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PATH30001 - Mechanisms of Disease > Lecture 20 - Asthma > Flashcards

Lecture 20 - Asthma Flashcards

1
Q

Describe the normal airway structure

A

Trachea
Bronchi
Bronchioles
Alveoli

Tissue structure:
 • Epithelium
 • Lamina propria
 • Muscle layer
 • Serosa
 • + Cartilage

BALT:
• Bronchial associated lymphoid tissue
• Similar to MALT

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2
Q

Describe the epithelium in the airways.

A

Pseudostratified columnar epithelium

Cell types:
• Ciliated cells
• Goblet cells

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3
Q

What happens to the thickness of the airway wall in asthma?

Why does this happen?

A

Normally: very thin wall
Disease: thickened, due to inflammatory cell infiltrate

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4
Q

Which inflammatory cell is the most important in asthma?

Describe the major features of this cell

A

Mast cells:
• Cytoplasm filled with granules
• Binds IgE with the Fc(e)R

To a lesser extent:
• Neutrophils
• Eosinophils

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5
Q

Which part of the respiratory tract is affected by asthma?

A

Bronchi

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6
Q

What are the symptoms of asthma?

A
  • Wheeze
  • Cough
  • Sputum
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7
Q

Give the defining features of asthma.

Give the more resent, more inclusive definition

A
  • Chronic, relapsing
  • Inflammatory disorder
  • Hyper-reactive airways
  • Reversible (episodic) constriction

More inclusive definition:
“Bronchial hyper-reactivity due to inflammation in response to diverse stimuli”

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8
Q

What is atopy?

A

Increased susceptibility to generation of IgE in response to external allergens

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9
Q

How common is asthma in Australia?

What is the trend in incidence?

What is its importance?

A

It is the most common chronic disease in children

Children: 1 in 4
Teenagers: 1 in 7
Adults: 1 in 10

< 14 years: boys more than girls
>15: women more than men

Big economic burden

Incidence rising, but death rates falling

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10
Q

Describe the ‘relapsing’ feature of asthma

A

May be asymptomatic between attacks

NB There may be underlying chronic airway obstruction

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11
Q

What are the classifications of asthma?

Briefly outline both

A
  1. Extrinsic:
    • Atopy
    • Type I hypersensitivity
  2. Intrinsic:
    • Airway constriction through non-immune mechanism
    eg. Drugs, Pulmonary infection, Cold, Exercise
Many others, but they are all very similar:
Steroid dependent
Steroid resistant
Difficult
Seasonal 
Exercise induced
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12
Q

What is the main treatment for asthma?

Describe how this works

A
  1. Inhaled corticosteroids

Function:
• Suppression of Th2 cytokines

  1. mAbs
    • Anti-IL4
    • Anti-IL13
    etc.
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13
Q

When does atopic asthma begin?

A

Childhood

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14
Q

What triggers atopic asthma?

A 
Environmental allergens:
 • Dust
 • Pollens
 • Animal fur
 • Foods
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15
Q

What often precedes asthma?

A
  • Allergic rhinitis
  • Urticaria (hives)
  • Eczema

These are related allergic diseases w/ similar root causes

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16
Q

Describe the mechanism of Type I Hypersensitivity

A 
1. Initial sensitisation
 • Antigen crosses epithelium
 • Binds to APCs in epithelium
 • Interacts w/ Th2 cell
 • Secretion of IgE from B cells
 • IgE binds to Fc(e)R on Mast cells

2. When the Ag is encountered again:
 • Cross linking os IgE bound to mast cells
 • Activation of Mast cells:
- Degranulation
- Activation of Arachidonic acid pathway
- Cytokine gene transcription
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17
Q

What are the mediators released in degranulation of Mast cells?

What are the functions of these mediators?

A 
1. Granule associated pre-formed mediators
 • Histamine
 • Heparin
 • Proteases (e.g. tryptase)
 • Chemotactic factors
  1. Newly formed mediators:
A. Membrane phospholipid metabolism
 • PAF
 • Prostaglandins
 • Thromboxanes
 • Leukotrienes

B. Cytokine expression

Functions:
1. Early phase reaction
 • Increased vascular permeability
 • Smooth muscle spasm
 • Oedema
  1. Late phase reaction
    • Chemoattractants: leukocyte recruitment
    • Bronchospasm
    • Epithelial damage
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18
Q

What are spasmogens?

