Transcript Inflammatory Response

Biology of Disease CH0576
The Inflammatory Response I
Dr Stephen Todryk
Inflammation:
•Painful
•Unsightly
•Essential process
•Response to a foreign object or to damage
Major cells
Neutrophil
50-70%
(5000/mm3)
Eosinophil
1-3%
Basophil
<1%
polymorphonuclear
Major cells
Monocyte
1-6%
macrophage
mast cell (tissue)
platelets
Inflammation - Introduction
• Inflammation is the local physiological tissue
response to injury, cell death, infection and is
classified according to duration
Acute inflammation:- Initial and often transient
response. Short-lived.
Chronic Inflammation:- Subsequent and often
prolonged response that follows acute stages.
Associated with / cause:
cancer, atherosclerosis, asthma, psoriasis, arthritis
Inflammation - Introduction
• Inflammation is a reaction to trauma e.g.the
invasion of microorganisms through the skin
or through the epithelial layers of the
respiratory, digestive, or urinary system
• characterized by four signs:
Acute Inflammation
•
The ‘cardinal signs’ of inflammation were first
described some 2000 years ago by the Roman
Physician Celcus.
•Calor = Heat
•Rubor = Redness
•Tumor = Swelling
•Dolor = Pain
Table 4.
Cardinal Signs
English
Greek/Latin
Caused By
Redness
Rubor
Hyperemia
Warmth
Calor
Hyperemia
Increased
Swelling
Tumor
permeability
Pain
Dolor
Low pH
Loss of
Functio laesa Pain, swelling
function
These normally give rise to a fifth: loss of function
Inflammation
•Usually localised,
but can get whole body effects
•Multiple injuries
•Systemic infection
•Multiple organ failure
Causes of Acute Inflammation
The causes of acute inflammation are
1. Physical agents (physical trauma, radiation, burns).
2. Chemical agents (corrosive chemicals).
3. Immunological mechanisms (hypersensitivity
reactions - certain allergies).
4. Tissue necrosis (death of tissue from lack of
nutrients or oxygen due to lack of blood flow –
INFARCTION).
5. Microbial Infections (viruses, bacteria, fungi and
parasites)
Acute Bronchitis
Medlineplus, National Library of Medicine, U.S.A.
Inflammatory Response
• Inflammatory response The body's reaction
to trauma
• includes an increase in blood flow to the
affected area (controlled by “chemicals”)
• release of “chemicals” to attract white blood
cells (Neutrophils)
• an increased flow of plasma
• the arrival of monocytes to clean up the
debris.
Functions of Acute Inflammation
The acute inflammatory response is relatively
non-specific (primitive program; innate) and has
three main functions:
1. Damaged tissue is broken down and dead
cells and debris are removed from the site.
2. If an infective agent is present (bacteria) it
can be destroyed and eliminated
3. Allows the immune response (cells and molecules)
access to the damaged site. Focusing the immune
response.
Effects of Acute Inflammation
BENEFICIAL EFFECTS:
1. Dilutes toxins
2. Allows entry of antibodies to site of inflammation
3. Delivers nutrients and oxygen to site of inflammation
(essential for cells such as neutrophils which
have a high metabolic activity)
Effects of Acute Inflammation
• BENEFICIAL EFFECTS :
• 4. Fibrin formation (Exuded fibrinogen, clot, may
impede the movement of microorganisms, limiting
their spread; facilitating phagocytosis)
• 5. Stimulation of the immune response
(Drainage of fluid exudate to the lymphatics
allows antigens to reach the local lymph nodes)
• 6. Promotes repair and healing
Acute Inflammation
Effects of Acute Inflammation
HARMFUL EFFECTS:
1. Release of lysosomal enzymes by inflammatory
cells can digest normal tissues (collagenases
and proteases) as well as damaged tissue
2. Swelling of acutely inflamed tissue may be harmful
e.g. Swelling of the epiglottis due to Haemophilus
influenzae infection may obstruct airway and cause
death. In Acute Meningitis inflammatory swelling is
especially serious as it may impair blood flow to
brain
3. Inappropriate inflammatory responses.
(Type I hypersensitivity reactions to harmless antigen
- allergy)
Inflammatory Response
The inflammatory response consists of:
a) Vasodilation - causing increased blood flow
(hyperaemia)
b) Increased vascular permeability - causing
vessels to become leaky
c) Leakage of plasma from blood to tissues
(fluid exudate)
d) Emigration of inflammatory cells (mostly
neutrophils) from blood to tissues
(cellular exudate)
Steps in the Inflammatory Response
Steps involved in the acute inflammatory response
a) Small blood vessels adjacent to the area
of tissue damage become dilated with
increased blood flow which then slows down
b) Endothelial cells swell and partially retract
so they no longer form a completely intact
internal lining.
