INFLAMMATION

Inflammation – an overview
• The response of living tissues to injury
– The goal of the inflammatory reaction is to bring
leukocytes and plasma proteins normally circulating in
blood to the site of infection or tissue damage, eliminate
the causative agent and initiate healing

• Is it harmful or beneficial?
– Generally beneficial - essential for survival
– If very severe or if unable to eradicate causative agent or
if inappropriately directed (eg against host)
inflammatory reaction may cause damage
 Types of inflammation
• Classified as chronic or acute BUT some overlap exists

Feature Acute Chronic

Onset Fast: minutes or hours Slow: days, months or years

Cells involved Mainly neutrophils Monocytes/macrophages,

lymphocytes
Tissue injury, fibrosis Mild, self limited Often severe, progressive

Local and systemic signs Prominent Less prominent

 A common inflammatory condition

• Skin furuncle (boil) – inflammation of the skin

caused by Staphylococcus
Cardinal signs of inflammation
 Cardinal signs of inflammation
• 4 cardinal signs of Celsus (1st century AD)
– Rubor (redness)
• Increased blood flow
– Calor (heat)
• Increased blood flow
– Tumor (swelling)
• Leakage of cells and fluid into tissues
– Dolor (pain)
• Increased nerve sensitivity due to chemical mediators

• 5th sign added by Virchow (19th century)

– Function laesa (loss function)
 Causes of inflammation
• Infective agents
– bacteria, viruses, parasites

• Foreign bodies
– dirt, splinters, suture material, implants

• Immune reactions
– allergic, hypersensitivity & autoimmune reactions

• Tissue necrosis (death)

– multiple causes

• Physical agents
– trauma, heat,
cold,
irradiation

• Chemical
 The inflammatory process
• Offending agent is recognized by
host cells and molecules which then
produce chemical mediators
• Leukocytes and plasma proteins are
recruited from the circulation to the
site where the offending agent is
located
• Leukocytes and proteins are
activated to destroy and eliminate
the offending substance
• The reaction is controlled and
terminated
• The damaged tissue is repaired
 Inflammatory responses: two components
• Vascular changes that maximize movement of proteins and
leukocytes from circulation to site of infection/injury
– Vasodilation - changes in calibre of vessels
– Changes in blood flow (increased at first, later slows)
– Changes in permeability (leakage of fluid and protein)

• Cellular events that recruit leukocytes to site of

infection/injury and allow them to effect a response
– Leukocyte migration through endothelium (emigration)
– Migration of leukocytes to site of injury (chemotaxis)
– Recognition/removal of offending agent by phagocytes
(phagocytosis)
– Other leukocyte responses – initiation of repair process
Normal
Vascular changes
• Vasodilation
– action of mediators (eg histamine) on
vascular smooth muscle
– initial constriction (transient)
– arterioles dilate followed by capillary bed
expansion
– increased blood flow → redness & heat
Inflamed
• Increased permeability
– outpouring of protein rich fluid into the
extravascular tissues – EXUDATE
– swelling (edema)

• Cellular emigration occurs last

 Vascular changes
• Changes to permeability can
occur in two ways

1. Retraction of endothelial cells

– Mediators cause endothelial cell
contraction
– Gaps appear between endothelial
cells

2. Endothelial injury
– Direct damage caused by burns,
microbial toxins

• End result is the same

– Fluid and proteins escape
– small molecules first, fibrinogen
last (cells later)
– ↑ osmotic pressure of tissue
– swelling
Chemical mediators of the vascular response
Mediator Principle Source Actions
Histamine Mast cells, platelets, Vasodilation, ↑ permeability, endothelial
basophils activation
Seretonin Platelets Vasodilation, ↑ permeability
Prostaglandins Mast cells, Dilation (+ pain, fever)

leukocytes
Leukotrienes Mast cells, ↑ permeability

leukocytes
Platelet- Leukocytes, mast Vasodilation, ↑ permeability
activating factor cells
Cytokines TNF, IL-1 Macrophages, EC, Endothelial activation
mast cells (+ pain, fever, metabolic abnormalities)
Complement Plasma protein Vasodilation
(liver)
Kinins Plasma protein Vasodilation, ↑ permeability
(liver) (+ pain)
Proteases activated Plasma proteins Endothelial activation
during coagulation (liver)
 Cellular events
• Leukocytes that are recruited to sites of inflammation perform the key
function of eliminating the offending agents following their activation
• Most important leukocytes in typical inflammatory reactions are the ones
capable of phagocytosis
• Neutrophils
– rapidly recruited to sites of inflammation
– use cytoskeletal rearrangements & enzyme assembly to mount rapid, transient
response

• Macrophages
– slower responders
– ingest and destroy
microbes,
necrotic tissue
and foreign
substances
– produce growth
factors that aid in
repair
 Cellular events – leukocyte emigration
• Infectious microbes that breach the epithelium are
recognised by sub-epithelial dendritic cells and macrophages