A

Factors released by Mast cells once activated

Bring about:
• Contraction of bronchial smooth muscle
• Mucosal oedema & secretion

Ultimately leading to:
→ Airway constriction

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19
Q

Describe the function of chemotactic factors released by Mast cells

A

Act on inflammatory cells, stimulating chemotaxis towards the source, i.e. into the bronchi

Cells:
• Eosinophils
• Neutrophils

Once in the airways, these cells contribute to:
• Chronic inflammation
• Constriction of the airway

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20
Q

Compare direct & indirect effects of Mast cell degranulation

A

Direct:
• Granule contents
→ Airway constriction
→ Oedema

Indirect:
• Chemotactic factors
• Recruit more inflammatory cells
→ Airway inflammation constriction

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21
Q

What are the three phases of asthma?

Outline these phases

A
  1. Sensitisation w/ allergen
    - Occurs sometime before triggering of asthma attack -
    • Ag (e.g. pollen grain) sticks to airway epithelium
    • Processing by DC’s in LP
    • Ag presented on MHC II of DC to Th2
    • Th2 releases cytokines that stimulate B cells that recognise the Ag
    • B cells produce & secrete Ab (IgE)
    • IgE binds to Mast cell via Fc(e)R
    • Concurrent recruitment of eosinophils
  2. Early phase response
    - Triggering of attack -
    • Allergen is re-encountered
    • Allergen binds to Mast cell bound IgE; cross linking → degranulation
    • Allergen binds nerves → bronchial smooth muscle constriction
3. Late phase response
 • Effector inflammatory cells infiltrate
(Neutrophils & Eosinophils)
 • Release of various proteins:
- Major basic protein
- Eosinophil cationic protein
 • Epithelial damage
 • Much mucous in the airways
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22
Q

Describe the acute response

What is the time frame?

A

Occurring in the first few minutes:

 • Opening of tight junctions  → increased vascular permeability → oedema
 • Mucous hyper secretion
 • Vagal stimulation → broncho-constriction
 • Recruitment of inflammation cells:
- Eosinophils
- Neutrophils
- Monocytes
- Lymphocytes
- Basophils
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23
Q

What mediators do neutrophils & eosinophils release once recruited to the airways?

When are they recruited?

A

Neutrophils:
• Neutrophil elastase

Eosinophils:
• Major basic protein
• Cationic protein

Function:
• Supposed to be bactericidal
• End up damaging the tissue

Recruited in the late phase

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24
Q

What is one of the effects of damaged tissue in the airways in the late phase response?

