Asthma

Question 1

what type of disease is asthma?

Answer 1

Inflammatory disease that causes occasional breathing difficulties. Type-1 hypersensitivity

Question 2

What are the symptoms of asthma?

Answer 2

Wheezing - whistling sound when breathing
Breathlessnes
Tight chest - like a band around the chest
Coughing
Symptoms may temporarily worsen - an asthma attack

Question 3

What are the type of triggers causing an attack?

Answer 3

allergens like house dust mits, cigarette smoke, strong smells, gases and cold air, exercise

Question 4

What is the Sensitisation of Asthma

Answer 4

This is an Innate and Adaptive response. The individual must be allergic and be able to recognise the protein as a pathogen (foreign protein)
Exposure of genetically predisposed (the individual will be more likely to get a reaction due to their genes) individuals to the allergen.

Question 5

What are the steps in the Sensitisation of Asthma?

Answer 5

1) The dendritic cells are antigen presenting (accessory cells) cells and sit in the in the environment processing materiial, and will present any foreign proteins to the T-cells of the Immune system.
2) A foreign proetin will be presented by the dendtritic cells to the surface of a Type 0 T-helper cell (Th0) which is a naive T-cell that has differentiated from the bone marrow
3) Th0 will then differentiate to Type 2 T-helper cell (Th2) which is unique for asthma.
4) Th2 will start to release cytokines which are signaling proteins like Interleukin 1,2,4,5. These are all involved in different processes.
5) The TH2 will activate B-cells either by direct interaction or by the release of Interleukins 1,2,or 5 cytokines. The B-cells are important for the memory of the immune system by producing IgE antibodies.
6) IgE antibodies are the immunoglobulin type for allergens. They are less specific than IgG, and recognise many protein allergens. The IgE levels of an asthmatic patient will be elevated, although not neccessarily circulating because IgE bind to mast cells which triggers degranulation.
7) IL5 will also activate another type of blood cells called Eosinophils. These are expressed in the lungs of asthmatics (and not non-asthmatics) They will differentiate and express more receptors to attract more eosinophils. The receptors are on the vasculature of the lung, and circulating eosinophils will bind and enter the lung.
8) IL-4 will act on the mast cells by causing them to express IgE receptors. IgE will then bind to the IgE-R and cause mast cell degranulation, triggering an asthma attack.
9) IL4 will also affect the vascular endothelial cells, causing an increase in vasoactive substances causing an increase or decrease in BP, the expression of eosinophils receptors, and synthesis of inflammatory mediators like chemoatractants.

Question 6

What is the Innate immune response?

Answer 6

nonspecific defense mechanisms that come into play immediately or within hours of an antigen’s appearance in the body. These mechanisms include physical barriers such as skin, chemicals in the blood, and immune system cells that attack foreign cells in the body. The innate immune response is activated by chemical properties of the antigen.

Question 7

What is the Adaptive immune response?

Answer 7

The adaptive immune response is more complex than the innate. The antigen first must be processed and recognized. Once an antigen has been recognized, the adaptive immune system creates an army of immune cells specifically designed to attack that antigen. Adaptive immunity also includes a “memory” that makes future responses against a specific antigen more efficient.

Question 8

What are the triggers for asthmatics?

Answer 8

THey are not allergic to all foreign proteins, and usually know what they are allergic to.
Allergens: specific e.g. pollen, dust mites, etc. These are immune related.
Occupational agents: specific and non-specific e.g. An agent in cigarette smoke or smoke in general
Others: non-specific e.g. cold air, excercise, stress, drugs - these are not immune related

Question 9

What type of asthma involves a specific trigger?

Answer 9

Extrinsic asthma because it involves a specific allergen from outside the body

Question 10

What type of asthma involves non-specific triggers?

Answer 10

Intrinsic asthma as it is a defect in the body, where the person’s lungs are hypersensitive.

Question 11

What is Early phase asthma attack?

Answer 11

This is an increase in resistance to flow that peaks at the highest bronchoconstriction 30-60 minutes after allergen exposure. It will subside 30-90 minutes later. The symptoms are a result of inflammatory mediators released from the mast cells.

Question 12

What is Late phase asthma attack?

Answer 12

This is an asthma attack that occurs many hours (6+) after allergen exposure, and the response does not need the allergen to be present at the time. If follows on from early phase asthma. The response is due to an influx of eosinophils into the lungs, triggering another asthma attack. A late phase asthma attack is also the cause of many Night-time asthma attacks.

Question 13

Why do many people think they are allergic to bed bugs?

Answer 13

Many people axperience night time asthma attacks thinking that it is due to bed bugs, when infact is is due to a late-phase asthma attack from an allergen exposed to many hours earlier. Regular steroid use will prevent late-phase asthma due to the blocking of eosinophils entry into the lungs.

Question 14

What is people experiencing night-time asthma often a sign of?

Answer 14

That they are not using their steroid inhalers properly because that steroid will prevent eosinophils entry into the lungs, preventing night-time asthma.

Question 15

What is the broad paradigm (pattern of) asthma?

Answer 15

1) Mast cell activation and degranulation
2) Early-phase asthma
3) Late- phase asthma
4) Inflammation induced airway remodelling

Question 16

What is Inflammation induced airway remodelling?

Answer 16

This is airway thickening, causing a decrease in airway diameter, leading to a more sever attack next time

Question 17

What do we know about why antihistamines don’t work against asthma?

Answer 17

We know that histamine is released during mast cell degranulation, causing brnochoconstriction. However antihistamines don’t work against asthma meaning that other mediators are released during degranulation.

Question 18

Why does an asthma attack cause difficulty breathing?

Answer 18

Asthma attack is an inappropriate response to what the body thinks is a pathogen. It will cause bronchoconstriction, and also vasodilation, making the blood vessels more leaky, causing oedema in the lung. The tissue in the lung swells around the airway making it harder to breathe.

