Week 10: Airway Hypersensitivity and Asthma Flashcards
Describe cholinergic control (parasympathetic) of airway smooth muscle and what effect will cholinergic stimulation have in the airways
Vagus nerve releases ACh which acts on muscarinic 3 cholinergic receptors. When these are stimulated they produce contraction of bronchial smooth muscle.
- Bronchial smooth muscle contraction (bronchoconstriction)
- They will increase glandular secretion
- Increased viscosity of mucous produced
- It is also going to release a whole range of local cytokines (e.g. histamine, leukotrienes) which lead to damage of the epithelium and attraction of white blood cells
There will also vascular leakage (from loosened capillary epithelial cells) causing increased fluid leak and the resulting oedema
Describe adrenergic (sympathetic) control if airway smooth muscle.
There aren’t very many sympathetic nerves going to the airways.
- controlling airways smooth muscle is not via the Sympathetic nerves, but via circulating catecholamines (we still have receptors, just no nerve innervation from SNS)
It is adrenaline that acrts on airway beta 2 adrenoceptors. Acted on by an agonist –> causes relaxation
Adrenaline can be known as a beta 2 agonists
What is the mechanism of action of beta 2 agonists
- G protein adenylyl cyclase (which is coupled with the beta 2 receptors) is activated to increase cAMP
- This is going to activate Protein Kinase A which have a whole range of effects
- In terms of smooth muscle, this decreases Myosin Light Chain Kinase (which is an enzyme that enables myosin to interact with the active sights on actin)
- Which will decrease the contraction of the smooth muscle as well as; decrease mucous production, reduce histamine release from certain cells
Where are beta 2 adrenergic receptors found
- Mostly on the bronchiolar smooth muscle
- These are most numerous in the small airways
- There are normally 3 x more beta 2 receptors than beta 1 receptors (particularly within the small airways) - Airway epithelium
- Some vascular smooth muscle
- However, this is mostly home to alpha 1 receptor
Describe NANC (NONADRENERGIC NONCHOLINERGIC) CONTROL control of airway smooth muscle
CONTROL (NONADRENERGIC NONCHOLINERGIC CONTROL)
- This is known as NANC as it was found to be neither adrenergic or cholinergic and is the 3rd autonomic system that controls the airways
- It is the only direct bronchodilator system and acts mainly through nitric oxide (NO)
- Nitric oxide is a vasodilator, in terms of the lung smooth muscle it acts to decrease calcium ion levels within the smooth muscle cells which will cause the muscles to relax, causing bronchodilation
- As the sympathetic are not under neural control in the airways but rather act through circulating catecholamines, it means that this NANC control is our only neural bronchodilator that we have
- NO activates secondary messenger which decreases calcium in ASM à causes ASM relaxation à bronchodilation
What is asthma
- Is a chronic relapsing inflammatory disorder that is characterised by hyperactive airways that leads to episodic, reversible bronchoconstriction that is caused by increase responsiveness of the tracheobronchial tree to a range of different stimuli
What are the 2 overview types of asthma and the sub types of asthma under them (x3 and x1)
- Extrinsic (allergic)
- Is the most common form of asthma
- – Atopic/allergic: initiated by a Type 1 hypersensitivity reaction induced by exposure to an extrinsic allergen –
- Occupational (extrinsic but may/may not be atopic)
- Exercise induced bronchoconstriction (extrinsic but may/may not be atopic) - Intrinsic (non allergic)
- Also known as idiosyncratic, has vastly lower incidences
What are the structural changes (the remodelling) that occur in the airway in asthma
- Hypertrophied smooth muscle (which eventually makes asthma worsen)
- Oedema (caused by vascular leak)
- Hypertrophied mucosal glands (therefore increased mucus released)
- Increased airway mucus
- All of these are going to increase airway obstruction, and therefore increase resistance to airflow
Describe the pathology of asthma
- During an attack, the most obvious pathology is the contraction of hypertrophied airway smooth muscle
- Other changes include;
- There will be increased mucus production, from the hypertrophied mucus glands
- There will be increased oedema of the airway itself
- Extensive infiltration by eosinophils and lymphocytes
what happens to the FEV1, FEV1/FVC, PEFR and RV in asthma
- FEV1 decreased
- FEV1 / FVC decreased
- PEFR (peak expiratory flow rate) decreased
- RV increases (due to gas trapping)
What is atopic asthma
extrinsic or intrinsic?
when does it usually begin?
What is it triggered by?
