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Acute Inflammation

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 involves 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
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
Hypersensitivity reactions –
parasites, TB
Physical agents – trauma, radiation,
heat, cold
Chemicals – corrosives,bacterial
toxins
Tissue necrosis - infarction
ACUTE INFLAMMATION
Cardinal Signs
Redness (rubor)
Swelling (tumor)
Heat (calor)
Pain (dolor)
Loss of function
(functio laesa)
Phases of Acute Inflammation
1- Initiation:
1- Stimulation (injury) with changes in microvasculature
2- Structural changes leading to fluid extravasation
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
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

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 –

few cells-

specific gravity <1.012)

Hydrostatic Oncotic

pressure pressure
Inflammation
Increased Vascular Permeability
EDEMA -EXUDATE
(protein content high:
numerous neutrophils:
specific gravity >1.020)

Hydrostatic Oncotic

pressure pressure
Diapedesis
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 new capillaries
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
SEQUENCE OF LEUKOCYTE EVENTS

Margination
Pavementing
Emigration
Chemotaxis
Phagocytosis and
Synthesis of
biochemical Mediators
Intracellular
Degradation
Extracellular Release of
Leukocyte Products
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
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
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)
Tissue
injury
Vasoactive Production of  Chemotactic
mediators inflammatory  factors (eg. c5a)
(eg. histamine) mediators

Recruitment of inflammatory 
cells
Increased vascular
permeability Acute   Chronic 
inflammation inflammation

Edema PMNs Monos


CHEMICAL MEDIATORS OF
INFLAMMATION
· Production of active mediators is triggered
by microbial products or host proteins.
· Most require binding to specific receptors
on target cells for biologic activity.
· Some have direct enzymatic activity,
· One mediator can stimulate the release of
other mediators by target cells- amplification
· May have different affects on different cells.
· Most are short lived.
· Many have the potential to be harmful.
CHEMICAL MEDIATORS OF
INFLAMMATION
General Principles:
Originate from plasma and cells.

When in plasma are found in inactive


state and must be activated.
When in cells are often within granules
and are synthesized in response to a
stimulus.
Inflammation
Chemical Mediators of
Inflammation
Plasma mediators Cellular mediators
1. Complement system Preformed
2. Kinin system 2. Vasoactive amines
3. Coagulation and 3. Proteases – lysosomal
fibrinolytic pathway constituents
Newly synthesized
5. Arachidonic acid
metabolites
6. Platelet activating factor
7. Cytokines
8. Nitric oxide
9. Oxygen-derived free
radicals
1 - Plasma Factors
Four enzymatic cascade and interrelated
systems, important in the
inflammatory response are found
within plasma. These systems include
the
1. complement,
2. kinins
3. coagulation and system
Inflammation
2 - Chemical Mediators released from
Cells
Vasoactive amines
2.1- Histamine
 Found in mast cells, basophils and platelets
 Released in response to stimuli
 Promotes arteriolar dilation and venular
endothelial contraction
 results in widening of interendothelial cell
junctions with increased vascular permeability
2.2- Serotonin
Vasoactive effects similar to histamine
Found in platelets
Inflammation
Chemical Mediators released from Cells
The following agents can stimulate
release of histamine from mast cells:
* Physical injury, mechanical trauma, heat,
chemical agents, Snake venoms, toxins, bile
salts, ATP
* Immune reactions involving binding of
antibodies to mast cells
* Fragments of complement called
anaphylatoxins (C3a and C5a)
* Histamine-releasing factors from
neutrophils, monocytes, and platelets
* Cytokines (interleukin-1, IL-8)
Inflammation
Chemical Mediators released from
Cells
2.3 - Arachidonic acid metabolites
These lipid mediators are short-
range hormones -formed rapidly
- exert their effects locally and
are then inactivated.
Synthesized from cell membrane
phospholipids through the
action of phospho-lipases
(inhibited by corticosteroids)
Form leukotrienes via 5-
lipoxygenase
Form prostaglandins and
thromboxane A2 via cyclo-
oxygenase (COX-1 inhibited by
aspirin and indomethacin )
Inflammation
Chemical Mediators released from
Cells
2.4 - Platelet activating factor
-Produced by a variety of cells, including
platelets, basophils, mast cells,
neutrophils, monocytes,macrophages
and endothelial cells
* Platelet aggregation and release
* Vasodilation and increased vascular
permeability (100-10,000 X histamine)
* Increased leukocyte adhesion to
endothelium
Morphology and function of inflammatory cells
Inflammation
Inflammatory Cell Activation
Polymorphonuclear cells 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
Best when coated with
opsonins
Important Opsonins
i. Antibody (Fc
fragment)
ii. Fibronectin
iii. C3b
Engulfment Phagolysosome
formation
- 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
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
H2O2 – Myeloperoxidase-Halide system
Nitric Oxide - Peroxynitrite
Haber-Weiss reaction - Hydroxyl ion

2) Oxygen-independent
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
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
Inflammation - Systemic
• Fever - clinical Manifestations
hallmark of inflammation
- Endogenous pyrogens: IL-2 ,TNF-α
• Constitutional symptoms - malaise, anorexia,nausea
• Weight loss - due to negative nitrogen balance
• Hyperplasia of mononuclear phagocyte system
• Leukocytosis - may be neutrophils, eosinophils, or
lymphocytes
• Anemia –blood loss,chronic due to toxic depression of
bone marrow
• Acute Phase Reactants - non-specific elevation of
many serum proteins
• marked increase in ESR
• Amyloidosis – longstanding chronic infection
Inflammation
Systemic Manifestations
Leukocytosis: most bacterial infection
Lymphocytosis: Infectious mononucleosis,
mumps,
German measles
Eosinophilia: bronchial asthma,
hay fever,
parasitic infestations
Leukopenia: typhoid fever,
infection with
rickettsiae/protozoa
Systemic effects of Inflammation

Acute phase Liver


reaction/response -IL-6, IL-1, TNF
- IL-1 and TNF -Acute phase proteins
- Fever C-reactive protein
- Malaise Lipopolysaccharide
binding protein
- Anorexia Serum amyloid A
Bone marrow a-2 macroglobulin
- leukocytosis Haptoglobin
- IL-1 + TNF Ceruloplasmin
fibrinogen
Lymphoid organs
 Suppuration-
Abscess
formation

 Persistent
inflammation
(chronic
inflammation)

 Organisation-
scar formation
Resolution
Means complete restoration of the tissues to normal
Favouring factors
Minimal cell death and tissue damage
Occurrence in an organ or tissue which has
regenerative capacity (eg the liver) rather than in one
which cannot regenerate (eg. the central nervous
system)
Rapid destruction of the causal agent
(eg. phagocytosis of bacteria)
Rapid removal of fluid and debris by good local
vascular drainage

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