Acute Inflammation-I

Kusum Kapila
September,2006
 Lectures
Inflammation – generalities
Classification of inflammation
Acute inflammation
- Vascular events/permeability
- Inflammatory Cell Types
- Sequence of events
- Chemical Mediators
Chronic Inflammation and Granulomatous
Inflammation
Repair
Wound Healing
Healing in Specific Tissues
 Inflammation
"Inflammation is one of the most important
and most useful of our host defense
mechanisms, and without an adequate
inflammatory response none of us or our
patients would be living.
It is not a disease but a manifestation of a
disease
Ironically it is also one of the most common
means whereby our own tissues are injured."
 GENERALITIES REGARDING THE
INFLAMMATORY RESPONSE:

process involving multiple participants.

Inflammation is the reaction of vascularized
living tissues to local injury
fairly stereotypical
It is a series of events which overlap and form a
continuum in the terminal vascular bed, in
blood and in connective tissues
It is a response to an initiating event a defense
mechanism.
purpose is to eliminate the offending irritant
and to repair the damaged tissue.
It can be harmful.
 Roles of Inflammation:
Protection
-Contain and isolate the injury
-Destroy invading organisms
and inactive toxins
Achieve healing and repair
-ideally tissue should return to normal
-abscess formation may occur
-persistent infection
-chronic infection
-scar formation-may distort tissue and
alter their function
 Outcome of Acute Inflammation

Resolution

Mediators
INJURY Acute inflammation Abscess formation

Healing
Mediators Regeneration
Persistent infection
Chronic inflammation Scarring
Persistent toxins
Autoimmune diseases
 CLASSIFICATION OF
INFLAMMATION
Extent Exudate
Mild Suppurative
Moderate Fibrinous
Severe Serofibrinous
Duration Fibrino-purulent
Peracute Necrotizing
Acute Granulomatous,
Subacute Anatomic Modifiers
Chronic Interstitial
Chronic-active Broncho-interstital
Distribution Glomerulonephritis
Focal Submandibular
Multifocal Organ
Coalescent Nephritis
Locally Extensive Hepatitis
Diffuse Enteritis
Etc
 Extent – how severe?
Mild - not too bad
Minimal tissue damage
few inflammatory cells
- small edema and/or congestion
Moderate – pretty bad
Some obvious tissue damage
Some inflammatory cells
Vascular involvement
edema/haemorrhage +
Severe – really bad
Lots of tissue damage
Lots of inflammatory cells
Lots of edema and haemorrhage
Duration – how long has the
processes been underway?

Peracute
Acute
Subacute
Chronic
Chronic -active
 PERACUTE INFLAMMATION:

Usually caused by a potent stimulus

Eg: Bee Sting
Time: 0-4 hours
Vascular Involvement: Hyperaemia,
Slight edema, Haemorrhage
Inflammatory cells: Not usually
numerous, Few leucocytes
Clinical Signs: Shock, sudden death
 Inflammation
“Is a reaction of a tissue and its
microcirculation to a pathogenic insult”

It is characterized by the generation

of inflammatory mediators and
movement of fluid & leukocytes from
the blood into extravascular tissues.
 Causes of Inflammation

microbial Infections – pyogenic

bacteria, virus
hypersesitivity reactions – parasites,
TB
physical agents – trauma, radiation,
heat, cold
Chemicals – corrosives,bacterial
toxins
Tissue necrosis - infarction
 ACUTE INFLAMMATION
Cardinal Signs
(Celsus, 2 AD)
Redness (rubor)
Swelling (tumor)
Heat (calor)
Pain (dolor)
Loss of function
(functio laesa)
(added by Virchow)
Phases of Acute Inflammation
1- Initiation:
1- Stimulation (injury) with changes in microvasculature
2- Structural changes leading to fluid extra-vasation
3- Emigration of WBCs to the site of injury

2- Amplification:
Both soluble mediators and cellular inflammatory
systems are activated and amplified

3- Termination:
Specific inhibition or dissipation of the mediators
 Acute Inflammation
Acute inflammation involves several processes:

Vascular component- Alterations in vascular

caliber leading to increased blood flow
Exudative component- Changes in the micro-
vasculature causing protein rich fluid to leave
circulation
Cellular component- recruitment and emigration
of the leukocytes outside circulation and
accumulation in the focus of injury
Proliferative component- resulting in tissue
regeneration,granulation tissue and healing
Acute Inflammation-
Vascular events
Triple response to injury
The white line - momentary -arteriolar
vasoconstriction
The flush - dull red line - cap.dilatation-
relaxed precapillary sphincters
The flare – red irregular surrounding
zone – arteriolar dilatation
The wheal – edema – fluid extravasation
 Components of the vascular
response

