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SGUL - Physiology 1 > Pathophysiology of Respiratory Diseases - Asthma > Flashcards

Pathophysiology of Respiratory Diseases - Asthma Flashcards

1
Q

What is asthma characterised by?

A
  • Airflow limitation
  • Bronchial hyperresponsiveness
  • Breathing difficulty (dyspnoea)
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2
Q

Asthma consists of an inflammatory and an airway component.

Describe the inflammatory component.

A
  • Being sensitive to a specific allergen such as pollen or dust
  • This allergen will trigger an inflammatory response
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3
Q

Asthma consists of an inflammatory and an airway component.

Describe the airway component.

A
  • The inflammatory response release mediators
  • These mediators cause airflow limitation and breathing difficulty
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4
Q

Describe the general pathway for asthma

A
  • Allergen inhalation/presence
  • Immune response
  • Inflammatory response
  • Tissue i.e airway limitation
  • Symptoms e.g dyspnoea
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5
Q

Name two pathological changes that come with asthma

A

Airway smooth muscle contraction
Mucus secretion

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6
Q

What are the effects of the pathological changes that come with asthma

A

Size of the airway lumen reduces
- Greater resistance to airflow therefore airflow is reduced

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7
Q

What is the main difference between asthma and COPD patients?

A
  • Symptoms in asthmatics are reversible - airflow resistance will reduce over time
  • Symptoms in COPD patients are irreversible and generally become worse over time
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8
Q

Allergic asthma has two steps - sensitisation and allergic response.

Describe sensitisation

A
  • Patient exposed to allergen
  • Allergen encountered and processed by adaptive immune system
  • Antibodies produced
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9
Q

Allergic asthma has two steps - sensitisation and allergic response.

Describe the allergic response

A
  • Patient exposed to allergen again
  • Allergen binds to antibodies
  • This causes an immune response, which in turn triggers inflammation
  • Symptoms produced
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10
Q

SENSITISATION IN DETAIL

Describe the first step of sensitisation

A
  • Allergen is inhaled and enters airway tissue
  • Allergen encountered by antigen-presenting cells e.g dendritic cells
  • Allergen is engulfed
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11
Q

SENSITISATION IN DETAIL

Describe the second step of sensitisation

A
  • 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
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12
Q

SENSITISATION IN DETAIL

Describe the third step of sensitisation

A
  • 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
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13
Q

SENSITISATION IN DETAIL

Describe the final step of sensitisation

A
  • Th2 cells can also secrete cytokines such as IL-5 to modulate the immune system
  • IL-5 will allow eosinophils to proliferate
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14
Q

ALLERGIC RESPONSE IN DETAIL

Describe the first step of the allergic response

A
  • 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
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15
Q

ALLERGIC RESPONSE IN DETAIL

Describe the second step of the allergic response

A
  • 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
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16
Q

Why are anti-histamines not generally prescribed for asthma?

A
  • Anti-histamines block the action of histamine
  • Histamine does not have a significant role in causing asthma symptoms
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17
Q

ALLERGIC RESPONSE IN DETAIL

Describe the final step of the allergic response

A
  • 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
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18
Q

What is airway remodelling and when may it occur during asthma?

A
  • 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
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19
Q

How might epithelial cells cause asthma symptoms?

A
  • Detect molecular patterns on allergens using pattern recognition receptors
  • Generates local inflammation through triggering of alarmins and other mediators
20
Q

How might Type 2-innate lymphoid cells cause asthma symptoms?

A
  • 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
21
Q

What are the two mechanisms by which airway smooth muscle contraction increases?

A
  • Becoming more sensitive to calcium ions which cause contraction
  • Increasing the movement of calcium from intracellular stores
22
Q

Outline the mechanism of action for bronchodilators.

A
  • 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
23
Q

What are the two types of beta-agonists?

A

SABAs - short-acting beta-agonists
LABAs - long-acting beta-agonists

24
Q

When are SABAs used by asthma patients? Give an example.

A

EXAMPLE: salbutamol
- Administered through an inhaler
- Often used on the spot when patient has an asthma attack

25
Q

When are LABAs used by asthma patients? Give an example.

A

EXAMPLE: salmeterol
- Prescribed in combination with corticosteroids. Administered through inhaler
- Often used for long-term treatment

26
Q

Outline the mechanism of action for long-acting muscarinic antagonists.

A
  • 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.
27
Q

When might a long-acting muscarinic antagonist be prescribed.

A
  • Treatment of chronic bronchitis in COPD patients
  • Prevention therapy for asthma patients
28
Q

Why might a doctor choose to prescribe a bronchodilator rather than a long-acting muscarinic antagonist?

A
  • 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.
29
Q

What is the clinical significance of knowing that asthma inflammation is caused by several factors?

A
  • 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
30
Q

Why do most anti-inflammatory drugs target cytokine action?

A

Cytokines play dominant roles in asthma inflammation

31
Q

Name possible pathways that anti-inflammatory drugs can target to prevent inflammation during asthma.

A
  • Cytokine production and release
  • Antibody production
  • IgE crosslinking
32
Q

What are the most effective medications for asthma patients?

A

Corticosteroids

33
Q

Give an example of a corticosteroid and how it is administered

A

Fluticasone
- Administered by inhaler

34
Q

Outline the mechanism of action of corticosteroids

A
  • 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
35
Q

Outline the mechanism of action of leukotriene antagonists

A
  • Competitive antagonism of leukotriene receptors
  • Pro-inflammatory mediators would usually bind to these receptors to induce inflammation
36
Q

Genetically, who might be more likely to have asthma?

A
  • Children who have parents with asthma
  • Children with susceptibility genes
37
Q

Genetically, who might be less likely to have asthma?

A
  • Children who don’t have parents with asthma
  • Children with protective genes
38
Q

Environmentally, who might be more likely to have asthma?

A
  • Children with infant respiratory virus infections
  • Children born by Caesarean delivery
  • Generally people living in urban environments with poor diets
39
Q

Environmentally, who might be less likely to have asthma?

A
  • Children born by vaginal delivery
  • Generally people living in rural environments with less pollution and healthier diets
40
Q

What are the four endotypes of asthma?

A
  • Aspirin associated respiratory disease
  • cold air/exercise induced asthma
  • allergic broncho-pulmonary mycosis
  • allergic asthma
41
Q

What effect do glucocorticoids have on cells?

A
  • Inhibits mucus secretion
  • reduces number of mast cells and dendritic cells
  • decreases release of cytokines from macrophages and T-lymphocytes
  • Cause apoptosis in eosinophils
42
Q

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

A

BETA AGONISTS - relief medication after attacks
CORTICOSTEROIDS - prevent reoccurrence of symptoms

43
Q

What aspects of acute airway pathology can be treated with drugs?

A
  • Contraction of smooth muscle.
  • Excess mucus secretion.
  • Oedema/swelling.
  • Irritation of sensory neurons (cough).
44
Q

What aspects of acute airway pathology cannot be treated with drugs?

A
  • Cause of inflammation.
  • Airway / lung remodeling.
  • Tissue damage.
45
Q

How do inflammatory mediators induce airway smooth muscle cell (ASMC) contraction?

A
  • 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.
46
Q

How do phosphodiesterase inhibitors act to relax the ASMCs?

A
  • 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.
47
Q

List some side effects that long-term/ high-dose corticosteroid administration is associated with.

A
  • Stunted growth.
  • Hypercortisolism
  • Depression.
  • Osteoporosis

SGUL - Physiology 1 (68 decks)

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