Inflammatory mediators Flashcards
What is the inflammatory response?
- short term acute response
- defensive
- quickly resolved
- innate, non-adaptive
(BUT the immune response is adaptive)
microvascular effects are triggered from a variety of cells and plasma around these vessels
involves local hormones, inflammatory mediators
Acute microvascular changes in the inflammatory response
- release of inflammatory mediators
- accumulation of inflammatory cells
- repair and healing
types of inflammatory mediators produced
- histamine- amine
- bradykinin- peptide
- nitric oxide
- eicosanoid- lipid
protaglandins
leukotrienes - neuropeptides- peptides
substance P - cytokines- peptides
interleukin 1 - complement
PAF
what changes occur to the microcirculation?
- increased blood flow in arterioles
- oedema formation and cell accumulation due to increased vascular permeability in the venules
in what cells, tissues and fluid does increased blood flow occur?
- endothelial cells
- inflammatory cells
- sensory nerves
what vasodilators act on endothelial cells and inflammatory cells?
- prostaglandins and nitric oxide
vasodilators that act on sensory nerves?
neuropeptides e.g. CGRP
Direct acting oedema producing mediators?
- histamine
- substance P
- bradykinin
- PAF
- leukotrienes
cause plasma extravasation leading to oedema formation
5 steps in neutrophil- endothelial cell interactions
1) rolling
2) cell adhesion molecule expression CAM
3) adherence
4) extravasation
5) phagocytosis
mediators that lead to neutrophil accumulation in tissues
1) neutrophil activating agents
LTB4, C5a, IL-8
2) endothelial adhesion molecule stimulants
TNF, IL-1
what is histamine formed from?
source of histamine?
from L-histidine
mast cells and basophils
preformed/ release in allergic/ hypersensitivity (IgE) responses
What do H1 receptors mediate?
- vasodilation/ increased blood flow
- increased microvascular permeability
- itch
- gastric acid secretion
- smooth muscle contraction e.g. bronchoconstriction
Name some H1 antagonists
chlorpheniramine
mepyramine
involved in allergy, hayfever and skin irritations
Sedating H1 receptor antagonist
chlorpheniramine
non sedating H1 receptor antagonist
terfenadine
cetirizine
astemizole
role of sensory C and A delta fibres
- transmit sensory info to CNS
- initiate reflexes
- nociception (pain and itch)
- release neuropeptides- substance P, CGRP and VIP
stimulants of sensory nerves, C and A delta fibres
- mechanical (pressure)
- temperature (cold and heat)
- chemical (mediators & capsaicin)
effect of histamine when injected into the skin
1) local reddening due to increased blood flow
forms a wheal (up to 1cm)
2) oedema- wheal at site of intradermal injection
3) axon reflex flare
mediated by sensory nerves C & A(delta) fibres
response is inhibited by H1 receptor antagonist
what nerve fibres mediate itch?
5% of afferent C fibres in the skin
- respond to histamine
- insensitive to mechanical stimuli
- conduct velocities of 0.5m/s
(1/2 of that of normal C fibres)
anti-histamines are effective anti-itch agents
what is NO synthesised from
L- arginine
- constitutive nitric oxide synthase in endothelial cells and neurones (eNOS & nNOS)
- synthesis of NO in other cells- macrophages involved inducible nitric oxide iNOS
roles of NO
- regulation of blood flow/pressure
- host response to infection
- neurotransmitter
- pain
can react to yield further cytotoxic radicals e.g. peroxynitrite
actions of nNOS
- long term potentiation
- coordination between neuronal activity and blood flow
- pain modulation
action of eNOS
- regulation of vascular tone
- inhibition of SMC proliferation
- inhibition of platelet aggregation
action of iNOS
- cytotoxicity against bacteria, viruses and other microorganisms
what is bradykinin
one of a family of peptides formed in the plasma by the activity of enzymes on tissue fluid substrates called kininogens
what is bradykinin metabolised by
ACE
carboxypeptidase
where is bradykinin found
- in nasal cavity
during allergic rhinitis
actions of B2 receptors
- increased blood flow
- increased microvascular permeability
- nociception
- bronchoconstriction
- nasal blockage
are constitutive
what are B2 antagonists used for ?
to inhibit the effect of some angioedemas
action of B1 receptors
- induced in inflammation
mediate similar responses
esp pain
what two enzymes act on arachidonic acid and what do they form?
COX- PG’s and TXA
5- lipoxygenase- leukotrienes
what are LT-antagonists or inhibitors used for?
in asthma
what do PGE2 & PGI2 mediate?
released from endothelial cells and white blood cells
- mediate increased blood flow and hyperalgesia
action of PGD2
are released from mast cells and are less potent
actions of LTC4 and LTD4
increase microvascular permeability and are bronchoconstrictors
action of LTB4
a chemotaxin
recruits neutrophils to inflammatory sites
name some non-selective inhibitors of PG’s
- aspirin
- ibuprofen
- indomethacin
side effects on the gut and kidney
name some COX-2 selective inhibitors
- celecoxib
- roecoxib
- meloxicam
fewer gut side effects but adverse cardiac effects
how does ice help in inflammation
suppress vasoactive components e.g. swelling
local anaesthetics and noradrenaline
- suppress sensory nerve activity
- reduce blood flow
