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Mediators of
Inflammation.
Lymphocyte
Recirculation.
What is inflammation?
In Latin: inflammare (to set on fire).
It is body defence reaction in order to eliminate or limit the
spread of injurious agent as well as to remove necrotic cells
and tissues. Initiates the proces of repair
Also a potentially harmful process. Components of
inflammation that are capable of destroying microbes can
also injury normal tissue
Inflammation is
normally
controlled and
self-limited
Types of Inflammation
Heat
Redness
Swelling
Pain
Loss of Function
The local reactions are described as the cardinal signs and symptoms of
inflammation
Vascular changes
o vasoconstriction (momentary constriction of small blood vessels in the
area) to decrease blood flow (very brief - first seconds after tissue injury).
Leukocyte extravasation
Leukocytes must be able to get to the site of injury
from their usual location in the blood
The process of leukocyte movement from the blood
to the tissues through the blood vessels is known as
extravasation.
E-selectin is also
responsible for slow
rolling interactions below
5mm/s and possibly the
initiation of adhesion.
3. Transmigration (diapedesis)
Migration across the endothelium
Occurs after adhesion within system of venules and capillaries via
PECAM-1 (CD31) (platelet endothelial cell adhesion molecule) on
endothelial cells, neutrophils, monocytes/macrophages,
lymphocytes
Mediators of Inflammation
Derive from cells or plasma proteins
Cell-derived stored in granules and can be rapidly
secreted by exocytosis or synthesized de novo
Plasma-derived produced in liver and present in
blood as inactive precursors
Active mediators can be produced in response to
stimuli
One mediator can stimulate release of other mediator
Vary in range of cellular targets
Short-lived
Cell-derived Mediators
Mediator
Sources
Actions
Histamine
Mast cells,
basophils, platelets
Vasodilation,
vascular
permeability,
endothelial
activation
Serotonin
platelets
Vasodilation,
vascular
permeability
Prostaglandins
Mast cells,
leukocytes
Vasodilation, pain,
fever
Leukotriens
Mast cells,
leukocytes
vascular
permeability,
chemotaxis,
leukocyte adhesion
and activation
Platelet-activating
neutrophils,
Vasodilation,
Inflammatory Mediators
Platelet-activating factor (PAF)
It is generated from a lipid complex stored in cell
membranes;
It affects a variety of cell types and induces platelet
aggregation;
It activates neutrophils and is a potent eosinophil
chemoattractant;
It contributes to extravascularization of plasma proteins
and so, to edema.
Cell-derived Mediators
Mediator
Sources
Actions
Reactive oxygen
species
leukocytes
Killing of microbes,
tissue damage
Nitric oxide
Endothelium,
macrophages
Vascular smooth
muscle relaxation,
killing of microbes
Macrophages,
endothelium, mast
cells
Endothelial
activation, fever,
pain, anorexia,
hypotension,
vascular resistance
(shock)
Chemokines
Leukocytes,
macrophages
Chemotaxis,
leukocyte
activation
Plasma protein-derived
mediators
Mediator
Source
Actions
Complement
products (C5a,
C3a, C4a)
Plasma (produced in
liver)
Leukocyte
chemotaxis and
activation,
vasodilation
vascular
permeability,
smooth muscle
contraction,
vasodilation, pain
Proteases
activated during
coagulation
Endothelial
activation,
leukocyte
recruitment
Plasma (produced in
liver)
Mediators of Inflammation
Role of mediators in
inflammation
Role in Inflammation
Mediators
Vasodilation
vascular permeability
Fever
Pain
Prostaglandins, bradykinin
Tissue damage
Short term
friend, Long
term foe
Types of Inflammation
It is rapid response to injury or microbes and other foreign
substances that is designed to deliver leukocytes and plasma
proteins to sites of injury
1. Acute Inflammation
2. Chronic Inflammation
It is inflammation of prolonged duration (week to months to
years) in which active inflammation, tissue injury and healing
proceed simultaneously
Acute inflammation
Chronic inflammation
Duration of corse
Short [days]
Causative agents
Cardinal signs
Fundamental cells
Neutrophils
macrophages
Fluid Exudation
and Edema
Present
Absent
Fibrosis
Absent
Present
Present
Primary Mediators
Serotonin; Histamine;
prostaglandins; tromboxane
Chronic inflammation
1. Infiltration of mononuclear
phagocyting cells
a. Macrophages /circulate as monocytes
and reach site of injury within 24-48
hours and transform. Activated by
numerous cytokines from the injured site/
b. T and B cells /Recruited and activated by
APC like macrophages and DC/
c. B cells will be become plasma cells and
produce antibodies
d. T cells will produce cytokines to activated
the B cells and also macrophages
2. Tissue destruction (due to massive
production of ROS, hydrolytic enzymes)
3. Tissue repair (Angiogenesis at the injured
sites. Formation of granulomas. Fibrosis)
Lymphocyte recirculation
Lymphocyte extravasation is similar to neutrophil extravasation,
Lymphocytes continuously travel from the blood to secondary lymphoid
tissues and then return to the blood.