• These cells respond by producing cytokines & chemokines

• Cytokines (TNF and IL-1) act on the endothelium of venules

near the site of infection to initiate leukocyte emigration
into tissues

• Chemokines provide signals to leukocytes to help them

traffic to the site of infection once they have migrated into
tissues – this is known as chemotaxis
Cellular events – leukocyte emigration
 Cellular events – leukocyte emigration
• Loose attachment & rolling of leukocytes
– in response to cytokines, endothelial cells upregulate expression of adhesion
molecules called selectins
– selectins bind to surface carbohydrates on leukocytes
– repetitive process of leukocytes becoming tethered to the endothelium, flowing
blood disrupting binding and bonds reforming downstream

• Firm adhesion
– in response to chemokines, integrins expressed on leukocytes assume a high-
affinity state
– endothelial cells upregulate expression of adhesion molecules ICAM-1 and
VCAM-1 that bind to integrins expressed by leukocytes
– firm binding of integrins to their ligands arrests the rolling, cytoskeleton of
leukocytes is reorganised such that they spread out on the endothelial surface

• Leukocyte migration
– chemokines stimulate the motility of leukocytes, as do bacterial products and
products of complement activation
– leukocytes begin to migrate between endothelial cells, through the vessel
wall
Cellular events - chemotaxis
Cellular events - chemotaxis
• Movement of leukocytes
after emigration towards an
increasing concentration of
a chemotactic agent (usually
a protein or polypeptide)

• Both exogenous and

endogenous substances can
act as chemoattractants
– Bacterial products
– Chemokines
– Complement components
(C5a)
Microscopic changes in early inflammation
 Cellular events – leukocyte activation
• Leukocytes require activation in order to perform their many
functions

• Both neutrophils and macrophages can become activated

• Activation is induced by a variety of chemical mediators

• Following activation, leukocytes are capable of:

– phagocytosis
– lysis/killing of injurious particles
– release of further chemical mediators
Cellular events - phagocytosis
• The process by which neutrophils and
macrophages ingest debris / foreign particles
• 3 phases
1. Recognition and attachment by receptors
on
surface of macrophages
– Mannose receptor binds to mannose, fructose on
bacteria
– Scavenger receptors
– Opsonins (IgG/C3/some lectins)

2. Engulfment
– Pseudopods form around organism
– Foreign material incorporated within cell vacuole
(phagosome)
– Fusion with lysosomes and release of lysosomal
contents

3. Killing and degradation

Cellular events - phagocytosis
 Sequelae of phagocytosis
• Neutrophil (lives 1-2 days)
years)
• Lysosomal enzymes discharged
into vacuole
• Oxidising agents may kill or digest
bacteria
• Neutrophil degranulates
released
enzymes may cause injury
• Virulent bacteria may resist killing
• Bacteria liberated as cell dies and
can cause further damage
• Macrophage (lives months-
• Successful kill may be accomplished
• If bacteria persist may remain at site
or move via lymphatics to other areas
• All debris including dead polymorphs
gradually removed
• Antigenic material presented to
immune system
• Release of enzymes, oxidising agents
into tissues can cause ongoing
damage eg rheumatoid disease
 Chemical mediators of the cellular response
Mediator Principle Source Actions
Leukotrienes Mast cells, leukocytes Chemotaxis, leukocyte adhesion & activation

PAF Mast cells, leukocytes Leukocyte adhesion, chemotaxis, degranulation,

oxidative burst
Cytokines MP, EC, Mast cells Endothelial activation (expression of adhesion
molecules)
Nitric oxide Endothelium, MP Killing of microbes

Reactive O2 sp. Leukocytes Killing of microbes

Chemokines Leukocytes,active MP Chemotaxis, leukocyte activation

Complement Plasma (liver) Leukocyte chemotaxis & activation

Proteases Plasma (liver) Endothelial activation, WBC recruitment

MP – macrophages, EC – endothelial cells

Summary of vascular and cellular events
 Outcomes of acute inflammation
• Ideal outcome: the harmful agent will be
removed or killed and the damaged tissue
will return to nomal = RESOLUTION

• Other outcomes are possible – next

lecture
 Resolution
• Restoration of tissue to a completely normal state after
acute inflammation or other tissue damage or death

• Most likely to occur:

– when cell death and tissue damage is minimal
– when damaged cells are capable of regeneration
– when causative organism is rapidly eliminated
– where local conditions favour removal of exudate
 The process of resolution
• Fibrin and other proteins
dissolved by fibrinolysin and
enzymes produced by
neutrophils and
macrophages

• Fluid removed in blood

and lymphatic vessels

• Removal of all debris by

phagocytes to lymph nodes

• Blood flow returns to

normal
 Classification of inflammation
1. Acute or chronic
– previously discussed
 Classification of inflammation
1. Acute or chronic
2. According to site
 Classification of inflammation
1. Acute or chronic
2. According to site
3. According to predominant component of exudate
Serous exudate
Fibrinous pericarditis
 Classification of inflammation
1. Acute or chronic
2. According to site
3. According to predominant component of exudate
4. According to morphology – shape & anatomy
Gastric Ulcer