MEDIATORS OF INFLAMMATION

MEDIATORS OF INFLAMMATION

• The substances that initiate and regulate inflammatory

reactions.
• It is worthy of note that this knowledge has been used to
design a large armamentarium of antiinflammatory agents
that are used every day by many people
• The most important mediators of acute
inflammation are vasoactive amines,
lipid products (prostaglandins and
leukotrienes), cytokines (including
chemokines), and products of
complement activation
General properties
Major cell types: Tissue
Macrophage, Dendritic
cells, mast cells
Cell-
derived
mediators Platelets, neutrophils, endothelial
1
cells, and most epithelia also can be
induced to elaborate some of the
SOURCE mediators
Plasma-derived
mediators Mainly produced in liver and
(require can be recruited into tissues
activation)
General properties

STIMULUS In response to molecules that

stimulate inflammation

Microbial products Substance released

from necrotic cells
General properties System of
check and
balance

Quickly decay

3 Inactivated by
Most mediators are enzymes
short-lived

Scavenged

Inhibited
General properties

Action of secondary
mediators = Intial Amplifying
4
One mediator can mediators
stimulate the release of
other mediators Action of secondary
mediators ≠ Initial Counteracting
mediators
 Vasoactive Amines: Histamine and Serotonin
• Two major VA: Histamine and Serotonin
• Important actions on blood vessels (vasoactive)
• Stored as performed molecules in cells
• First mediators to be released during inflammation
HISTAMINE

•The richest sources: mast cells (normally present in the connective

tissue adjacent to blood vessels). Also is found in blood basophils and
platelets.
•Stored in mast cell granules. Released by degranulation in response
to a variety of stimuli.
 Vasoactive Amines: Histamine and Serotonin
HISTAMINE
•Stimuli:
• Physical injury, such as trauma, cold, or heat, by unknown mechanisms;
• Binding of antibodies to mast cells, which underlies immediate hypersensitivity (allergic)
reactions; and
• Products of complement called anaphylatoxins (C3a and C5a).
•Other stimuli: Neuropeptides (e.g., substance P) & cytokines
(IL-1, IL-8).
•Its vasoactive effects are mediated mainly via binding to
receptors (H1) on microvascular endothelial cells.
 Vasoactive Amines: Histamine and Serotonin
HISTAMINE
•Effects:
•Dilation of arterioles and increases the permeability of venules.
•Contraction of some smooth muscles.

• The antihistamine drugs that are commonly used to treat some

inflammatory reactions, such as allergies, are H1 receptor antagonists
that bind to and block the receptor.
 Vasoactive Amines: Histamine and Serotonin
SEROTONIN (5-hydroxytryptamine)
• Source: Platelets and certain neuroendocrine cells, such as in
the gastrointestinal tract, and in mast cells (in rodents but not
humans).
• Its primary function:
• As a neurotransmitter in the gastrointestinal tract.
• Vasoconstrictor
• The importance of this action in inflammation is unclear.
 Arachidonic Acid Metabolites
• Lipid mediators: prostaglandins and leukotrienes
• Produced from arachidonic acid present in membrane Phospholipids
• Stimulate vascular and cellular reactions in acute inflammation

• AA = 20-carbon PUFA that is derived from dietary sources or by

conversion from the essential fatty acid linoleic acid.
• Most cellular AA is esterified & incorporated into membrane
phospholipids.
• Stimuli trigger the release of AA from membranes by activating
cellular phospholipases, mainly phospholipase A2.
• Stimuli: Mechanical,
chemical, and physical
stimuli or other mediators
(e.g., C5a)
• Once freed from the
membrane, AA is rapidly
converted to bioactive
mediators (eicosanoids)
• Eicosanoids are synthesized
by two major classes of
enzymes:
 cyclooxygenases
(generate prostaglandins)
 lipoxygenases (produce
leukotrienes and lipoxins)
Eicosanoids bind to G protein-coupled receptors on many cell types and
can mediate virtually every step of inflammation
 Arachidonic Acid Metabolites
PROSTAGLANDINS

• Source: mast cells, macrophages, endothelial cells, and

many other cell types.
• Involved in the vascular and systemic reactions of
inflammation.
• Generated by the actions of two cyclooxygenases called
COX-1 and COX-2.
 Arachidonic Acid Metabolites
PROSTAGLANDINS
• COX-1:
Constitutively expressed in most tissues, where it may serve a
homeostatic function (e.g., fluid and electrolyte balance in the
kidneys, cytoprotection in the gastrointestinal tract).
• COX-2:
Generates the PGs that are involved in inflammatory reactions, but it
is low or absent in most normal tissues.
 Arachidonic Acid Metabolites
PROSTAGLANDINS

• Named based on structural features coded by a letter (e.g.,

PGD, PGE, PGF, PGG, and PGH) and a subscript numeral (e.g.,
1, 2).
• The most important prostaglandins in inflammation are PGE2,
PGD2, PGF2a, PGI2 (prostacyclin), and TXA2 (thromboxane
A2).
 Arachidonic Acid Metabolites
PROSTAGLANDINS
• PGD2:
• The major prostaglandin made by mast cells;
• Along with PGE2 (which is more widely distributed), it
causes vasodilation and increases the permeability of
postcapillary venules, thus potentiating exudation and
resultant edema.
• Chemoattractant for neutrophils.
 Arachidonic Acid Metabolites
PROSTAGLANDINS
• Prostacyclin (PGI2): a vasodilator
• TXA2: a potent platelet-
& a potent inhibitor of platelet
aggregating agent and
aggregation, and thus serves to
vasoconstrictor, and thus
prevent thrombus formation on
promote thrombosis.
normal endothelial cells.

