Intro into asthma Flashcards
What happens in asthma?
Smooth muscle contracts in bronchoconstriction
Blood vessels infiltrated by immune cells
decreased lumen diater due to bronchoconstriction
Inflammation and swelling
Excess mucus
Fibrosis
What are the goals of treatment for asthma?
Reduce symptoms using minimum medication
We aim to provide effective anti-inflammatory and bronchodilatory therapy
Need to remember that symptoms vary over time and so therapy needs to be flexible - can allow medication to be tailored to patients needs by getting them to self monitor with a peak flow meter.
How should asthma be viewed as in summary
Should be viewed primarily as an inflammatory illness with bronchial hypersensitivty with bronchospasm as a result.
why do asthmatic patients get bronchospasm occur?
Results from a combination of:
- a release of mediators
- and an exaggerated response to their effects
What is the mechanism for how bronchoconstriction occurs in asthmatics?
released mediators activates neuronal pathways increasing the acitvity of afferent parasympathetic vagal nerves, causing them to release Ach onto smooth muscle to cause bronchoconstriction.
In asthma, after being presented the antigen by a antigen presenting cell, what does Th2 activation result in?
- synthesis and release of proinflammatory cytokines (e.g. interleukins, especially IL-4)
- Cytokines cause inflammtory cells to be recruited, such as eosinophils, monocytes, lymphocytes, basophils)
- Increases IgE levels (Due to IL-4 production) which correlates with worsening asthma symptoms
Describe the type I hypersensitivity reaction in asthma
IgE receptors are expressed on mast cells. IgE produces via the Th2 response bind.
When an allergen binds to the Fc IgE receptors of two IgE ABs, they cross link and this signals synthesis and release of mediators.
airways become inflamed and hyper-reactive.
Where are mediators stored before their release?
Stored in the cytoplasmic granules with mast cels and basophils
These are released during allergic or inflamatory reactions, includes:
- histamine
- chemotactic factors
- neutral proteases
- acid hydrolases
- heparin
Which mediators are pre-formed and stored in the cytoplasmic granues of mast cells and basophils prior to allergic or inflammatory reactions?
- Histamine
- chemotactic factors
- neutral proteases
- acid hydrolases
- heparin
What mediators are synthesised at the time of mast cell stimulation?
And where are they released from?
Arachadonic acid and other metabolites (leukotrienes, prostanoids) are released from phospholipid by phospholipase A2 from activated inflammatory cells.
Also get platelet activating factor.
In general, what do leukotrienes do?
Smooth muscle contraction, leading to bronchoconstriction.
Vasoconstriction.
Increase vascular permeability.
What does thromboxane A2 do, and what do prostaglandin do in asthma?
TXA2 causes vasoconstriction and bronchoconstriction.
PGD2 causes vasodilaton and bronchoconstriction.
What enzyme breaks down arachadonic acid into the leukotrienes?
5-Lipoxygenase
What enzyme breaks down arachadonic acid into the prostanoids (prostaglandins, TXA2)
Cyclooxygenase
when leukotrienes increase vascular permeability, what affect does this have?
Allows for inflammatory cell infiltration, and oedema
What does LTB4 do? (leukotriene B4)
LTB4 has a chemotactic affect, it attracts inflammatory cells to the site and causes reactive oxygen species to be produced, and enzymes are induced - this causes damage to the hosts own tissues.
What enzyme do we target to reduce the amount of leukotrienes produced in asthmatic patients?
5-Lipoxygenase
What enzyme is targetted to prevent arachadonic acid being broken down into prostanoids? (TXA2, PGI2)
Cyclooxygenase
What other effects does prostaglandin E1 have?
If negatively feeds back and down regulates lipoxygenase pathway. Meaning that there is decreased production of leukotrienes.
How does aspirin induced asthma occur?
NSAIDs (like aspirin) inhibit COX enzyme, preventing production of prostaglandin E1. Therefore there is no longer a down regulating effect on 5-Lipoxygenase, meaning that it’s activity increases and can produce more pro-inflammatory leukotrienes.
(characterised by symptoms of rhinitis(nasal obstruction, rhinorrhoea and sneezing) and facial flushing. Ensuring asthma triggered within 1-3 hours of ingestion of aspirin and other NSAIDs (eg. ibuprofen)
How do B2-adrenergic agonists cause bronchodilation
B-agonist binds to B2-AR, couples with adenalyl cyclase via g protein.
Adenylate cyclase converts ATP to cAMP, and cAMP activates protein kinase A.
Protein Kinase A has three effects.
- Increases conductance of Ca2+ activated K+ channels, hyperpolarising the cell
- Inhibits IP3/Ca2+, decreasing intracellular Ca2+ conc.
- Inhibits MLCK - preventing cross bridge formation
What affect does Ach binding to M2 have on the B2-AR pathway?
When Ach binds to M2 receptors they block adenylate cyclase activity, and this inhibits the B2-AR pathway (relaxation pathway), thus promoting bronchoconstriction due to the decrease in cAMP (since adenylate cyclase convertes ATP to cAMP).
After being released by mast cells, what receptor do cysteinyl leukotrienes bind to
CysLT receptor 1
Increases production of IP3, which mobilises more Ca2+ from Ca2+ stores to promote smooth muscle contraction.
What occurs when Ach binds to M3 receptor on bronchial smooth muscle?
Ach binds to M3, which activates PLC-β (phospholipase), this increases production of IP3 (by breaking down PIP2) to increase intracelluar Ca2+, which promotes bronchial smooth muscle contraction.
What can we use to inhibit PDE?
Theophylline, this keeps cAMP levels elevates to inhibit bronchoconstriction
How can we target muscarinic receptors to promote bronchodialtion?
Use muscarinic antagonists
Or can use atropine to inhibit the PNS (decreasing Ach release)
