cellular and biochemical mediators of inflammation

1. --- Shravankumar S Kolli
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2. • Inflammatory mediators are the substances that initiate and
regulate inflammatory reactions.
• In 1933 ‘Sir Henry-Dale’ modified version , it is more
applicable to the field today, and it was considered by Dale
(1994).
• There are two types of mediators they are
1. Cell derived mediators and
2. Plasma protein derived mediators
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6. • 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.
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7. 1. Performed mediators in secretory granules
Histamine (mast cell, basophils and platelets)
Serotonin ( platelets )
2. Newly synthesized mediators
Prostaglandins ( mast cell and all leukotriene's )
leukotriene's ( all leukotriene's and mast cell )
Platelet activating factor ( all leukocytes )and
Cytokinin’s ( macrophages, lymphocytes and mast cells ).
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8. • Introduction
Histamine is naturally occurring imidazole derivative.
It is widely distributed in skin, GIT mucosa, lungs, brain,
cerebro-spinal fluid and bone marrow. It is also a
component of some venoms and string secretion.
Histamine is released from mast cells by exocytosis
during inflammatory or allergic reactions. Stimuli include
C3a and C5a that interact with specific surface receptor
and the combination of antigen with cell-fixed IgE
antibodies.
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9. Histamine release is initiated by a rise in cytosolic
Ca2+. Various basic drugs such as morphine and
tubocurarine, release histamine through a non-receptor
action. Agents that increase cAMP formation (Ex: β-
adrenoreceptor agonist) inhibit histamine secretion.
Replenishment of secreted histamine by mast cells or
basophils is a slow process. Which may take days or
weeks, whereas turnover of histamine in the gastric
histaminocyte is very rapid. Histamine is metabolised by
histaminase and/or by the methylating enzyme imidazole
N-methyltransferase.
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10. • Mast cells are richest source of histamine
• Histamine stored as granules and released by
degranulation in response to various stimuli.
1. physical injuries
2.Antibodies mediated – hypersensitivity reaction
3. Complement products- anaphyltoxin C3a, C5a.
• Histamine causes dilation of arterioles and increases the
permeability of venules.
• it increased vascular permeability, producing inter-
endothelial gaps in venules.
• Act via H1 receptors present on micro-vascular
endothelial cells. 10

11. • Gastric secretion - Histamine stimulates the secretion of
gastric acid by action on H2 receptor. This is the most
important action of histamine, because it is implicated in the
pathogenesis of peptic ulcer.
• Smooth muscle effect - Histamine acting on H1 receptor,
contracts the smooth muscle of the ileum, bronchi,
bronchioles and uterus. Histamine reduces air flow in the
first phase of bronchial asthma.
• Cardiovascular effect - Histamine dilates human blood
vessel by an action on H1 receptors, the effect being partly
endothelium-dependent in some vascular beds. it also
increases the rate and the output of the heart by action on
cardiac H2 receptor.
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12. Serotonin (5-hydroxytryptamine)
 5-Hydroxytryptamine (5-HT) has diverse pharmacological
physiological role in the body which includes as a
neurotransmitter in CNS as a regulator of smooth muscle
function in CVS GIT and regulator of platelet function,
beside other subsidiary role in several functions.
 As a matter of fact it is a autacoid mediator without
portfolio, which is discharging its responsibilities with full
freedom and yet enjoying freedom from all responsibilities.
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13. Actions of 5-HT in inflammation
 Serotonin (5-hydroxytryptamine) is a vasoactive mediator
similar to histamine found in mast cells and platelets in the
GI tract and CNS.
 Serotonin also increases vascular permeability, dilates
capillaries, and causes contraction of nonvascular smooth
muscle.
 In some species, including rodents and domestic
ruminants, serotonin may be the predominant vasoactive
amine.
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14. 
 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 .
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Prostaglandins

15. 
 These compounds are known as PG endoperoxides
and are further transformed by specific enzymes into
the different PGs, notably the thromboxane's and
PGI2 (epoprostenol).
 PGs are not prestored in tissues, but are formed
when activation of phospholipase or other lipases
takes place in a tissue.
 PGs exhibit a number of biological effects, primarily
upon those cells immediately surrounding the site of
their synthesis, partly because they are rapidly
inactivated.
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Role of Prostaglandin in inflammation

16. 
 Prostanoids have been shown to have a wide range
of effects on many physiological systems and a role
for PGs in tissue inflammation and injury has been
proposed.
 Over the years, evidence of the powerful pro-
inflammatory action of PGs has accumulated,
nevertheless, recent findings on anti-inflammatory
effects of PGs, as well as on mechanisms of action of
NSAIDs, other than inhibition of PG biosynthesis
suggest a modulatory role for PGs in the
inflammatory process.
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17. Leukotriene's
 Leukotriene's are synthesized from arachidonic acid by
lipoxygenase-catalysed pathway. These soluble cytosolic enzymes
are mainly found in lung, platelets, mast cells and white blood cells.
 The main enzyme in this group is 5-lipoxygenase. On cell activation,
this enzyme translocate to the nuclear membrane, where it associates
with a crucial accessory protein affectionately termed FLAP ( five-
lipoxygenase activating protein ).
 The 5-lipoxygenase incarporates a hydroxy group at C5 in
arachidonic acid, leading to the production of unstable compound
leukotrine (LT) A4. this may be converted enzymically to LTB4 and
also the precursor of the cysteinyl-containing leukotrines LTC4.
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18. Role of leukotriene's in inflammation
 Leukotriene B4 is found in inflammatory excluded and tissues
in many inflammatory conditions, including rheumatoid
arthritis, psoriasis and ulcerative colitis.
 The cysteinyl - leukotriene's are present in the sputum of
chronic bronchitis in amounts that are biologically active. On
antigen challenge, they are released from samples of human
asthmatic lung invitro, and into nasal lavage fluid in subjects
with allergic rhinitis.
 There is a evidence that they contribute to the underlying
bronchial hyper – activity in asthmatic , and it is thought that
they are among the main mediators of both the early and late
phase of asthma.
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19.  Platelet activating factor also variously termed PAF-
acether and AGEPC (acetyl-glyceryl-ether-
phosphorylcholine), is a biologically active lipid
that can produce effect at exceedingly low
concentrations.
 The name is somewhat misleading, because PAF has
actions on variety of different target cells, and is
believed to be an important mediator in both acute
and chronic allergic and inflammatory phenomena.
 PAF Secreted by platelets, basophils, mast cells,
neutrophils, macrophages, and endothelial cells
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20.  By acting in specific receptor, PAF is capable of producing many of the signs and
symptoms of inflammations. Injected locally, it produces vasodilation ( and thus
erythema), increased vascular permeability and weal formation.
 Higher doses produce hyperalgesia , it is a potent chemotaxin for neutrophils and
monocytes, and recruits ecosinophils into the bronchial mucosa in the late phase
of asthma. It can activate PLA2 and initiates eicosanoid synthesis.
 On platelets, PAF triggers arachidonates turnover and TXA2 generation.
Producing shape change and the release of the granule contents. This is important
in hemostasis and thrombosis .
 The anti-inflammatory actions of glucocorticoids may be caused, at least in part,
by inhibition of PAF synthesis. Competitive antagonist of PAF and/or specific
inhibition of lyso-PAF acetyl transferase could will be usefull anti-inflammatory
drugs and/or anti-asthmatic agents.
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21. REFERENCE
 Text book of PHARMACOLOGY by Rang
and Dale – 6th edition page no- 213 to 220.
 www.google.com.
 https://link.springer.com/article/10.1007/BF03
258310.
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