Question 19

How does is Leukotrines, Thromboxane, and Prostacyclin produced in the mast cells?

Answer 19

The cytoplasm of the mast cells contain many organelles including lipid bodies. In the lipid bodies, arachidonic acid is produced from phospholipids by phospholipase A2. The Arachidonic acid is then metabolisd by:
-Lipoxygenase to form Leukotrines,
-Cyclo-oxygenase to form PG-endoperoxides
PG-endoperoxidases are then metabolised by:
-Prostacyclin synthetase to form Prostacyclin
-Thromboxane synthetase to form Thromboxane.
These are then stored ready for degranulation

Question 20

What are the function of Prostacyclin and Thromboxane?

Answer 20

Thromboxane induces blood platelet aggregation causing vasocinstriction.
Prostacyclin prevents platelet plug formation by inhibiting platelet activation causing vasodilation.

Question 21

What are the drugs that inhibit Mast cell actuvation?

Answer 21

Glucocorticoids, NSAIDs,

Question 22

How do Glucocorticoids inhibit Mast cell activation?

Answer 22

They block the activation of Phospholipids by inhibiting phospholipase A2 so less Arachidonic acid is produced leading to less mediators being produced and therefore less released duting degranulation.

Question 23

How do NSAIDs inhibit Mast cell activation?

Answer 23

They inhibit cyclo-oxygenase and therefore block the production of PG (preostaglandin)-endoperoxidases from Arachidonic acid.

Question 24

Which type of Cyclo-oxygenase enzyme is importatn for normal Homeostasis? and what is the effect of inhibiting this?

Answer 24

COX-1. Inhibiting this disrupts homeostasis and will therefore cause side effects like Ulcers in the GI tract

Question 25

What type of Cyclo-oxygenase enzyme is importatn for Inflammation? and what is the effect of inhibiting this?

Answer 25

COX-2 is induced by inflammation so is not present without inflammation. Inhibiting this is a better target than COX 1, but the disadvantage is that it has cardiac toxicity as a side effect.

Question 26

How will an antigen cause mast cell degranulation?

Answer 26

The cross-linking between two IgE antibodies on the surface of a mast-cell by an antigen results in mast-cell degranulation and release of histamine and other mediators.

Question 27

When degranulation occurs, what do the mediators released cause?

Answer 27

Bronchoconstriction
Increased mucous production by goblet cells
Vasodilation
Increased vascular permeability
Leukocyte recruitment.

Question 28

What is the only medication that can block all the mediators released during degranulation?

Answer 28

Corticosteroids.

Question 29

What can’t corticosteroids block?

Answer 29

Early phase asthma - steroids don’t block the allergen, but will block late-phase mast cell degranulation.

Question 30

What is bronchoconstriction?

Answer 30

This is smooth muscle contraction which narrows the airway, making it hard to breathe due to increased resistance. It also causes air-trapping in the alveoli called Hyperinflation.

Question 31

What is meant by incresaed mucous production?

Answer 31

INcreased mucous production by the goblet cells due to the luekotrines can cause plugging in the alveoli, trapping de-oxygenated air inside, and preventing any new oxygenated air from getting in. This is HYPERINFLATION. This can eventually kill a patient if this happens in larger tissues.

Question 32

What does increased Vasodilation and permeability cause?

Answer 32

Both of these together will casue OEDEMA which is excess fluid in the cavities and tissues of the body.
In this case, it will cause pulmonary Oedema, where fluid will collect around the broncus, decreasing the diameter of the lumen and therefore increaseing resistance, making it harder to breathe.

Question 33

What is late-phase bronchoconstriciton?

Answer 33

This follows on from the early phase:
Oedema becomes more prominent, and causes narrowing in the airways.
Sympathetic nerve fibers release inflammatory agents leading to bronchoconstriciton
The parasympathetic nervous system is activated, and casues the release of Acetyl CHoline which goes on to bind to M3 receptors in the lung, and cause bronchoconstriciton.

Question 34

When are Eosinophils attracted, what are they, and in the long term, what do they cause?

Answer 34

These are attracted during early phase asthma
They are cytotoxic mediators
In long term they will cause remodelling and thickening of the airway

Question 35

What are the 2 types of pharmacological treatment for asthma?

Answer 35

No cure,
Palliative reliever
Preventer cortiocsteroids

Question 36

What are the Palliative reliever?

Answer 36

Palliative : relieve symptoms but not treat underlying condition.
B2-agonists causing immediate vasodilation, relieveing the symptoms of asthma by opening the airways
e.g. Ventolin (salbutamol)

Question 37

What are the Preventer corticosteroids?

Answer 37

These treat the condition, and not the immeidate symptoms. In the long twem, they intervene in the remodelling process. Compliance is an issue due to not seeing short term effects.

Question 38

WHat are the advantages of being able to deliver Salbutamol and corticosteroids locally?

Answer 38

There are no systemic side effects delivering both to the lungs.
Steroid systemic side effects: round face, red cheecks, thin legs, round belly, hump back etc
Salbutamol systemic side effects: B2 agonists will cause vasodilation in the body, therefore a decrease in BP.

Question 39

Why is the formulation of Aerosols difficult?

Answer 39

The diameter of particels must be from 1-5micrometers. The particles must be small enough to penetrate the lower airways, but be lagre enough not to be breathed out during exhalation.
They musn’t have too much momentum, or when inhaled, they would hit the back of the throat and dissolve.
Depending on the type of inhalor, if the momentum of particles isn’t right, they won’t reach the target.

Question 40

Why does disease progression cause issues with drug delivery?

Answer 40

If the patient has a reduced ability to take a breath, then their ability to get the drug to the target is reduced.