23) Pathophysiology of respiratory diseases - Asthma

Question 1

What is asthma?

Answer 1

• 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

Question 2

What does endotype mean?

Answer 2

• The different types/variation of a health condition.

Question 3

What are the different asthma endotypes?

Answer 3

• Aspirin associated respiratory disease
• Cold air/ exercise induced asthma
• Allergic Broncho-pulmonary mycosis
• Allergic asthma

Question 4

What is the importance of knowing the different asthma endotype?

Answer 4

• 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

Question 5

What are the symptoms of asthma?

Answer 5

• Wheezing
• Coughing
• Dyspnoea (shortness of breath)

Question 6

What changes are seen in the body during inflammation?

Answer 6

• Contraction of smooth muscle
• Excess mucus secretion
• Oedema/swelling
• Irritation of sensory neurons (cough)

Question 7

What is the overall effect of the pathologies in asthma?

Answer 7

• 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

Question 8

How does respiratory fatigue occur in asthma?

Answer 8

• 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

Question 9

What is the effect of contraction of smooth muscles on the airways?

Answer 9

• During contraction the smooth muscles get smaller

- As a result the lumen diameter/area decreases causing increased resistance and decreased air flow

Question 10

What is the effect of relaxation of smooth muscles on the airways?

Answer 10

• During relaxation the smooth muscles get larger

- As a result the lumen diameter/area increases causing decreased resistance and increased air flow

Question 11

What causes the smooth muscles in the airways to contract during asthma?

Answer 11

• When allergen are inhaled they cause degranulation (called allergen-induced degranulation) which releases inflammatory mediators
• These mediators cause the smooth muscles to contract

Question 12

How can we treat the bronchoconstriction part of an asthma attack?

Answer 12

• 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

Question 13

What is the mechanism for Airway Smooth Muscle Cell (ASMC) contraction in an asthma attack?

Answer 13

• 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

Question 14

How do asthma inhalers cure an asthma attack?

Answer 14

• 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

Question 15

How are immune cells generated in asthma?

Answer 15

• 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

Question 16

How is primary inflammation triggered?

Answer 16

• 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

Question 17

How is a late asthmatic response triggered?

Answer 17

• 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)

Question 18

How do we treat asthmatic inflammation?

Answer 18

• Corticosteroids reduce the level of inflammation by modulating the function of multiple immune and structural cells

Question 19

How do corticosteroids affect immune system cells?

Answer 19

• 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

Question 20

How do corticosteroids affect structural cells?

Answer 20

• 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

Question 21

What is the mechanism by which corticosteroids work?

Answer 21

• 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

Question 22

When are beta-2 agonist drugs used and when are corticosteroids taken?

Answer 22

• 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