23) Pathophysiology of respiratory diseases - Asthma Flashcards
1
Q
What is asthma?
A
- A chronic, inflammatory obstructive disease of the airways
- It occurs over a long period of time with repeated episodes of inflammation.
- This inflammation is caused by an exaggerated immune response to allergens (e.g. pollen) which is inhaled
- It is this inflammation that obstructs the airways and causes difficulty breathing
2
Q
What does endotype mean?
A
- The different types/variation of a health condition.
3
Q
What are the different asthma endotypes?
A
- Aspirin associated respiratory disease
- Cold air/ exercise induced asthma
- Allergic Broncho-pulmonary mycosis
- Allergic asthma
4
Q
What is the importance of knowing the different asthma endotype?
A
- Although some treatments for asthma are very broad and work on all types (e.g, corticosteroids and beta-2-agonists) some treatments of asthma are specific to one endotype.
- The reason for this specificity is because they target specific mechanisms which may not be present in all endotypes of asthma
5
Q
What are the symptoms of asthma?
A
- Wheezing
- Coughing
- Dyspnoea (shortness of breath)
6
Q
What changes are seen in the body during inflammation?
A
- Contraction of smooth muscle
- Excess mucus secretion
- Oedema/swelling
- Irritation of sensory neurons (cough)
7
Q
What is the overall effect of the pathologies in asthma?
A
- The pathologies cause luminal area to decrease which increases airway resistance
- This causes air flow to decrease leading to the different symptoms we see
- Furthermore there is also an increased respiratory effort in order to pull the air through airways with more resistance
8
Q
How does respiratory fatigue occur in asthma?
A
- In asthma we often have to exert more respiratory effort in order to pull air through the pipes with greater airway resistance
- Prolonged exertion of this respiratory effort can cause respiratory muscles to get tired and are unable to keep exerting the force necessary to maintain the level of ventilation
- This tiredness is known as respiratory fatigue
9
Q
What is the effect of contraction of smooth muscles on the airways?
A
- During contraction the smooth muscles get smaller
- As a result the lumen diameter/area decreases causing increased resistance and decreased air flow
10
Q
What is the effect of relaxation of smooth muscles on the airways?
A
- During relaxation the smooth muscles get larger
- As a result the lumen diameter/area increases causing decreased resistance and increased air flow
11
Q
What causes the smooth muscles in the airways to contract during asthma?
A
- When allergen are inhaled they cause degranulation (called allergen-induced degranulation) which releases inflammatory mediators
- These mediators cause the smooth muscles to contract
12
Q
How can we treat the bronchoconstriction part of an asthma attack?
A
- Bronchodilators (e.g. beta-2-adrenergenic receptor agonists) in inhalers remove the contractile element from the smooth muscle cells
- This stops them from contracting and makes them relax resulting in bronchodilation
13
Q
What is the mechanism for Airway Smooth Muscle Cell (ASMC) contraction in an asthma attack?
A
- During an asthma attack inflammatory mediators are released by active immune cells which bind to (and activate) GPCRs in the membrane of smooth muscle cells
- This triggers an intracellular pathway (via Gq) which increases Ca2+ mobilisation and sensitivity.
- This means Ca2+ are free to leave intracellular stores or to enter the cell through Ca2+ channels.
- This increase in Ca2+ causes muscle contraction
14
Q
How do asthma inhalers cure an asthma attack?
A
- Asthma inhalers contain Beta-2-adrenergenic agonists which bind to Beta-2 adrenoreceptors in the smooth muscles of the airways
- This activates the receptor and stimulates an intracellular pathway (via Gs) which stimulates Adenylyl Cyclase
- Adenylyl Cyclase converts ATP into cAMP.
- cAMP then activates Protein Kinase A.
- Protein Kinase A phosphorylates different protein channels and enzymes in the cell to change their function (e.g. causing channels to open more)
- As a result of these changes we see a decrease in Ca2+ mobility and sensitivity.
- This decrease in Ca2+ causes muscle relaxation
15
Q
How are immune cells generated in asthma?
A
- Allergic responses require prior exposure and sensitisation
- First there is an allergen sensitisation phase where the immune system is first activated by the allergen
- This activation causes the immune system to be primed and increases its sensitivity
- The immune system becomes more primed with further exposures to the allergens and so more antibodies are formed
- When the person is then exposed to the same allergen an allergic response is triggered
- The allergens bind to the antibodies and so causes immune cell activation and an inflammatory response
16
Q
How is primary inflammation triggered?
A
- First the person inhales the allergen which binds to the IgE antibodies on mast cells which are made during allergic sensitisation
- Upon binding the allergen cross links the receptors and triggers the mast cell to release inflammatory mediators into the tissue (called mass cell degranulation)
- This causes the activation of other granulocytes (e.g. eosinophils) and degranulates without needing crosslinking of receptors
- The activated granulocyte releases further inflammatory mediators into the tissue
- The release of inflammatory mediators from both cells causes the different changes in asthma leading to reduced airways and generates symptoms
17
Q
How is a late asthmatic response triggered?
A
- The allergen can also bind to T-helper (Th2) cells which release cytokines to recruit more immune cells to the airways
- After this recruitment they degranulate
- This causes a second wave of inflammation many hours after the initial asthma attack (called the late asthmatic response)
18
Q
How do we treat asthmatic inflammation?
A
- Corticosteroids reduce the level of inflammation by modulating the function of multiple immune and structural cells
19
Q
How do corticosteroids affect immune system cells?
A
- In immune cells they can decrease the manner in which the cells proliferate to reduce the number of immune cells
- They can further reduce number of immune system cells by increasing apoptosis.
- Finally they can also reduce the amount of cytokine released by immune system cells
20
Q
How do corticosteroids affect structural cells?
A
- They can cause epithelial cells to reduce production of cytokines and their release
- They can reduce extravascular leak by vessels by acting on endothelial cells
- They can cause airway smooth muscle cells to express more Beta-2 receptors so that beta-2-agnoist drugs are more effective
- They work on mucus glands to reduce mucus secretion
21
Q
What is the mechanism by which corticosteroids work?
A
- They are non polar (as they are steroids) and so diffuse directly through the plasma membrane
- The bind to the glucocorticoid receptors to form a drug-receptor complex
- This complex translocates into the nucleus where it binds to particular regions of the DNA and affects transcription of certain genes
- As a result of this altered transcription (either an increase or decrease in transcription) there will be an altered translation into proteins (either increased or decreased translation/number)
- Corticosteroids can either increase the expression of anti-inflammatory genes or decrease the expression of pro-inflammatory genes
22
Q
When are beta-2 agonist drugs used and when are corticosteroids taken?
A
- Beta-2-agonist drugs are taken as relief medication (i.e. they take the medication after having an attack)
- Corticosteroids are used everyday/regularly in order to prevent symptoms from reoccurring however they do not treat an asthma attack already taking place
- This is due to the difference in their mechanisms of action