Vascular Changes
- Vasodilation (change in caliber and flow)
- increased vascular permeability
- acute local active hyperemia
Cellular Events
- Movement from capillaries and post
capillary venules - emigration
-Accumulation of leukocytes at sites of
injury - migration
-Activation of inflammatory cells
 Sequence of Events

What happens?
Arteries dilate Simply speaking
 Volume of blood flow  Increase vascular
increases
permeability
 Capillary beds open
 Congestion of veins
 Increase permeability of  Exudation of
microvasculature plasma proteins
 RBC’s become
concentrated
 Blood flow slows down  Leukocytes enter
 Margination, the tissue
Pavementing and
Emigration of WBC’s
 Sequence of events

Increased Vascular
permeability
Escape of protein
rich fluid into
extravascular space
-immunoglobulins
-coagulation factors
-fibrinogen
Results in edema
Inflammation
Pathogenesis of Edema

Inflammatory edema:

1. Direct, irreversible injury - all vessels (burns)

2. Transient increase in vascular permeability, i.e.,
the effect of mediators on post-capillary venules
3- Increased hydrostatic pressure
Inflammation
Increased Hydrostatic Pressure

EDEMA -TRANSUDATE
(protein content low - specific gravity <1.012)

Hydrostatic Oncotic

pressure pressure
Inflammation
Increased Vascular Permeability

EDEMA -EXUDATE
(protein content high: specific gravity >1.015)

Hydrostatic Oncotic

pressure pressure
Diapedesis
 Here is an example of
Increased Vascular the fibrin mesh in fluid
permeability with PMN's that has
Escape of protein rich formed in the area of
fluid into acute inflammation. It is
extravascular space this fluid collection that
-immunoglobulins produces the "tumor" or
-coagulation factors swelling aspect of acute
inflammation
-fibrinogen
Results in edema
Mechanisms of increased vascular
permeability
Mechanisms of increased vascular
permeability
1- Formation of
endothelial gaps in
post capillary
venules
2- Direct injury to
endothelial cell
3-Leukocyte
Dependent
Endothelial Injury
4-Increased
Transcytosis
5- Leakage from
 Vascular Permeability
Although mechanisms are separable
All may participate at same time
example: Thermal burn
 Chemically mediated endothelial
contraction

 Direct injury

 Leukocyte mediated
COMPONENTS OF THE INFLAMMATORY
RESPONSE

Vascular Changes
- Vasodilation (change in caliber and flow)
-Increased Vascular Permeability – Acute
Local Active Hyperemia
Cellular Events
- Movement from capillaries and post
capillary venules - emigration
-Accumulation of leukocytes at sites of
injury - migration
-Activation of inflammatory cells
 Cellular component

Accumulation of
neutrophil
polymorphs in the
extracellular space
is the diagnostic
histologic feature of
acute inflammation
 Increased Permeability

 Post capillary venules

Concentration of RBC’s increases as

fluid decreases

Blood flow decreases ( slows-stasis)

Leucocytes interact with

endothelium
 Margination

Slowing and
stagnation of blood
flow
WBC’s fall out of
the central column
Tumble slowly and
roll along the
endothelium of
venules
PAVEMENTING -
endothelium appears
to be essentially lined
by white cells
 Adhesion and Emigration

Prerequisite for cells to get to site of inflammation

through endothelium.
Leukocyte-Endothelial interaction –important
Leukocyte aggregation – WBC stick to endothelium
and to each other.
Adhesion molecules
- molecular surface of WBC’s and endothelium.
- Bind together to allow WBC’s to adhere.
Sequential involvement of
adhesion molecules
Rolling  Adhesion  Transmigration

Central Axial Stream

SELECTINS (E&P) INTEGRINS & Ig-LIKE MOLECULES (ICAM, VCAM)

Qualitative and Quantitative Endothelial and PMN Changes

 EMIGRATION

Process by which
leukocytes escape
from their location
in the blood to reach
the perivascular
tissues, (sometimes
referred to as
Diapedesis…)
 Emigration - Process

1. After adhesion - leukocytes

move along the endothelial surface
2. Insert large cytoplasmic
extension pseudopodia into
endothelial gaps
3. Gaps created by actions of
histamine and other chemical
mediators as well as by the
leukocytes themselves
4. PECAM – adhesion molecule is
important in this process
5. Entire cell passes through once
pseudopodia are through
6. Collagenase excreted -
breakdown basement membrane
 Transmigration