A thromboxane-prostacyclin imbalance has been implicated in

promotes thrombosis.
 Arachidonic Acid Metabolites
PROSTAGLANDINS

• In addition to their local effects, prostaglandins are involved

in the pathogenesis of two common systemic manifestations
of inflammation  pain and fever.
• PGE2 makes the skin hypersensitive to painful stimuli, and
causes fever during infections.
 Arachidonic Acid Metabolites
LEUKOTRIENES

• Source: leukocytes and mast cells

• Involved in:
• Vascular & smooth muscle reactions
• Leukocyte recruitment.
 Arachidonic Acid Metabolites
LEUKOTRIENES
• The synthesis of leukotrienes
involves multiple steps, the first of
which generates leukotriene A4
(LTA4), which in turn gives rise to
LTB4 or LTC4.
• LTB4:
• Source: neutrophils & some
macrophages,
• A potent chemotactic agent &
activator of neutrophils, causing
aggregation & adhesion of the cells to
venular endothelium, generation of
ROS, & release of lysosomal enzymes.
 Arachidonic Acid Metabolites
LIPOXINS
• Also are generated from AA by the lipoxygenase pathway,
• Suppress inflammation by inhibiting the recruitment of
leukocytes (neutrophil chemotaxis & adhesion to endothel).
• Leukocytes, particularly neutrophils, produce intermediates in
lipoxin synthesis, and these are converted to lipoxins by
platelets interacting with the leukocytes.
 Arachidonic Acid Metabolites
Pharmacologic Inhibitors of Prostaglandins
and Leukotrienes
• COX inhibitors (include aspirin and other NSAIDs, such
as ibuprofen).
• Inhibit both COX-1 and COX-2, block all prostaglandin
synthesis (hence their efficacy in treating pain and
fever); aspirin does this by irreversibly inactivating
COX.
 Arachidonic Acid Metabolites
Pharmacologic Inhibitors of Prostaglandins
and Leukotrienes
• Selective COX-2 inhibitors are 200- to 300-fold more
potent in blocking COX-2 than COX-1 (therapeutic
target), but may increase the risk of cardiovascular and
cerebrovascular events, possibly because it tilt the
balance toward vascular thrombosis.
 Arachidonic Acid Metabolites
Pharmacologic Inhibitors of Prostaglandins
and Leukotrienes
• Lipoxygenase inhibitors. 5-lipoxygenase is not affected
by NSAIDs, and many new inhibitors of this enzyme
pathway have been developed. Pharmacologic agents
that inhibit leukotriene production (e.g., zileuton) are
useful in the treatment of asthma.
 Arachidonic Acid Metabolites
Pharmacologic Inhibitors of Prostaglandins
and Leukotrienes
• Corticosteroids are broad-spectrum anti-inflammatory
agents that reduce the transcription of genes encoding
COX-2, phospholipase A2, proinflammatory cytokines
(e.g., IL-1 and TNF), and iNOS.
 Arachidonic Acid Metabolites
Pharmacologic Inhibitors of Prostaglandins
and Leukotrienes
• Leukotriene receptor antagonists block leukotriene
receptors and prevent the actions of the leukotrienes.
• These drugs (e.g., Montelukast) are useful in the
treatment of asthma.
 Cytokines and Chemokines

