Acute inflammatory response? Flashcards
What is inflammation?
Normal part of immune response to tissue injury -to attack and remove cause of injury, repair damaged tissue.
to be beneficial and self-limiting.
-All itis diseases…
including atherosclerosis…
Interplay between tissue cells, nerves, leukocytes, microvasculature via chemical mediators.
What are the cardinal signs of inflammation?
Heat + Redness.
= Arteriolar dilation brings increased blood flow inflamed tissue.
Swelling - Blood vessel leakiness drives plasma extravasation.
But chronic inflammation can lead to a loss of function - cell accumulation, tissue remodelling, tissue destruction + fibrin deposition causing scarring. (Arthritis = joint bone remodelled + excessive bone degradation)
Pain - As a result of endogenous pro-inflammatory mediators or external injury triggering sensory nerve.
What cells contribute to inflammation?
WBCs = neutrophils, basophils, eosinophils.
Macrophages + Lymphocytes..
Mast cells.
Endothelial cells.
Platelets
How do tissue mast cells contribute to inflammation?
Tissue mast cells are widely distributed throughout connective tissue and mucosal surfaces - lungs, skin, gut, nose etc.
Synthesise and release inflammatory mediators in response to stimuli in the form of granules.
Mast cell degranulation due to:
Mechanical injury to skin.
Type 1 immediate hypersensitivity via IgE = allergy.
Insect bites.
How do endothelial cells contribute to inflammation?
Endothelial cells;
eNOS generates NO from L-arginine and O2.
NO released to stimulate GC to produce cGMP, activate PKG = cause arteriolar vasodilation in vascular SM.
= Increased blood flow = Redness.
diapedesis of immune cells by upregulating VCAM-1 and adhesion receptors….
Increased permeability = venules are leaky… swelling.
(Histamine-induced) (Venule endothelial cell contraction makes venules leaky)
What is the triple response to skin injury?
Arteriolar vasodilation = redness.
Flare - activated sensory nerves, pain + Itch, Neuropeptide release (Bradykinin, Histamine)…
Wheal = swelling.
What receptors does histamine act on in inflammation?
H1 - mostly, with some H4 too.
H1 is Gq linked = ACtivators PLC = IP3 + DAG.
Resulting in release of NO = Vasodilation for arterioles.
In venules, Histamine at H1 induces endothelial cell contraction - increasing permeability - can form an oedema.
H1 and H4 triggers pain + itch pathways in C fibre sensory nerves.
H4 - Gi coupled.
Inhibits AC - reduces cAMP BUT:
B/y subunit activates PLC.
Involved in leukocyte chemotaxis
What are the chemical mediators of inflammation?
Diverse molecules produced by HOST in response to infection + immune reaction.
With LOW specificity.
Effectors of the innate system - but can modulate adaptive system.
Liver produces systemic mediators which are precursors in blood plasma.. (Complement…)
Promote inflammation + initiate repair..
How does histamine act on blood vessels?
H1 - Gq coupled.
Arteriolar vasodilation = increased blood flow.
Venular endothelium contraction = increased permeability.
How do neuropeptides amplify histamine response?
Mast cell degranulation releases Histamine.
Histamine acts on H1 receptors in sensory nerve C fibres.
C fibres release NKA and CGRP - neuropeptides.
NKA also promotes histamine release in mast cell degranulation.
NKA (Neurokinin A) acts on NK1 receptors in blood vessels.
CGRP acts on CGRP receptors in blood vessels.
= Gq-coupled = IP3-induced Ca2+ contraction of venular endothelium.
= Permeability + Blood flow.
What are the anti-histamines role in inflammation?
Antagonists to H1 receptors.
H1 receptors mediate C fibre stimulation, NKA and CGRP release to amplify inflammation caused by venular endothelium contraction (Permeability) and vasodilation of arterioles (Reddening)….
Astemizole and Loratidine are low-lipophilicty anti-histamines which do not cross BBB.
= no effects on wakefulness.
= Allergy, urticaria + nasal congestion…
What are the neutrophil dependent and independent inflammatory responses?
Neutrophils can trigger increased endothelial permeability through release of C5a, LTB4 and Il-8.
(C5a causes increased expression of adhesion molecules on endothelium)
Indepndently to neutrophils, Histamine, NKA and Bradykinin can also increase permeability.
Plasma extravasation can lead to oedema.
How do chemical mediators differ for arterioles and venules?
PGI2, Histamine and Bradykinin all induce arteriolar vasodilation.
Histamine, Bradykinin, NKA, C5a, Il-8, LTB4 induce venular endothelial contraction and permeability.
These mediators work in synergy!
Why is the synergy of mediators in inflammation so important?
Inflammatory mediators work in synergy - NKA and Histamine, PGI2 and Bradykinin etc…
Antagonising a single mediator is only effective in inflammation driven by 1 substance - H1 antagonists only effective against Histamine component of allergy.
Maybe more effective to target leukocytes themselves, as opposed to the mediators they release..
What is the temporal release of mediators in response to injury?
1st = release of pre-formed mediators = histamine.
2nd = Production of mediators from membrane lipids = Eicosanoids (PGE2, PGI2) + Leukotrienes (LTB4)…
Release of neuropeptides from C fibres - NKA, CGRP.
NExt = Proteinase activation of complement factors - C5a, C3a, and activation of bradykinin from plasma precursor.
Transcription + translation of enzymes - iNOS, COX-2…