Location: postcapillary
venule because:
-Adequate number of inter-
endothelial gaps
-Adequate number of
histamine receptors
Time: with Mild Inflam
-Neutrophils peak 4-6 hours
-Mononuclear cells peak 18-
24 hours-emigration begins
when PMN’s decrease and
lasts longer
 SEQUENCE OF LEUKOCYTE EVENTS

Margination
Pavementing
Emigration
Chemotaxis
Phagocytosis and
Synthesis of
biochemical Mediators
Intracellular
Degradation
Extracellular Release of
Leukocyte Products
 Regulation
of Leucocyte
Recruitment

Binding of
chemical
agents to
specific
receptors of
leukocyte cell
membranes
stimulates a
variety of
events
including
chemotaxis
 Chemotaxis
Chemotaxis: Directional migration in response
to a chemical gradient of chemoattractant.It is a
dynamic and energy dependent activity –
-process is receptor mediated.
-implies directed locomotion

Chemotaxins and Chemokines:

- mediators which make leukocytes travel
- chemoattractants
 Mechanisms of Chemotaxis

Leukocytes crawl - require

adhesive surface
Undergo morphological
shape changes
- Release of calcium
Migrate towards the
highest concentration of
chemoattractant
(Adherence, secretion and
locomotion)
Inflammation
Chemotaxis

Exogenous mediators, e.g.:

a- N-formyl methionine terminal amino acids
from bacteria
b- Lipids from destroyed or damaged
membranes (including LPS)
Endogenous mediators, e.g.:
a- Complement proteins (C5a)
b- Chemokines, particularly IL-8
c-Arachidonic acid products (LTB4)
 LEUKOCYTES
- CHEMOATTRACTANTS
Plasma-derived
- C5a, C5a des-Arg
- Fibrin degradation products
Inflammatory Cell derived
- LTB4, HETE’s - from arachidonic acid metabolism
- PAF, cytokines – IL-8
Others
- Bacterial - fMLP-like peptides, lipid products
- Dead cells – necrotaxis
Chemokines
-Small proteins divided into families.
- A form of cytokine.
Inflammation
Inflammatory Cell Activation
PMNs are activated by many
substances:

The Fc portion of IgM and IgG

molecules
C5a, C3b, and iC3b
Leukotriene B4
Cytokines (TNF-α)
Formylated chemotactic peptides
derived from bacteria
Inflammation
Activation of Inflammatory Cells
Macrophages are activated by many
substances:
Lipopolysaccharide (LPS), found in
Gram-negative bacteria
Platelet activating factor (PAF)
Cytokines produced by T-cells,
particularly interferon gamma (IFN-γ)
Fibronectin, a component of
extracellular matrix
PHAGOCYTOSIS AND INTRACELLULAR
DEGRADATION

Purpose- engulf, kill

and degrade
bacteria
Recognise the
enemy
Engulf it
Fuse with enzymes
Recognition and attachment
of bacteria
Best when coated
with opsonins
- bind to specific
receptors
- phagocytosis
Important Opsonins
i. Antibody (Fc
fragment)
ii. Fibronectin
iii. C3b
 Engulfment
- Small cytoplasmic
extensions or
pseudopods extended
by cell
- Flow around the
attached particle until
it is engulfed
- Cytoplasmic
processes pinch
together, meet, and
fuse - Form a
phagosome
Phagolysosome formation
Fusion of lysosomal
granules with
phagosome
Degranulation of
lysosomes into
phagosome
Cellular mechanisms
similar to that of
chemotaxis
 Intracellular killing and
degradation

Two categories of bactericidal

mechanisms are recognized
1) Oxygen-dependent
2) Oxygen-independent
 Oxygen-dependent mechanism
Respiratory burst of phagocytosis

1. 2-3 x O2 consumption

2. superoxide anion generation (02-)

3. H202 production

4. Glucose metabolism
via hexose monophosphate shunt
 The Killers

H2O2 – Myeloperoxidase-Halide system

Myeloperoxidase-dependent killing
H2O2 + Cl HOCL

Myeloperoxidase
Haber-Weiss reaction
O2 + H2O2 iron HO + OH + O2
- Hydroxyl ion Fe++