• Cytokines are proteins secreted by many cell types (principally

activated lymphocytes, macrophages, and dendritic cells, but also
endothelial, epithelial, and connective tissue cells)
• Mediate and regulate immune and inflammatory reactions.
 Cytokines and Chemokines
TNF and IL-1
• Roles in leukocyte recruitment by promoting adhesion
of leukocytes to endothelium and their migration
through vessels.
• Source: Mainly produced by activated macrophages &
dendritic cells mainly produce these cytokines, T
lymphocytes, mast cells, and some epithelial cells.
 Cytokines and Chemokines
TNF and IL-1
• Stimuli: Microbial products, foreign bodies, necrotic
cells, and a variety of other inflammatory stimuli.
• The production is induced by signals through TLRs and
other microbial sensors.
 Cytokines and Chemokines
TNF and IL-1
•Major Roles:
•Endothelial activation.
•Activation of leukocytes and other cells.
•Systemic acute-phase response.
•TNF regulates energy balance by promoting lipid &
protein catabolism and by suppressing appetite.
 Cytokines and Chemokines
TNF and IL-1
• TNF antagonists have been remarkably effective in the treatment of
chronic inflammatory diseases, particularly rheumatoid arthritis,
psoriasis, and some types of inflammatory bowel disease.
• One complication of this therapy is increased susceptibility to
mycobacterial infection
• IL-1 antagonists are not as effective, for reasons that remain obscure.
 Cytokines and Chemokines
CHEMOKINES
• A family of small (8–10 kD) proteins, act primarily as
chemoattractants for specific types of leukocytes.
• About 40 different chemokines and 20 different receptors for
chemokines are classified into four major groups.
• C-X-C chemokines
• C-C chemokines
• C chemokines
• CX3C chemokines
 Cytokines and Chemokines
CHEMOKINES
• Chemokines bind to proteoglycans, displayed at high concentrations
on the surface of endothelial cells & in the extracellular matrix.
• Two main functions:
• Acute inflammation. increase the affinity of integrins, chemoattractants.
 Inflammatory chemokines
• Maintenance of tissue architecture. Some chemokines are produced by
stromal cells in tissues, such as T and B lymphocytes in discrete areas of
the spleen and lymph nodes  Homeostatic chemokines
 Cytokines and Chemokines
CHEMOKINES
• IL-6 receptor antagonists  rheumatoid arthritis,
• IL-17 antagonists  psoriasis and other inflammatory
diseases.
• Type I interferons  contribute to some of the systemic
manifestations of inflammation.
• Cytokines also play key roles in chronic inflammation
 Complement System
• Collection of soluble proteins & membrane receptors that
function mainly against microbes and in pathologic
inflammatory reactions.
• >20 complement proteins, some are numbered C1-C9.
• In the process of complement activation, several cleavage
products of complement proteins are elaborated that cause
increased vascular permeability, chemotaxis, and
opsonization.
 Complement System
• Complement proteins are present in inactive forms in the plasma,
and many of them are activated to become proteolytic enzymes
that degrade other complement proteins, thus forming an
enzymatic cascade capable of tremendous amplification.
• The critical step in complement activation is the proteolysis of the
third (and most abundant) component, C3.
• Cleavage of C3 can occur by one of three pathways:
• The classical, alternative, and lectin pathway.
 Complement System
• Complement proteins are present in inactive forms in the plasma,
and many of them are activated to become proteolytic enzymes
that degrade other complement proteins, thus forming an
enzymatic cascade capable of tremendous amplification.
• The critical step in complement activation is the proteolysis of the
third (and most abundant) component, C3.
• Cleavage of C3 can occur by one of three pathways:
• The classical, alternative, and lectin pathway.
FUNCTIONS
 Other Mediators of Inflammation
Platelet-Activating Factor
Platelet aggregation, vasoconstriction and bronchoconstriction, and at
low concentrations it induces vasodilation and increased vascular
permeability.

Products of Coagulation
Whether the products of coagulation, per se, have a significant role in
stimulating inflammation is still not established.
 Other Mediators of Inflammation
Kinins
Bradykinin increases vascular permeability and causes contraction of
smooth muscle, dilation of blood vessels, and pain when injected into
the skin.

Neuropeptides
Substance P has many biologic functions, including the transmission of
pain signals, regulation of blood pressure, stimulation of hormone
secretion by endocrine cells, and in increasing vascular permeability.
TERIMA KASIH
 Other Mediators of Inflammation
Platelet-Activating Factor
• PAF: Platelet aggregation, vasoconstriction and bronchoconstriction, and at low
concentrations it induces vasodilation and increased vascular permeability.
Products of Coagulation
• Protease-activated receptors (PARs), which are activated by thrombin (the protease that
cleaves fibrinogen to produce a fibrin clot), are expressed on leukocytes, suggesting a role in
inflammation, but their clearest role is in platelets, in which thrombin activation of a PAR
known as the thrombin receptor is a potent trigger of platelet aggregation during the process
of clot formation (Chapter 4). Whether the products of coagulation, per se, have a significant
role in stimulating inflammation is still not established.
 Other Mediators of Inflammation
Kinins
• Vasoactive peptides derived from plasma proteins, called kininogens, by the action of specific proteases called kallikreins.
The enzyme kallikrein cleaves a plasma glycoprotein precursor, high-molecular-weight kininogen, to produce bradykinin.
Bradykinin increases vascular permeability and causes contraction of smooth muscle, dilation of blood vessels, and pain
when injected into the skin. These effects are similar to those of histamine. The action of bradykinin is short-lived, because
it is quickly inactivated by an enzyme called kininase. Bradykinin has been implicated as a mediator in some forms of
allergic reaction, such as anaphylaxis.
Neuropeptides
• Neuropeptides are secreted by sensory nerves and various leukocytes, and may play a role in the initiation and regulation
of inflammatory responses. These small peptides, including substance P and neurokinin A, are produced in the central and
peripheral nervous systems. Nerve fibers containing substance P are prominent in the lung and gastrointestinal tract.
Substance P has many biologic functions, including the transmission of pain signals, regulation of blood pressure,
stimulation of hormone secretion by endocrine cells, and in increasing vascular permeability.