Lec 29- Histamine and other mediators Flashcards
1
Q
Nitric oxide (NO)
A
- A gaseous molecule important in inflammation as a vasodilator and anti-bactericidal molecule
- Synthesised by endothelial cells, macrophage , monocytes and neuronal cells
2
Q
NO synthesis during inflammation is controlled by inducible inctrig oxide synthase
A
- iNOS is found in macrophages and endothelial cells
- Expression is increased at the gene level by agonists such as PGE2, IL-1 and TNF-a
- These activate the transcription factor NFkB to cause synthesis of iNOS
3
Q
Effects of NO- bacterial toxicity
A
- No released from activated phagocyte reacts with superoxide anion radicals
- O2 + NO –> ONO2-
- Peroxynitrite is formed which is an oxidising agent and nitrating agent
- Peroxynitrite can damage DNA, lipids and proteins and is cytotoxic
4
Q
Histamine
A
- An amine that has many action in both the periphery and in the CNS
- Released in type | hypersensitivity. Common allergies/allergens include contact dermatitis (jewellery), eczema (milk/flour), hay fever (pollen), food allergy (peanuts)
5
Q
What is histamine
A
- Basic amine
- Formed from histidine by histidine decarboxylase
- Actively taken up by platelets
- Held in granules associated with heparin and acidic protein
- All modes of secretion involve Ca2+ dependant exocytosis
- Stores are slowly replenished after degranulation
- Broken down non-specifically by N-methyltransferase or diamine oxidase
6
Q
Where is histamine found
A
-Present in almost all mammalian tissues which express histidine decarboxylase or can take up histamine High levels in \+Mast cells- skin; lung; intestine Basophils - blood \+Histaminocytes- gastric mucosa \+CNS- histaminergic neurones -Stored in secretory granules
7
Q
What triggers histamine release
A
- Activated complement C3a, C5a
- IgE immune complex interacting with antigen
- Increase in [Ca+] triggers release
- Increase in cAMp inhibits release
- NB morphine elicits histamine release without receptor activation
8
Q
Histamine and allergy (how do you become allergic)
A
- In hypersensitivity individual, an allergen e.g. grass pollen presented to T cells promotes IgE production from plasma cells
- IgE binds to mast cells via specific Fc (antibodies) receptors and mast cells are said to be sensitised
- Re-exposure to the allergen crosslinks mast cell-bound IgE causes increase in Ca2+ and mast cell activation
- 5-Hydroxytryptamine (5-HT) is also release; this is another biologically active amine
9
Q
Modulation of histamine release (treatments to prevent histamine release)
A
- Omalizumab (Xolair) is anti-IgE monoclonal Ab ; binds to IgE and neutralises it
- Licenced for use as add on to standard therapy in severe allergic asthma and also chronic spontaneous urticaria
- Sodium cromoglycate and mast cell stabilisers;
10
Q
Histamine receptors
A
- H1-linked via Gq/11 to activation of PLC –> increase [Ca2+]I and the subsequent contraction of smooth muscle, for example in the lungs
- H2- causes stimulation of adenylyl cyclase activity, and in the stomach leads to release of acid into the gastric lumen
- H3- pre-synaptic neuronal- linked via Gi/Go to adenylate cyclase –> decrease cAMP- this prevents release of neurotransmitters from presynaptic- terminals by opening K+ channels causing hyperpolarisation
- H4- cells of the immune system, Gi/Go (this is normally decrease of Ca2+ by suppressing voltage Ca channels so is unusual) and increase [Ca2+]I via beta-gamma subunits
11
Q
Histamine decreases BP mainly via the H1 receptors
A
- IV –> decrease BP
- Arteriolar dilation (H1>H2)
- Venules dilate (H1)
- Large arteries and veins constrict (H1)
12
Q
Histamine increases vascular permeability
A
- Increased inflow (arteriolar and venular dilation) but
- Decreased outflow (constriction of veins) –> increase in venular hydrostatic preassure
- Post-capillary venlue endothelial cells contract forming intercellular gaps (H1)- increase in vascular permeability (allows proteins into site of inflammation)
- Combination of (i) and (ii)–> increase vascular permeability i.e. leak of plasma proteins (antibodies and complement factors), fluid and leucocytes into interstitial space –> oedema (swelling)
13
Q
Actions of histamine on smooth muscle mediated via H1 activity
A
- Gut- contraction H1
- Bronchi- Contraction H1
- NB. allergic bronchospasm of asthma not mediated by histamine but by LTC4, LTD4 and TXA2 (but H4 receptors on eosinophils
- Role in allergy and hay fever is mainly exudative types e.g. hay fever (runny eyes and nose due to increased vascular permeability H1)
14
Q
Neurogenic effects of histamine (H1 and H3)
A
- Itching and pain due to stimulation of sensory nerve endings (H1); also axon response
- H3 activation been shown to pre-synaptically inhibit release of neurotransmitters including dopeamine, GABA, ACh, NA, 5-HT
15
Q
The triple response
A
- Flush- direct arteriolar dilatation at site of injection
- Flare- axon reflex –> dilation of surrounding vessels (by substance P released from sensory nerves)
- Wheal- local oedema at site of injection
- All components mediated by H1 receptors