Lymphocytes leave blood via high endothelial venules (HEVs) (HEVs need to allow egress of naive cells from the circulation)
Lymphocyte trafficking exposes antigen to a large number of
lymphocytes
Naive T cells:
Express chemokine receptors CCR7 and CXCR4 which allow them to
respond to chemokines (CCL21) expressed in lymphoid tissues;
Respond to chemokines CCL18 and CCL19 produced by dendritic cells,
which is thought to direct them to the appropriate T cell areas of lymph
node where dendritic cells can present antigen to them
B cells:
Express CCR7 and use similar mechanisms to migrate into the lymphoid
tissues.
B cells also express CXCR5, which allows them to respond to CXCL13, a
chemokine produced in lymphoid follicles B cells are therefore directed
to the B cell areas of the node.
Process of inflammation
Inflammatory Mediators
Complement fragments and cytokines
It stimulates chemotaxis of neutrophils, eosinophils and
monocytes;
C3a, C5a increase vascular permeability;
Cytokines
Interleukins (IL-1, IL-6, IL-8)
Stimulates the chemotaxis, degranulation of neutrophils and
their phagocytic activity
Induce extravascularization of granulocytes
Fever
Tumor necrosis factor (TNF) and IL-8
Leukocytosis
Fever
Stimulates prostaglandins production
C5s
IL-8
Inflammatory Mediators
Prostaglandins
Prostaglandins contribute to vasodilation, capillary
permeability, and the pain and fever that accompany
inflammation.
The stable prostaglandins (PGE1 and PGE2) induce
inflammation and potentiate the effects of histamine and
other inflammatory mediators:
They cause the dilation of precapillary arterioles (edema),
lower the blood pressure, affect the phagocytic activity of
leukocytes.
The prostaglandin thromboxane A2 promotes platelet
aggregation and vasoconstriction.
Inflammatory Mediators
Leukotrienes
The leukotrienes have been reported to affect the
permeability of the postcapillary venules, the adhesion
properties of endothelial cells, and stimulates the
chemotaxis and extravascularization of neutrophils,
eosinophils, and monocytes.
Inflammatory Mediators
Histamine
It is found in high concentration in platelets,
basophils, and mast cells.
Causes dilation and increased permeability of
capillaries (it causes dilatation of precapillary
arterioles, contraction of endothelial cells and
dilation of postcapillary venules).
Inflammatory Mediators
Platelet-activating factor (PAF)
It is generated from a lipid complex stored in cell
membranes;
It affects a variety of cell types and induces platelet
aggregation;
It activates neutrophils and is a potent eosinophil
chemoattractant;
It contributes to extravascularization of plasma proteins
and so, to edema.
Inflammatory Mediators
Plasma Proteases
The plasma proteases consist of:
Kinins
Bradykinin - causes increased capillary permeability
(implicated in hyperthermia and redness) and pain;
Clotting factors
The clotting system contributes to the vascular
phase of inflammation, mainly through fibrin
peptides that are formed during the final steps of the
clotting process.
Inflammation-induced lymphocyte
recirculation
During the initiation of an adaptive immune response, a
large number of naive lymphocytes are recruited
specifically to the LNs draining the site of immunization
or infection.
This process facilitates the search of rare antigen
specific lymphocytes by increasing the efficiency of
screening cognate lymphocytes within the secondary
lymphoid organs.
Increased input of naive lymphocytes to the LN is in part
mediated by a rapid increase in the number of HEVs.