Download Mediators of inflammation

MEDIATORS OF
INFLAMMATION
Meadiators of inflammation
• Mediators are the substances that
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initiate and regulate inflammatory reactions.
These are: cell derived or plasma protein derived
vasoactive amines,
lipid products,
cytokines,
products of complement activation
Mediators of inflammation
• Active mediators are produced only in response to various
stimuli like microbial products
• life span of mediators are very short
• one mediator can stimulate the release of other like
complement activation cause release of histamine and
cytokines
Vasoactive Amines: Histamine and
Serotonin
• Acts on blood vessels.
• First mediators
• Histamine
• Mast cells are richest source of histamine
• Histamine stored as granules and released by degranulation
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in response to various stimuli
1. physical injuries
2.Antibodies mediated – hypersensitivity reaction
3. Complement products- anaphyltoxin C3a, C5a.
4. Neuropeptides (e.g., substance P) and cytokines (IL1, IL8)
• Histamine causes dilation of arterioles and increases the
permeability of venules.
• principal mediator of the immediate transient phase it
• it increased vascular permeability, producing
interendothelial gaps in venules.
• Act via H1 receptors present on microvascular endothelial
cells.
Serotonin((5-hydroxytryptamine)
• preformed mediator
• Present in plateletes and certain neuroendocrinal cells
like GIT.
• primary function is as a neurotransmitter.
• vasoconstriction
Arachidonic Acid Metabolites
• The lipid mediators prostaglandins and leukotrienes are
produced from arachidonic acid (AA) present in
membrane phospholipids
• Stimulate vascular and cellular reactions.
• Arachidonic acid derived from dietary sources or by
conversion from the linoleic acid.
• Mechanical, chemical, and physical stimuli or
other mediators (e.g., C5a) release AA from membrane
phospholipids through the action of cellular
phospholipases, mainly phospholipase A2
• Phospholipase A2 Activation occur via increase in
cytosolic Ca2 + and kinase in response to external
stimuli.
Prostaglandins
• Produced by mast cells , macrophages, endothelial cells, .
• it involved in vascular and systemic reactions of
inflammation.
• COX-1 & COX-2 is involved in synthesis of prostaglandins.
• COX -1 is produced in response to inflammatory stimuli and
is also constitutively expressed
• COX2 is induced by inflammatory stimuli .
Thromboxane A2 (TxA2)
• derived by action of thromboxane synthase present in
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platelets.
Functions –
platelets aggregation
Vasoconstrictions
it is unstable and converted to inactive forms TxB2
Prostacyclin( PGI2)
• formed by action of prostacyclin synthase present in
vascular endothelium.
• Functions
• increase vascular permeability
• inhibit platelets aggregation
• PGD2 produced by mast cells along with PGE2.
• it causes vasodilation and increases the permeability of
postcapillary venules, thus potentiating edema formation.
• PGF2- stimulates contraction of uterine and bronchial
smooth muscles and small arterioles.
• Prostaglandins involved in the pathogenesis of pain and
fever in inflmmation.
• PGE2 is hyperalgesic makes the skin hypersensitive to
painful stimuli
Leukotriene
• produced by leukocytes and mast cells by the action of
lipoxygenase.
• It involved in vascular and smooth muscle reactions and
leukocyte recruitment.
• Three types of lipoxygenase
1. - lipoxygenase – present in neutrophils, convert AA to
5hydroxyeicosatetraenoic acid
• Act as chemotactic for neutrophils
• LTB4- Chemotactic and neutrophil activator.
• leads to aggregation and adhesion of the cells to venular
endothelium.
• Generation of ROS
• Release of lysosomal enzymes.
• LTC4, LTD4, and LTE4- causes
• vasoconstrictions
• Bronchospasm
• increased permeability of venules
• Leukotrienes are more potent than is histamine in
increasing vascular permeability and causing
bronchospasm.
Lipoxins
• Generated from AA by the lipoxygenase
pathway.
• It suppress inflammation by inhibiting recruitment of
leukocytes.
• Inhibit neutrophil chemotaxis and adhesion to
endothelium.
Pharmacologic Inhibitors of
Prostaglandins
and Leukotrienes
• Cyclooxygenase inhibitors- aspirin and other
nonsteroidal anti-inflammatory drugs (NSAIDs)
• inhibit both COX-1 and COX-2
• COX1 is responsible for the production of prostaglandins
that are involved in both inflammation and homeostatic
functions (e.g., fluid and electrolyte balance in the kidneys,
cytoprotection in the gastrointestinal
tract)
• COX2 generates prostaglandins that are
involved only in inflammatory reactions.
