Pathophysiology of Respiratory Disease 1 (asthma)

Question 1

Describe what asthma is

Answer 1

• A chronic inflammatory and obstructive disease of the airways
• There is first allergen inhalation or exercise which can initiate an abnormal immune response
• The subsequent inflammation of the airway then leads to impaired airway function and symptom presence such as a wheeze, cough, dyspnoea

Question 2

Describe how an asthmatic airway differs from a healthy airway

Answer 2

• In an asthmatic airway -
• Contraction of smooth muscle
• Excess mucus secretion
• Oedema/swelling
• Irritation of sensory neurons - causes a cough

The overall effect is that there is a reduced luminal area which increases airway resistance and decreases airflow

Question 3

Describe what can happen after an extended period of asthma and why it happens

Answer 3

• Overcoming the increased resistance to keep oxygenation levels adequate requires higher levels of energy to be used
• This cannot be maintained for an extended period and so after a while a person can get respiratory fatigue where respiratory muscles are no longer able to maintain the ventilation levels

Question 4

Describe how relaxation and contraction of smooth muscle affects the airways

Answer 4

• During smooth muscle contraction the lumen diameter decreased and so there is decreased luminal area which increases resistance and decreases flow
• During smooth muscle relaxation the lumen diameter increases and so there is increased luminal area which decreases resistance and increases flow

Question 5

Describe how inflammatory mediators cause smooth muscle contraction

Answer 5

• Contractile mediators bind to and activate g protein coupled receptors
• The G alpha q subunit is activated which increases phospholipase c activity
• There is then a series of intracellular signalling pathways whereby PIP2 is cleaved into IP3 and DAG which then leads to Ca2+ mobilisation and sensitivity so Ca2+ is released from the sarcoplasmic reticulum/comes from other stores and its levels rise
• This then causes smooth muscle contraction as more calcium binds to troponin so there is more frequent myosin power strokes

Question 6

Describe how beta 2 adrenoceptor activation initiates relaxation

Answer 6

• Agonist like salbutamol binds to a beta 2 adrenoceptor in the membrane
• This activates the G alpha s subunit which increases adenylate cyclase activity
• ATP is then converted into cAMP
• This then activates protein kinase A
• This decreases calcium mobilisation and sensitivity which then leads to smooth muscle relaxation

Question 7

What are the two main stages of asthma development - describe them

Answer 7

• An allergen sensitisation stage where the immune system is first activated by the presence of the allergens, activating the adaptive immune system and generating antibodies
• An allergic response whereby there is a subsequent infection by the same allergen which then binds to antibodies and activates immune cells as well as causes an inflammatory response which initiates symptoms

Question 8

Describe how allergen induced degranulation causes asthma symptoms

Answer 8

• The inhaled allergen enters the airway tissues
• The allergen then binds IgE receptors on mast cells inducing degranulation which releases cytotoxic contents like prostaglandins, chemokines etc which attract more immune cells to that area
• Eosinophils are then recruited to the area and then degranulate to release further inflammatory mediators such as enzymes, leukotrienes and reactive oxidative species
• It is this process that initiates contraction of the smooth muscle as well as excess mucus secretion which reduces the luminal diameter and so increases resistance and flow

Question 9

Describe how airway inflammation contributes to allergen induced degranulation

Answer 9

• The inhaled allergen enters the airway tissues
• This activates T helper cells. Eosinophils are then recruited to the airways and degranulate as before
• They release inflammatory mediators and so initiate contraction of smooth muscles and reduction in the airway diameter
• Hence inflammation speeds up the process of allergen induced degranulation

Question 10

Describe the effects that glucocorticoid hormones have on immune cells and structural cells

Answer 10

• Immune cells -
• Decrease numbers of eosinophils via apoptosis
• Reduce cytokine release by cells like T helper cells and macrophages
• Decrease the numbers of mast cells and dendritic cells
• Structural cells -
• Act on epithelial cells to reduce the release of cytokines mediators
• Reduce vascular leak by acting on endothelial cells
• Act on beta 2 adrenoceptors to relax airway smooth muscle
• Decrease mucus secretion by acting on mucus glands

Question 11

Describe how corticosteroid hormones exert their effects (transcription)

Answer 11

• The corticosteroid diffuses through the membrane and binds to an intracellular glucocorticoid receptor
• This drug-receptor complex then translocates to the nucleus
• The drug-receptor complex binds to DNA which affects transcription
• The altered transcription of those genes then leads to either increased or reduced transcription of a gene
• Corticosteroids can increase anti-inflammatory genes or decrease pro-inflammatory genes

Question 12

State some of the types of asthma that exist

(to be aware of that fact that asthma is complex and heterogenous, and treatment must be specific to the type present)

Answer 12

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