
2-Bring antibodies through the plasma to the inflamed area.
3-Bring leukocytes that engulf the invading microorganisms.
4-Bring fibrinogen through the plasma, which is converted, to fibrin mesh,
helping in trapping the microorganism and localize the infection.
Transudate
result of hydrostatic or osmotic imbalance
(ultrafiltrate of
plasma, no increased vascular permeability)
low protein content
Pus

inflammatory exudate
rich in neutrophils, debris of dead cells
microbes

THE VASCULAR EVENTS (cont.)

3. Stasis of the blood flow in small vessels (slow blood flow)
Mechanisms:
vasodilatation
blood viscosity due to fluid exudation into the extracellular
space
local edema
microtrombi via TxA2 release
Consequences:
1. Cellular hypoxia metabolic disturbances and endothelial
damage vascular reaction is amplified
2. Pain (DOLOR)
Accumulation of algogenic factors which stimulate the free
nervous fibers: H+, K+, PGE2, BK
Edema: compresses the free nervous fibers

THE VASCULAR EVENTS

Time scale
Variable
minor damage---- 15-30 minutes
severe damage---- a few minutes

What is the critical function of the vascular respons

to deliver leukocytes to the site of injury in
order to clear injurious agents.

OUTLINE
Acute inflammation
I. Definition, etiology, general characteristics
II. Manifestations
1. Local
2. Systemic
III. Pathogenesis of acute inflammation
1. Activation of initiation and control systems of
inflammatory reaction mediators of
inflammatory reaction
2. Vascular reaction inflammatory exudate
formation
3. Cellular reaction inflammatory cellular
infiltrate formation
4. Healing
IV. Clinical forms of acute inflammation

LEUKOCYTE CELLULAR EVENTS

Neutrophils are commonly the first inflammatory cells (first 6-24 hours)
recruited to a site of inflammation.
Divided into 4 steps
1. Margination, rolling, and adhesion to endothelium
2. Diapedesis (transmigration across the endothelium)
3. Chemotaxis
4. Phagocytosis

1. Margination, rolling, and adhesion to

endothelium
Normally, RBCs and WBCs flow in the center of the vessel

As blood flow slows, WBCs collect along the endothelium - this is

Margination
In order for leukocytes to leave the vessel lumen, endothelial
cells need to be activated and to upregulate adhesion molecules
that can interact with complementary adhesion molecules on
leukocytes

1. Margination, rolling, and adhesion to

endothelium
- Mediated by Selectins (bind selected sugars): Selected +
Lectins (sugars)
- transiently bind to receptors
PMNs bounce or roll along - this is Rolling

1. Margination, rolling, and adhesion to

endothelium
Mediated by
Integrins (expressed on leucocytes),
Immunoglobulins (expressed on activated endothelium):
ICAM-1 (intercellular adhesion molecule 1) and VCAM-1
(vascular adhesion molecule 1)

How do neutrophils escape from vessels?

Relaxation of inter-endothelial cell junctions
Mediated by histamine

How do neutrophils move?

2. Diapedesis (transmigration across the
endothelium)

Mediated by PECAM-1
(platelet endothelial
cell adhesion molecule-1)

3. Chemotaxis = migration toward a chemotactic stimuli

released from the source of tissue injury.

Chemotaxis
Chemotactic Factors:
-Complement components (C5,6,7)
-Arachidonic Acid metabolites (Lt
B4)
-Soluble bacterial products
- Cytokines (IL-8)

What do neutrophils do?

4. Phagocytosis

OUTCOMES OF ACUTE INFLAMMATION

Complete resolution
elimination of the offending agent and
regeneration of injured tissue with normal function
Healing by connective tissue replacement
(fibrosis/scar formation)
Progression to chronic inflammation
pathological if inappropriately triggered :
magnitude, duration, target

OUTLINE
Acute inflammation
I. Definition, etiology, general characteristics
II. Manifestations
1. Local
2. Systemic
III. Pathogenesis of acute inflammation
1. Activation of initiation and control systems of
inflammatory reaction mediators of
inflammatory reaction
2. Vascular reaction inflammatory exudate
formation
3. Cellular reaction inflammatory cellular
infiltrate formation
4. Healing
IV. Clinical forms of acute inflammation

Healing

http://www.healthyfellow.com/238/wound-healing-and-

Healing by primary or secondary intention

Depend weather edges of lesion can be brought together

- wounds with clean opposing edges

- in minimal tissue lesions (surgical incisions): small scar formati

- wounds with separated edges

- in important lesions (ulcer, abscess) that requires
abundance of granulation tissue for wound closure: big scar
formation

Complications from large scar formation

Loss of function
Contractures & obstructions
Can lead to stenosis
Adhesions
Ulceration

Factors promoting healing

Nutrition
Blood supply
Cleanness of area
Lack of complications

Factors delaying healing

Old age
Presence of foreign material
Poor blood supply
Poor nutrition
Complications (bleeding, excessive mobility)

The Inflammatory Response

Leukocytosis
Chemotaxis
Margination
Diapedesis

TAKE HOME MESSAGE

Acute inflammation
Key purposes = DEFENSE
1. To hunt & kill invaders
2. To limit their spread
3. To prepare tissue for repair
Key events
1. Vd + Increase of vascular permeability
+ Stasis
2. Recruitment (margination) &
emigration (diapedesis) of WBCs
3. Phagocytosis

OUTLINE
Acute inflammation
I. Definition, etiology, general characteristics
II. Manifestations
1. Local
2. Systemic
III. Pathogenesis of acute inflammation
1. Activation of initiation and control systems of
inflammatory reaction mediators of
inflammatory reaction
2. Vascular reaction inflammatory exudate
formation
3. Cellular reaction inflammatory cellular
infiltrate formation
4. Healing
IV. Clinical forms of acute inflammation

Clinical forms of acute inflammation

- based on type of exudates
1-Serous inflammation:
2-Fibrinous inflammation:
3-Catarrhal inflammation
4-Suppurative or purulent
inflammation
5-Hemorrhagic
inflammation:

Clinical forms of acute inflammation

Name

Occurs in

Characterized by

Serous

Mild inflammation in serous surface Extensive watery

low protein exudates
such as pleural cavity, joint cavity
with no damage in endothelium
- Tuberculosis pleurisy and Common
blisters

Fibrinous

Outpouring of exudates with high

protein and less volume
- in lobar pneumonia due to
Streptococcus pneumonia &
pericardium inflammation

Exudates rich in
fibrinogen

Catarrhal

Mild inflammation in mucous

membrane of respiratory or
alimentary tracts
- common cold and catarrhal
appendicitis

Exudates rich in
mucous

Hemorrhagi
- in fulminating infections
c
Suppurativ

Caused by pyogenic bacteria and is

characterized by pus formation

Exudates rich RBCs

Large amount of Pus
& purulent exudates

QUIZ
4. Which of the following are true about acute
inflammation?
A. Slow onset
B. Neutrophils are the predominant cells
C. Macrophages are the predominant cells
D. Alterations in blood vessels lead to accumulation
of fluid (edema), cells and mediators in
extravascular tissue
E. It never evolves to chronic inflammation

QUIZ
5. An exudate rich in mucous is seen in:
A. Serous inflammation
B. Fibrinous inflammation
C. Catarrhal inflammation
D. Purulent inflammation
E. Hemorrhagic inflammation

QUIZ
6. What is the difference between transudate and exudate?

(1) clear, low protein content, general low cellularity

transduate

(2) viscous, high protein concentration, contains cells/cellular debris

exudate