Steps in Inflammatory Response
c) The vessels become leaky, allowing the passage
of water, salts and some small plasma proteins
into the damaged area (EXUDATION)
d) Circulating neutrophils adhere to swollen
endothelial cells (MARGINATION) then migrate
through the vessel basement membrane
(EMIGRATION) passing into area of tissue damage
e) Small numbers of macrophages and lymphocytes
migrate in a similar way as do neutrophils.
Chemical Mediators in Acute Inflammation
Vascular response to injury is mediated by a
wide range of soluble mediators generated at the
site of tissue injury
PHASE
Vascular Dilation
CHEMICAL MEDIATOR
Histamine, Prostoglandins,
Complement components: C3a and C5a.
Increased vascular
permeability
Histamine, Kinins, Prostaglandins.
Emigration of
leukocytes
C5a, leukotrienes, IL-8, cationic proteins
of neutrophils.
Fluid Movement Across Capillaries
• Under physiological conditions there is a continuous
movement of fluid between capillaries and
extravascular tissues.
• The movement of fluid is dependent upon differential
pressure gradients across the vessel wall.
• The high colloid osmotic pressure inside the vessel
(due to plasma proteins) favours fluid return to the
vessel.
• Normally there is fluid movement OUT of capillary
at arteriolar end and INTO it at the venous end.
Non-inflammatory Oedema
• In certain circumstances fluid can move into the tissues
at a greater rate than it can be removed.
• This results in OEDEMA e.g. pulmonary oedema due to
left ventricular cardiac failure.
Non-inflammatory Oedema
• Obstruction to lymphatic
drainage from a
particular site can also
result in oedema –
LYMPHODEMA –
following surgery, in
tumour metastasis or
elephantiasis due to
parasitic worm infection
e.g. filiarisis
Inflammatory Oedema
• Oedema which occurs due to increased vascular
permeability following tisssue injury.
• Various vasoactive mediators originating from
plasma and cellular sources, also from injured
cells, are generated at the site of tissue injury.
• Their main site of action is at the post capillary
venule
Inflammatory Oedema
• The mediators induce changes in endothelial cell
wall of vessels, altering its permeability
• Binding of vasoactive mediators to their specific
receptors on endothelial cells results in endothelial
cell retraction and formation of gaps
• The integrity of the endothelial cell layer is lost.
• Endothelial cell retraction and gap formation are
reversible processes
Inflammatory Oedema
Experimental studies have shown three
patterns of oedema which occur at different
times following injury:
1. IMMEDATE - This is transient and lasts
for 30-60 minutes after injury and is mediated
by HISTAMINE acting on endothelium.
Inflammatory Oedema
• 2. DELAYED - starts 2-3 hours after injury and
lasts for up to 8 hours. This is mediated by
factors synthesised by local cells e.g.
BRADYKININ, Complement breakdown
products and factors released by dead
neutrophils
• 3. An immediate response that is prolonged for
over 24 hours and is seen if there has been
severe direct injury to the endothelium e.g. by
burns or caustic chemicals.
Mediators of Increased Vascular
Permeability
• The primary sources of these mediators are
either plasma or various cells types
e.g. Platelets, Tissue mast cells, Basophils,
Polymorphonuclear Leucocytes (neutrophils),
Endothelial cells, Monocytes and macrophages
and injured cells themselves
Mediators of Increased Vascular
Permeability
• Plasma derived factors are mostly precursor
proteins or zymogens, activated by proteolytic
enzymes.
• Once activated they generally have
a short half life.
• They are rapidly inactivated
in tissues by a variety of systems.
Cellular Mediators
The mediators of increased vascular permeability
released by cells are either preformed and stored
within the cell as cytoplasmic granules,
e.g. HISTAMINE, SERATONIN, LYSOSOMAL
HYDROLASES
or are derived from the metabolism of phospholipids
and arachidonic acid e.g. PROSTAGLANDINS,
PLATELET ACTIVATING FACTOR (PAF),
LEUKOTRIENES and THROMBOXANES
Outcomes of Acute Inflammation
• Foreign and/or infectious agents removed
and debris
• Damaged area regrows and trauma resolved
• Scar (collagenous) formed
• Formation of abscess
• Chronic inflammation
Time for a break…….
Glossary
• Post capillary venule: Arteries bringing blood from
heart divide into smaller arterioles which then divide
into capillaries when they enter tissue. Capillaries
exchange substances with tissue then reunite into
small veins – venules
•
zymogen (or proenzyme): The inactive or nearly
inactive precursor of an enzyme, converted into an
active enzyme by proteolysis
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