- This type of asthma occurs when you are sensitised to an inhaled allergen (usually through a Type 1 Hypersensitivity response)
- Falls under extrinsic, and is by far the most common cause of asthma
- This usually begins during childhood (however this is not a hard and fast rule)
- Atopic asthma is triggered by a range of allergens that differ from patient to patient. Some examples include;
- Dust
- Pollens
- Animal dander
- Foods
- There is usually a family history of atopy (allergic type response), however it may express differently in siblings. For example, hives, eczema, hay fever or allergic rhinitis
What is type 1 hyper sensitivity
- Is a rapidly developing immunologic reaction that occurs after an antigen combines with an antibody bound to a mast cell in individuals that have been previously sensitised to the antigen
What is the first step of type 1 hypersensitivity
- Pre-sensitisation
- Occurs when a patient is exposed to an antigen for the first time, which is then presented to Type 2 T-Helper cells (TH2)
- This TH2 cell then produces heaps of cytokines (particularly IL-4) which message the B cells to produce IgE
- This IgE is really important for atopy
- This IgE then goes off and attaches itself to the mast cells
- As a result of this, the mast cell now has an IgE that is specific for that antigen
- This process occurs upon the first exposure to the antigen
What is the second phase of type 1 hypersensitivity
- Early phase
- The next time the person is exposed to the antigen, the antigen will attach to the IgE that is attached to the mast cell which is going to cause a response
- The mast cell is going to degranulate, break apart and release its mediators known as cytokines
- These cytokines are going to have a range of different roles, including the direct stimulation of Parasympathetic nerve terminals
- This causes a number of things; bronchoconstriction, mucus production / secretion and loosening of the tight junctions between airway epithelial cells (which will allow the antigen access to submucosal layers)
What is the 3rd phase of type 1 hypersensitivity
- The start of the late phase is caused by the release of eotaxin by the epithelial cells which attracts the influx of white blood cells (particularly eosinophils)
- The eosinophils release a major basic protein and eosinophil cationic protein à destroy epithelium à the destruction of epithelium triggers release of more eotaxin and therefore more eosinophils.
- Through decreased mucus ciliary function, the consequent accumulation of mucus in our airways
- We will also get increase vascular permeability (causing leakage of fluid from capillaries causing edema)
- The airway will also get increasingly more responsive to the airway, as we have loosened the tight junctions between the epithelial cells
- This then allows the antigen and the mediators direct access to the parasympathetic nerves
What are the 3 main pharmacological agents that provoke asthma
- Aspirin
- Is very uncommon, is thought to produce bronchoconstricting agents obviously leading to bronchoconstriction - Codeine and morphine
- Stimulates the mast cells to degranulate directly - Melittin (bee venom)
- Stimulates the mast cells to degranulate directly
- Is a separate response to anaphylactic response
What are the occupational asthma triggers
- Fumes
- Expoxy resins
- plastics - Gases
- Toluene - Chemicals
- Formaldehyde, penicillin products - Dusts
- Wood, cotton, platinum
What does exercise induce asthma sometimes
he crucial factor in pathogenesis appears to be the cool dry air which drys the airway wall
What is idiosyncratic asthma
is it extrinsic or intrinsic
- Is a smaller subgroup of asthma, that seems to be triggered after viral respiratory infections
- Patients with this often have no family history of asthma, and have normal IgE levels
- There is often no other associated allergies
- The current hypothesis is that a viral induced inflammation of the respiratory mucosa lowers the threshold for stimulation of sub-epithelial vagal receptors (parasympathetic nerves), which leads to bronchoconstriction. However, it is not definitely known
- For some people it is for 3 – 4 months, for others it becomes permanent (we don’t know why)
Intrinsic
What is the most useful anti-inflammatory drug used for asthma
corticosteroids
Outline the steps in order that occur in airway smooth muscle contraction (include just first pathway)
- calcium enters the cell from sarcoplasmic reticulum
- calcium activates calmodulin
- calmodulin activatesa and phosphorylates MLCK
- cross bridge cycling then occurs
Outline the steps in order that occur in airway smooth muscle contraction (include just the second pathway)
agonist binds to GPCR –> activates PLC –> this activates IP3 to increase Caclium in SR (this goes to back to pathway 1). PLC also activates DAG which activates PKC which activates calcium sensitive latch bridge (makes cacliumbind more) –> incarease contraction
draw a basic diagram indicating how airway diameter is controlled (include receptors)
In a lung function test (shows results of FEV1, FEV1/FVC etc.) what results would be consistent with asthma?
should perform better than 12% in FEV1 after administered bronchodilator
Which phase would you use beta 2 agonist and or glucocorticosteroids