• Lipoxygenase inhibitors- Zileuton
• Corticosteroids - broad spectrum anti-inflammatory
• Reduce the transcription of genes encoding COX2,
phospholipase A2, proinflammatory cytokines (e.g., IL1
and TNF), and iNOS
• Leukotriene receptor antagonists- block receptor . eg
Montelukast
Cytokines and Chemokines
• Cytokines are proteins produced by many cell types
(activated lymphocytes, macrophages, and dendritic cells)
• mediate and regulate immune and inflammatory reactions
Tumor Necrosis Factor (TNF) and
Interleukin-1 (IL-1)
• roles in leukocyte recruitment
• promoting adhesion of leukocytes to endothelium and
their migration through vessels.
• Produced by – macrophages and dendritic cells.
• TNF also via T lymphocytes and mast
cells
• Stimulus for secretion- microbial products, immune
complexes, foreign bodies, physical
injury, and a variety of other inflammatory stimuli.
• TNF production is induced by TLRs and other microbial
sensors.
Roles of cytokines in inflammation
• Endothelial activation.- by TNF and IL-1
• increased expression of adhesion molecules ( P- and E•
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selectins and ligands foe leukocytes
increased production of various mediators
increased procoagulant activity
Activation of leukocytes and other cellsstimulates microbicidal activity of macrophages by inducing
production of NO.
IL1 activates fibroblasts to synthesize collagen
and stimulates proliferation of synovial and other
mesenchymal cells.
stimulates TH17 responses- induce acute inflmmation
• Systemic acute-phase response
• Induced by IL-1, TNF and IL-6
• TNF regulates energy balance by promoting lipid and
protein mobilization and by suppressing appetite leads to
cachexia
• TNF antagonists have been remarkably effective in the
treatment of chronic inflammatory diseases- Rheumatoid
arthritis and psoriasis
Roles of cytokines
Chemokines
• Chemokines are a family of small (8 to 10 kD) proteins
that act primarily as chemoattractants for specific
types
of leukocytes.
• About 40 different chemokines and 20 different receptors
for chemokines have been identifid.
Classification of chemokines
• Four major groups
• 1. C-X-C chemokines- have one amino acid residue
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separating the fist two of the four conserved cysteine
residues.
Act primarily on neutrophils.
Secreted by macrophages, endothelial cells
function- Activation and chemotaxis of neutrophils
Eg. IL-8
• 2. C-C chemokines- have the fist two conserved cysteine
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residues adjacent.
It includes- monocyte chemoattractant protein (MCP1),
eotaxin,
macrophage inflmmatory protein1 α (MIP1 α),
RANTES (regulated and normal Tcell expressed and
secreted)
attract monocytes, eosinophils, basophils and
lymphocytes.
eotaxin selectively recruits eosinophils.
• C chemokines -lack the first and third of the four
conserved cysteines.
• e.g., lymphotactin
• specific for lymphocytes.
• CX3C chemokines-contain three amino acids between
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the two cysteines.
eg- fractalkine exist in two forma
cell surface bound protein- promotes strong adhesion of
monocytes and T cells,
soluble form-derived
by proteolysis of the membrane bound protein,
potent chemo-attractant
• Chemokines mediate their activities by binding to seven•
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trans membrane G protein–coupled receptors.
Functions of chemokinesIn acute inflammation-stimulate leukocyte
attachment to endothelium by acting on leukocytes to
increase the affinity of integrins,
Chemotaxis
Maintenance of tissue architecture
homeostatic chemokines-produced constitutively in
tissues
Other Cytokines in Acute Inflammation
• IL- 6 – Secreted by macrophages involved in local and
systemic reactions
• IL-17 – Produced by T lymphocytes, promotes neutrophil
recruitment.
• Type I interferons – some systemic manifestations
Complement System
• The complement system is a collection of soluble
proteins and membrane receptors that function
mainly in host defense against microbes and in
pathologic inflammatory reactions.
• The system consists of more than 20 proteins, some of
which are numbered C1 through C9.
• functions in both innate and adaptive immunity
The activation and functions of the
complement system
• Complement proteins are present in inactive forms in the
plasma.
• The critical step in complement
activation is the proteolysis of the third
• Cleavage of C3 can occur by one of
three pathways:
• classical pathway- triggered by fixation of
C1 to antibody (IgM or IgG) that has combined with
antigen
• Alternative pathway- triggered by
microbial surface molecules (e.g., endotoxin, or LPS),
complex polysaccharides, cobra venom, and other
substances, in the absence of antibody
• The lectin pathway- plasma mannose binding
lectin binds to carbohydrates on microbes and directly
activates C1.
