Inflammation and inflammatory

mediators
 The acute inflammatory reaction
• The term 'acute inflammatory reaction' refers to the
events that occur in the tissues in response to an
invading pathogen (disease-causing organism) or the
presence of a noxious substance.
• It usually has two components: an innate non-
adaptive response and an adaptive or specific
immunological response.
• These reactions are protective, i.e. they have survival
value, but if inappropriately deployed they are
deleterious.
• The outcome can be healing with or without scarring or, if the
pathogen or noxious substance persists, chronic inflammation.
• Many of the diseases that need drug treatment involve
inflammatory processes. Understanding of the action and,
therefore, the use of anti-inflammatory and immunosuppressive
drugs necessitates an understanding of the inflammatory
reaction.

• In terms of what is happening locally within the tissues, the

changes can be divided into cellular and vascular events.
Mediators are generated both from plasma and from cells, and in
turn they modify and regulate the vascular and cellular reactions.
Diagram showing the four enzyme cascades that are activated when plasma leaks out into the
tissues as a result of the increased vascular permeability in an area of inflammation
 The innate non-adaptive response
• The innate response, which occurs soon after infection, has a
component linked to the specific immunological response and
also non-immunological vascular and cellular elements.
Mediators are generated both from cells and from plasma and,
in turn, modify and regulate the vascular and cellular events.
• Tissue macrophages recognise, by means of specific DNA-
encoded receptors, specific pathogen-associated molecular
patterns (PAMPs) on the microorganism; the interaction
triggers release of cytokines, particularly interleukin-1 (IL-1)
and tumour necrosis factor (TNF)-α and various chemokines.
• IL-1 and TNF-α act on local postcapillary venular endothelial
cells causing:
– vascular dilatation and exudation of fluid
– expression of adhesion molecules on the cell surfaces.
• The fluid exudate contains the components of enzyme
cascades that give rise to inflammatory mediators: bradykinin
from the kinin system, C5a and C3a from the complement
system; complement also gives rise to components that lyse
bacteria.
• C5a and C3a stimulate mast cells to release histamine, which
dilates local arterioles.
• Local tissue damage and the pro-inflammatory cytokines
release eicosanoids: prostoglandins I2 and E2 (vasodilators), and
leukotriene B4 (chemotaxin).
• Cytokines stimulate synthesis of nitric oxide (vasodilator;
increases vascular permeability).
• Leucocytes attach to the adhesion molecules then migrate out
towards the pathogen site (attracted by chemokines, IL-8, C5a,
leukotriene B4) where phagocytosis and killing of bacteria takes
• In addition to the local changes in an inflammatory area,
there are often various general responses such as a rise in
temperature and an increase in blood leucocytes, termed
'leucocytosis' (or neutrophilia if the increase is in the
neutrophils only).
• There is also an increase in certain plasma proteins termed
'acute phase proteins. These include C-reactive protein, α2-
macroglobulin, fibrinogen ,α1-antitrypsin, and some
complement components. C-reactive protein binds to
certain microorganisms and the resulting complex activates
complement
 UNWANTED INFLAMMATORY REACTIONS AND IMMUNE
RESPONSES

