Pathophysiology of Respiratory Diseases - Asthma Flashcards
What is asthma characterised by?
- Airflow limitation
- Bronchial hyperresponsiveness
- Breathing difficulty (dyspnoea)
Asthma consists of an inflammatory and an airway component.
Describe the inflammatory component.
- Being sensitive to a specific allergen such as pollen or dust
- This allergen will trigger an inflammatory response
Asthma consists of an inflammatory and an airway component.
Describe the airway component.
- The inflammatory response release mediators
- These mediators cause airflow limitation and breathing difficulty
Describe the general pathway for asthma
- Allergen inhalation/presence
- Immune response
- Inflammatory response
- Tissue i.e airway limitation
- Symptoms e.g dyspnoea
Name two pathological changes that come with asthma
Airway smooth muscle contraction
Mucus secretion
What are the effects of the pathological changes that come with asthma
Size of the airway lumen reduces
- Greater resistance to airflow therefore airflow is reduced
What is the main difference between asthma and COPD patients?
- Symptoms in asthmatics are reversible - airflow resistance will reduce over time
- Symptoms in COPD patients are irreversible and generally become worse over time
Allergic asthma has two steps - sensitisation and allergic response.
Describe sensitisation
- Patient exposed to allergen
- Allergen encountered and processed by adaptive immune system
- Antibodies produced
Allergic asthma has two steps - sensitisation and allergic response.
Describe the allergic response
- Patient exposed to allergen again
- Allergen binds to antibodies
- This causes an immune response, which in turn triggers inflammation
- Symptoms produced
SENSITISATION IN DETAIL
Describe the first step of sensitisation
- Allergen is inhaled and enters airway tissue
- Allergen encountered by antigen-presenting cells e.g dendritic cells
- Allergen is engulfed
SENSITISATION IN DETAIL
Describe the second step of sensitisation
- Fragment of the allergen is displayed on the external membrane of antigen-presenting cell
- APC is encountered by a T-helper cell with T-cell receptors
- Antigen is presented to the T-cell, causing it to activate and mature into a Th2 cell
SENSITISATION IN DETAIL
Describe the third step of sensitisation
- The activated Th2 cell interacts with a B-cell to initiate class-switching, growth and proliferation of IgE antibodies that bind to antigens present on the allergen
- These antibodies bind (via the Fc region) to IgE receptors on granulocytes - which contain granules that contain inflammatory mediators
- Antigens can still bind to the antibodies because the light chain is displayed
SENSITISATION IN DETAIL
Describe the final step of sensitisation
- Th2 cells can also secrete cytokines such as IL-5 to modulate the immune system
- IL-5 will allow eosinophils to proliferate
ALLERGIC RESPONSE IN DETAIL
Describe the first step of the allergic response
- The allergen has antigens that are recognised by IgE molecules
- The IgE molecules become cross-linked and trigger degranulation - causing the mass release of inflammatory mediators
- Examples of such mediators are prostaglandins and cytokines
ALLERGIC RESPONSE IN DETAIL
Describe the second step of the allergic response
- Mediators bind to receptors within airway to induce changes
- Examples of these changes are oedema, eosinophil activation (to trigger release of more inflammatory mediators) and contraction of airway smooth muscle
- Immediate symptoms are bronchospasm and a decrease in airflow
Why are anti-histamines not generally prescribed for asthma?
- Anti-histamines block the action of histamine
- Histamine does not have a significant role in causing asthma symptoms
ALLERGIC RESPONSE IN DETAIL
Describe the final step of the allergic response
- Allergen presence triggers activation of Th2 cells, inducing pro-inflammatory changes
- Th2 cytokines induce eosinophil transport to airways, causing release of pro-inflammatory mediators
- Th2 cells release interleukins e.g IL-4, IL-5 and IL-13
- Causes a period of airway hyper-responsiveness
What is airway remodelling and when may it occur during asthma?
- Frequent release of inflammatory mediators causing long-term tissue injury and cellular damage
- Consists of irreversible structural changes such as fibrosis, extreme mucus hypersecretion and smooth muscle hypertrophy
- Increased obstruction and resistance to airflow. Reduced FEV1 and FVC
How might epithelial cells cause asthma symptoms?
- Detect molecular patterns on allergens using pattern recognition receptors
- Generates local inflammation through triggering of alarmins and other mediators
How might Type 2-innate lymphoid cells cause asthma symptoms?
- Cause symptoms in a very similar way to Th2 cells (cytokine release, mediator release etc.)
- Activated by alarmins, and trigger release of IL-5 and IL-13
What are the two mechanisms by which airway smooth muscle contraction increases?
- Becoming more sensitive to calcium ions which cause contraction
- Increasing the movement of calcium from intracellular stores
Outline the mechanism of action for bronchodilators.