Functions of complements
• Inflammation- C3a, C5a and C4a
• stimulate histamine release
• They are called anaphylatoxins
• C5a – chemotactic to neutrophils, monocytes,
eosinophils, and basophils.
• Opsonization and phagocytosis- C3b and iC3b
• Cell lysis- deposition of the MAC on cells makes these
cells permeable to water and ions and results in death
(lysis) of the cells.
• The activation of complement is tightly controlled by cell•
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associated and circulating regulatory proteins.
C1 inhibitor (C1 INH)- block C1 activation
Inherited deficiency of this inhibitor is the cause of hereditary
angioedema
Decay accelerating factor (DAF) and CD59
DAF- inhibit C3 convertase formation
CD59 inhibits formation of the
membrane attack complex.
An acquired deficiency leads to PNH.
Other Mediators of Inflammation
• Platelet-Activating Factor (PAF)- phospholipid derived
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mediator
Secreted by platelets, basophils, mast cells, neutrophils,
macrophages, and endothelial cells
It causes- platelets aggregation
vasoconstriction
bronchoconstiction
at low concentrations it induces vasodilation and
increased venular permeability.
Products of Coagulation
• Kinins- vasoactive peptides derived from plasma
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proteins, called kininogens, by the action of specific
proteases called kallikreins.
Bradykinin- increases vascular permeability, and smooth
muscles contractions,
Dilatation of blood vessels and pain
Neuropeptides-secreted by sensory nerves and various
leukocytes.
substance P and neurokinin A
• Substance P- prominent in nerve fibers in lungs and GIT.
• Functions- transmission of pain signals
• regulation of blood pressure
• stimulation of hormone secretion by endocrine cells
• increasing vascular permeability.
Morphologic Patterns of Acute
Inflammation
• The morphologic hallmarks -dilation of small blood
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vessels
accumulation of leukocytes and fluid in the
extravascular tissue.
Various morphological pattern occurSerous inflammation
Fibrinous inflammation
Purulent (Suppurative) Inflammation, Abscess
Ulcers
Serous Inflammation
• Exudation of cell poor fluid into spaces created by cell
injury or into body cavities lined by the peritoneum,
pleura, or pericardium.
• not infected by destructive organisms and does not
contain large numbers of leukocytes.
• accumulation of fluid in these cavities is called an
effusion.
• Eg. Skin blister in burn or viral infections
cross-section of a skin blister showing the epidermis
separated from the dermis by a focal collection of serous
effusion
Fibrinous Inflammation
• A fibrinous exudate develops when the vascular leaks are
large or there is a local procoagulant stimulus (e.g.,
cancer cells)
• Fibrinous exudate is characteristic of inflammation in the
lining of body cavities, such as the meninges, pericardium
and pleura.
• Histologically, fibrin appears as an eosinophilic meshwork
of threads or sometimes as an amorphous coagulum.
• Fibrinous exudates may be dissolved by fibrinolysis and
cleared by macrophages.
• If fibrin not removed it stimulates ingrowth of fibroblast
and blood vessels leads to scarring.
• Conversion of the fibrinous exudate
to scar tissue (organization) within the pericardial sac
leads to opaque fibrous thickening of the pericardium and
epicardium.
Fibrinous pericarditis. A, Deposits of fibrin on the
pericardium. B, A pink meshwork of fibrin exudate
(F) overlies the pericardial surface (P)
Purulent (Suppurative) Inflammation,
Abscess
• characterized by the production
of pus, an exudate consisting of neutrophils, the liquefied
debris of necrotic cells, and edema fluid.
• Most common cause – bacterial infections
(staphylococci)
• Abscesses are localized collections of purulent
inflammatory tissue caused by suppuration buried in a
tissue, an organ, or a confined space.
• Abscesses have a central region that appears as a mass
of necrotic leukocytes and tissue cells.
• zone of preserved neutrophils around this necrotic focus,
and outside this region there may be vascular dilation and
parenchymal and fibroblastic proliferation.
Purulent inflammation. A, Multiple bacterial abscesses
(arrows) in the lung in a case of bronchopneumonia.
B, The abscess contains neutrophils and cellular
debris, and is surrounded by congested blood
Ulcers
• An ulcer is a local defect, or excavation, of the surface of
an organ or tissue that is produced by the sloughing
(shedding) of inflamed necrotic tissue
• Most commonly encountered in
• the mucosa of the mouth, stomach, intestines, or
genitourinary tract
• skin and subcutaneous tissue of the lower extremities
A chronic duodenal ulcer. B, Low-power cross-section view
of a duodenal ulcer crater with an acute inflammatory
exudate in the base.
Outcomes of Acute Inflammation