• in some circumstances, be inappropriately triggered

by substances that are innocuous or even
endogenous, as occurs in autoimmune* disease.
• It is when this happens that it becomes necessary
to use anti-inflammatory or immunosuppressive
drugs.
• Unwanted immune responses are termed allergic**
or hypersensitivity reactions and have been
classified into four types
 MEDIATORS OF INFLAMMATION AND
IMMUNE REACTIONS
• HISTAMINE
• BRADYKININ
• NO
• NEUROPEPTIDES
• CYTOKININS
• ECOSANOIDS
• Histamine Histamine is a basic amine, stored in granules within
mast cells and basophils and secreted when complement
components C3a and C5a interact with specific membrane
receptors, or when antigen interacts with cell-fixed IgE.
• It produces effects by acting on H1-, H2- or H3-receptors on target
cells.
• The main actions in humans (with the receptors involved) are:
– stimulation of gastric secretion (H2)
– contraction of most smooth muscle other than that of blood vessels (H1)
– cardiac stimulation (H2)
– vasodilatation (H1)
– increased vascular permeability (H1).
• Injected intradermally, histamine causes the 'triple response':
reddening from local vasodilatation, wheal by direct action on
blood vessels and vasodilatation, and flare from an 'axon'
reflex in sensory nerves releasing a peptide mediator.
• The main pathophysiological roles of histamine are:
– as a stimulant of gastric acid secretion (treated with H2-receptor
antagonists)
– as a mediator of type 1 hypersensitivity reactions such as urticaria
and hay fever (treated with H1-receptor antagonists).
• H3-receptors occur at presynaptic sites and inhibit the release
of a variety of neurotransmitters.
 Bradykinins
• Bradykinin and the closely related peptide
kallidin are vasoactive peptides formed by the
action of enzymes on protein substrates
termed kininogens The two peptides are
virtually identical, kallidin possessing one
additional amino acid residue
Kinidin cascade
 Pharmacological actions
– vasodilatation (largely endothelial cell-dependent,
caused both by generation of nitric oxide and by
activation of phospholipase A2, thus releasing
prostaglandin I2)
– increased vascular permeability
– stimulation of pain nerve endings
– stimulation of epithelial ion transport and fluid
secretion in airways and gastrointestinal tract
– contraction of intestinal and uterine smooth muscle
 NITRIC OXIDE
• It is mainly the inducible form of NO synthase (iNOS)
that is involved in inflammatory reactions.
• Virtually all inflammatory cells express the inducible
form of the enzyme in response to cytokine stimulation.
• NOS is also present
• in the bronchial epithelium of asthmatic subjects
• in the mucosa of the colon in patients with ulcerative
colitis and
• in synoviocytes in inflammatory joint disease.
NO has mainly pro-inflammatory actions:
• it is a potent vasodilator;
• it increases vascular permeability and it increases the
production of pro-inflammatory prostaglandins.
• NO, or compounds derived from it, have cytotoxic action
against bacteria, fungi, virus and metazoan parasites, and
NO is thought to enhance local defence mechanisms.
• However, produced in excess, it can be harmful to host
cells. Some of its actions are, however, anti-inflammatory
since, released from endothelial cells, it inhibits adhesion
of neutrophils and platelets and platelet aggregation
 NEUROPEPTIDES
• Neuropeptides released from sensory neurons contribute
to inflammatory reactions-constituting the phenomenon
known as 'neurogenic inflammation' (Maggi, 1996).
• The main peptides involved are substance P, neurokinin A
and CGRP.
• Substance P and neurokinin A (members of the
tachykinin family) act on mast cells, releasing histamine
and other mediators, and produce smooth muscle
contraction and mucus secretion; CGRP is a potent
• Neurogenic inflammation is implicated in the
pathogenesis of several inflammatory conditions including
the delayed phase of asthma, allergic rhinitis,
inflammatory bowel disease and some types of arthritis.
 CYTOKINES
• The term cytokine generally referring to protein
or large peptide mediator released by cells of the
immune system. More than 100 cytokines have
been identified, and the cytokine superfamily
includes: interleukins
• chemokines
• interferons
• colony-stimulating factors
• growth factors and tumour necrosis factors.
• those involved in the induction of the immune
response
• those involved in the effector phase of the
immune/ inflammatory response
• Pro-inflammatory cytokines
• These are the cytokines that participate in acute and
chronic inflammatory reactions and repair processes.
• The primary pro-inflammatory cytokines are TNF-α and IL-
1*
• These are released from macrophages and many other cells
and can start a cascade of secondary cytokines amongst
which are the chemokines (see below).
• Various cytokine growth factors (e.g. platelet-derived
growth factor, fibroblast growth factor, vascular endothelial
growth factor) are important in repair processes and are
implicated in chronic inflammation (see Ch. 5).
The anti-inflammatory cytokines
• These comprise those that inhibit aspects of the
inflammatory reaction) include TGF-β, IL-4, IL-
10 and IL-13.
• They can inhibit the production of chemokines
and the last three can inhibit responses
mediated by Th1 cells, i.e. those cells whose
inappropriate activation is involved in several
diseases
• Interleukin-1 and TNF-α are important primary
inflammatory cytokines, inducing the
formation of other cytokines.
• The interferons (IFNs) α and β have antiviral
activity and IFNα is used as an adjunct in the
treatment of viral infections. IFN-γ has
significant immunoregulatory function and is
used in the treatment of multiple sclerosis
 Clinical use of interferons
• IFNα is used in the treatment of chronic hepatitis B
and C, has some action against herpes zoster and in
the prevention of the common cold. Antitumour
action against some lymphomas and solid tumours
had been reported.
• A variety of dose-related side-effects may occur.
• IFNβ is used in some patients with multiple sclerosis.
• IFNγ is used in chronic granulomatous disease in
conjunction with antibacterial drugs
 EICOSANOIDS
• Prostaglandins (PGs), leukotrienes (LTs), and
related compounds are called eicosanoids,
from theGreek eikosi (“twenty”).
• They are implicated in the control of many
physiological processes and are among the
most important mediators and modulators of
the inflammatory reaction
 Precursor
• Precursor essential fatty acids contain 20 carbons and
three, four, or fivedouble bonds:
• 8,11,14-eicosatrienoic acid (dihomo-g-linolenic acid),
• 5,8,11,14-eicosatetraenoicacid (arachidonic acid [AA];
Figure 25–1), and
• 5,8,11,14,17-eicosapentaenoic acid (EPA).
• AA, the most abundant precursor,
• Products of Prostaglandin G/H Synthases