Nitric Oxide
- Peroxynitrite
 Oxygen Independent Mechanisms
Substances within granules
Lysozyme
- attacks bacterial cell walls
- especially gram + bacteria
Bacterial permeability increasing protein
(BPI)
- activates phospholipase degrades cell
membranes
Lactoferrin
- Iron binding glycoprotein
Defensins
- Cytotoxic to microbes and certain
mammalian
 Oxygen Independent
Mechanisms
others
Nramp1 protein
- (natural resistance-associated macrophage
protein one)
Major basic protein
- Cationic protein of eosinophils
- Limited bactericidal activity
- Cytotoxic to many parasites
Cathepsin G
- Antimicrobial properties
Lysosomal enzymes
 Degradation:

pH of the phagolysosome drops

(ph 4-5) after phagocytosis
This is the optimal pH for the action of
degradative enzymes within
lysosomes.
 Tissue Damage Resulting
During Phagocytosis
3 basic mechanisms whereby phagocytic cells
release their potent chemical and release tissue at
sites of inflammation and thereby contribute to
inflammation:
- Lysosomal Suicide
-Regurgitation during feeding
-Reverse endocytosis (frustrated phagocytosis)
Important Tissue Toxins
1. Lysosomal enzymes
2. Oxygen-derived active metabolites
3. Products of arachidonic acid metabolism
(prostaglandins and leukotrienes)
Lysosomal Suicide - Cytotoxic release
1. Pathogenic bacteria
overwhelms the
leukocyte
-Phagolysosome may
rupture into the
cytoplasm thus
releasing lysosomal
enzymes -Kill cell
2. Leukocyte dies •
-Releases lysosomal
enzymes into local
environment •
-Producing exudate
seen in inflammatory
conditions
 Regurgitation during
feeding

-Fusion of lysosome
occurs before
phagosome is closed
-Lysosomal contents
released to
environment
-Producing enzymatic
damage to host tissues
 Reverse endocytosis (frustrated
phagocytosis)

Phagocytic stimuli too

large to be internalized
-eg: bacteria on a fibrin
meshwork
-eg: complexes of antigen
antibody fixed against a
basement membrane
-eg; immune complexes
on joint surface
Can not form a phagosome
Discharge of lysosomal
contents (In frustration!)
Termination of the acute inflammatory
response
· Mediators have short half lives
· Mediators are degraded after release
· Produced in short bursts when stimulus
persists
· Switch to anti-inflammatory lipoxins from
arachidonic acid
· Production of anti-inflammatory cytokines
(TGF-•)
· Inhibit the production of TNF in
macrophages
 Survival of Phagocytosed
Microorganisms
Most bacteria are killed following phagocytosis.
some survive - either due to a disorder of the
host’s defense system – or due to their own
specialized protective mechanisms.
Organisms survive within phagolysosome
- eg. Coxiella burnetti, some
Mycobacterium
Some escape phagolysosome and grow in
cytoplasm
- Eg. Listeria, Rickettsiae
Some don’t allow lysosome to fuse with
phagosome
- Eg. Toxoplasma gondii
- Mycobacterium tuberculosis
Inflammation

Defects in Phagocytosis
Congenital:
1. Chediak-Higashi Syndrome (autosomal recessive)
Defective intracellular transport protein, inability to lyse
bacteria
2. Job Syndrome (Hyper IgE)
3. Chronic granulomatous disease (x-linked)
Neutrophils incapable of producing H2O2 during
phagocytosis - No oxidative burst
- Results in recurrent infections.
4. Myeloperoxidase deficiency
Inflammation

Defects in Phagocytosis
Acquired:
• Iatrogenic immunosuppression (most
common)
• Overwhelming infections
• Severe trauma or burn
• Diabetes mellitus
• Chronic debilitating disease
 Acute
inflammation
Time 4-6 hours to
3-5 days
Vascular
involvement
Active hyperemia
Edema, occ.fibrin
thrombi
Neutrophils
Cardinal signs of
inflammation
Lymphatics
Role to remove
exudate
Can lead to
inflammation.
Lymphangitis
The series of events in
the process of
inflammation in organs
are:
Vasodilation: leads to
greater blood flow to the
area of inflammation,
resulting in redness and
heat.
Vascular permeability:
endothelial cells become
"leaky" from either direct
endothelial cell injury or
via chemical mediators.
Exudation: fluid,
proteins, red blood cells,
and white blood cells
escape from the
intravascular space as a
result of increased
osmotic pressure
extravascularly and
increased hydrostatic
pressure intravascularly
here PMN's that are
marginated along the
dilated venule wall
(arrow) by process of
diapedesis spill out into
extravascular space.
FUNCTION OF THE LOCAL EVENTS OF
INFLAMMATION

Move defense mechanisms from vascular system

out to tissues
Results in several basic mechanisms activated at
once
1. Increased vascular permeability
2. Leukocyte production
3. Chemotaxis and phagocytosis
4. Coagulation
5. Neovascularization
6. Fibrinolysis
7. Fibroplasia and repair