- Most are beta-agonists which interrupt the contractile process and cause relaxation
- Bind and activate beta-adrenergic receptors on airway smooth muscle cell membranes
- Binding activates adenylate cyclase, which increases conversion of ATP to cAMP
- PKA activation increases. PKA phosphorylates multiple intracellular targets.
- Calcium mobilisation and sensitivity decreases. Muscle relaxes - luminal area increases. Reduced resistance to airflow
What are the two types of beta-agonists?
SABAs - short-acting beta-agonists
LABAs - long-acting beta-agonists
When are SABAs used by asthma patients? Give an example.
EXAMPLE: salbutamol
- Administered through an inhaler
- Often used on the spot when patient has an asthma attack
When are LABAs used by asthma patients? Give an example.
EXAMPLE: salmeterol
- Prescribed in combination with corticosteroids. Administered through inhaler
- Often used for long-term treatment
Outline the mechanism of action for long-acting muscarinic antagonists.
- Blocks M3 (muscarinic) receptors on airway smooth muscle cells
- Prevents binding of acetylcholine
- Acetylcholine would usually cause contraction though the Gq pathway
- Since the receptor is blocked, ACh-mediated contraction is reduced.
When might a long-acting muscarinic antagonist be prescribed.
- Treatment of chronic bronchitis in COPD patients
- Prevention therapy for asthma patients
Why might a doctor choose to prescribe a bronchodilator rather than a long-acting muscarinic antagonist?
- Antagonists block the action of ACh- acetylcholine has a limited role in airway smooth muscle contraction during asthma attacks.
- However, the antagonist does slightly reduce mucus secretion.
What is the clinical significance of knowing that asthma inflammation is caused by several factors?
- If inflammation is triggered by several factors, it will also be triggered by several distinct mechanisms of action
- Drugs can be developed to target these mechanisms
Why do most anti-inflammatory drugs target cytokine action?
Cytokines play dominant roles in asthma inflammation
Name possible pathways that anti-inflammatory drugs can target to prevent inflammation during asthma.
- Cytokine production and release
- Antibody production
- IgE crosslinking
What are the most effective medications for asthma patients?
Corticosteroids
Give an example of a corticosteroid and how it is administered
Fluticasone
- Administered by inhaler
Outline the mechanism of action of corticosteroids
- Bind to glucocorticoid receptors present on cytosol of structural cells
- Forms a drug-receptor complex which migrates to nucleus of cell
- This complex binds to DNA and modulates transcription and translation
- Reduces transcription of genes coding for pro-inflammatory mediators
- Increase anti-inflammatory mediator expression
Outline the mechanism of action of leukotriene antagonists
- Competitive antagonism of leukotriene receptors
- Pro-inflammatory mediators would usually bind to these receptors to induce inflammation
Genetically, who might be more likely to have asthma?
- Children who have parents with asthma
- Children with susceptibility genes
Genetically, who might be less likely to have asthma?
- Children who don’t have parents with asthma
- Children with protective genes
Environmentally, who might be more likely to have asthma?
- Children with infant respiratory virus infections
- Children born by Caesarean delivery
- Generally people living in urban environments with poor diets
Environmentally, who might be less likely to have asthma?
- Children born by vaginal delivery
- Generally people living in rural environments with less pollution and healthier diets
What are the four endotypes of asthma?
- Aspirin associated respiratory disease
- cold air/exercise induced asthma
- allergic broncho-pulmonary mycosis
- allergic asthma
What effect do glucocorticoids have on cells?
- Inhibits mucus secretion
- reduces number of mast cells and dendritic cells
- decreases release of cytokines from macrophages and T-lymphocytes
- Cause apoptosis in eosinophils
When are beta-2 agonist drugs used and when are corticosteroids taken?
BETA AGONISTS - relief medication after attacks
CORTICOSTEROIDS - prevent reoccurrence of symptoms
What aspects of acute airway pathology can be treated with drugs?
- Contraction of smooth muscle.
- Excess mucus secretion.
- Oedema/swelling.
- Irritation of sensory neurons (cough).
What aspects of acute airway pathology cannot be treated with drugs?
- Cause of inflammation.
- Airway / lung remodeling.
- Tissue damage.
How do inflammatory mediators induce airway smooth muscle cell (ASMC) contraction?
- Mediators bind to receptors
- This activates the Gq pathway.
- When this pathway is activated, it results in Ca2+ being able to leave the SR into the cytosol. This increase the Ca2+ mobilisation and sensitivity.
- The Ca2+ binds to calmodulin and activates myosin light chain kinase. This initiates muscle contraction.
How do phosphodiesterase inhibitors act to relax the ASMCs?
- Inhibition of phosphodiesterase reduces the breakdown of cAMP to AMP.
- The resulting increase in cAMP concentration, in turn, activates Protein Kinase A, which phosphorylates multiple intracellular targets, ultimately decreasing calcium levels, inducing relaxation.
List some side effects that long-term/ high-dose corticosteroid administration is associated with.
- Stunted growth.
- Hypercortisolism
- Depression.
- Osteoporosis