• Products of Lipoxygenases
The cyclooxygenase (COX) pathway
• Prostanoids The term 'prostanoids' encompasses the
prostaglandins (PGs) and the thromboxanes (TXs).
• Cyclooxygenase acts on arachidonate to produce cyclic
endoperoxides (PGG2, PGH2).
• There are two forms of cyclooxygenase: COX-1, a
constitutive enzyme, and COX-2, which is induced in
inflammatory cells by inflammatory stimuli.
• PGI2 (prostacyclin) predominantly from vascular
endothelium, acts on IP-receptors. Main effects are
vasodilatation and inhibition of platelet aggregation.
• TXA2 predominantly from platelets acts on TP-receptors.
Main effects are platelet aggregation and vasoconstriction.
• PGE2 is prominent in inflammatory responses and is a mediator of
fever. Main effects are:
– EP1-receptors: contraction of bronchial and gastrointestinal tract (GIT)
smooth muscle
– EP2-receptors: relaxation of bronchial, vascular and GIT smooth muscle
– EP3-receptors: inhibition of gastric acid secretion, increased gastric mucus
secretion, contraction of pregnant uterus and of GIT smooth muscle,
inhibition of lipolysis and of autonomic neurotransmitter release.
• PGF2α acts on FP-receptors, which are found in smooth muscle and
corpus luteum. Main effect in humans is contraction of the uterus.
• PGD2 is derived particularly from mast cells and acts on DP-
receptors. Its main effects are vasodilatation and inhibition of
platelet aggregation
 Clinical uses of prostanoids
• Gynaecological and obstetric
– for termination of pregnancy: gemeprost or
misoprostol (a metabolically stable prostaglandin (PG)
E analogue)
– for induction of labour: dinoprostone or misoprostol
– for postpartum haemorrhage: carboprost (if no
response to other oxytocics).
• Gastrointestinal:
– to prevent peptic ulcers in patients taking non-steroidal
anti-inflammatory agents: misoprostol
• Cardiovascular:
– to maintain the patency of the ductus arteriosus until
surgical correction of the defect in babies with certain
congenital heart malformations: alprostadil (PGE1).
– to inhibit platelet aggregation during haemodialysis:
PGI2 (epoprostenol) is given if heparin is
contraindicated , PGI2 is also used to treat primary
pulmonary hypertension.
• Ophthalmic:
– open-angle glaucoma: latanoprost eyedrops.
PAF