A

Increased access of the allergen to the tissue

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25
What is the role of mucous in the late phase response?
There is a lot of mucous in the airways | Airways are increasingly occluded
26
What is the effect of histamine?
* Increased VP | * Increased secretion of mucous
27
What are the enzyme mediators released by Mast cells? | What is their function?
Proteases | Break down of tissue to allow movement of cells
28
Which inflammatory cells are recruited?
``` • Eosinophils also: • Neutrophils • Basophils • Monocytes • Lymphocytes ```
29
What are the primary mediators released by Mast cells?
Biogenic amine: • Histamine Enzymes • Proteases Chemotactic factors
30
What are the secondary mediators released by Mast cells?
Arachidonic acid metabolites: • Leukotrienes • Prostaglandin • PAF Cytokines: • Pro-inflammatory & Th2 Cytokines
31
Describe targeting of mediators to attenuate asthma Give some examples
The mediators of asthma (i.e. released by Mast cells) can be targeted to possibly treat the disease Effective therapy: • Leukotrienes • ACh Ineffective therapy: • Histamine • Prostaglandin • PAF ``` No effective antagonists as yet: • Pro-inflammatory cytokines • Bradykinin • Eotaxin • NO ```
32
Describe the genetic pre-disposition hypothesis for Asthma
* GWAS have revealed a genetic pre-disposition * Inherited condition ``` Candidate genes: • HLA complex • TCR • Cytokine function • Receptors for bronchodilators (beta-2-adrenergic receptors) ```
33
Describe the Th1 / Th2 hypothesis for Asthma What is the evidence for this hypothesis?
Asthma is related to a preponderance of Th2 Th2 is central to allergy through release of IL-4, IL-5, IL-13 • Drives IgE secretion (IL-4, IL-5) • Eosinophil recruitment (IL-5) • Mucous production, goblet cell metaplasia (IL-13) Evidence: • 'helper' T cell from airways of asthma patients: • Lack T (bet) → Th2 subclass (T(bet) needed for IFN-gamma production) • T(bet)-/- mice spontaneously develop asthma
34
Compare cytokine release by Th1 and Th2
Th1 cell: • Secretion of IL-2 and IFN-gamma Th2 cell: • Secretion of IL-4, IL-5, IL-13
35
Describe the Hygiene hypothesis
``` Certain lifestyle factors skew towards to the Th2 phenotype • Antibiotic use • Western lifestyle • Urban environment • Diet ``` Neo-nates are skewed towards Th2; appropriate stimuli are needed to create a balance
36
What are Tregs? Describe their role in healthy airways
* FOXP3 positive * Suppress Th2 bias in asthma Healthy airways: 1. DC presents antigen to Treg 2. Suppression of Th2; no allergic response
37
Describe why TGF-beta is a double edged sword
1. Suppressive cytokine | 2. Role in fibrosis
38
Describe the Airway Remodelling hypothesis What is the criticism of this hypothesis?
"Abnormal genetically determined micro-environment in airway is necessary for asthma to develop" ``` Genes identified: • E-cadherin • β-catenin • ADAM-33 • TSLP ``` Mutant forms of these proteins leads to: • Aberrant healing in the lungs: Criticism: • It is thought that these changes are secondary to the allergic disease • However with recent studies they have found that airway remodelling is observed many years before the symptoms
39
``` Describe its hypothesised role in asthma of the following proteins: • E-cadherin • β-catenin • ADAM-33 • TSLP ```
1. E-cadherin • Cell-cell adherence molecule • Mutant forms lead to epithelial damage 2. β-catenin • Cell-cell adherence molecule • Mutant forms lead to epithelial damage 3. ADAM-33 • A metalloproteinase • Mutant form increases fibroblast activity 4. TSLP • Released in healing • Stimulates cytokine release from inflammatory cells and drives inflammatory processes
40
Describe the contribution of Mast cells to airway remodelling
Bronchial smooth muscle infiltrated w/ many Mast cells Effect: • Release of vasoactive mediators • GF release • Smooth muscle proliferation
41
Describe the concept of the Epithelial mesenchymal trophic unit
Link between atopic inflammatory part of asthma and airway remodelling These two factors co-exist in most cases of asthma
42
Is Asthma diverse? | Why / why not?
Very diverse: • Many genes • Many proteins In recent studies there have been dozens of candidate genes identified that may play a role in asthma pathogenesis
43
Describe the TNF-alpha hypothesis for asthma causation
In asthmatics: increased TNF-alpha Functions: • Increases adhesion molecules in endothelium → leukocyte recruitment • Increased mucous secretion • Increased fibroblasts → fibrosis & remodelling • Smooth muscle constriction
44
What are some possible asthma therapeutics?
* TNF-alpha inhibitors | * mAbs against Th2 cytokines
45
What are the triggers of non-atopic asthma?
Viral infection: • Rhinovirus • Parainfluenza virus Inhaled pollutants: • SO2 • NO2
46
Is family history common in: • Atopic asthma • Non-atopic asthma?
Atopic: yes Non-atopic: no
47
Which drug is often responsible for drug induced asthma?
Aspirin
48
What is occupational asthma?
Various occupations involved with inhalation of various chemicals: • Formaldehyde etc.
49
Describe the macroscopic morphology in asthma
Lungs overextended | Over-inflation / collapse
50
What is the microscopic morphology in asthma?
* Occlusion of bronchi / bronchioles * Thick mucous * Mucous containing sloughed off epithelium * Charcot-Leydon crystals * Thickened basement membrane * Oedema * Inflammatory infiltrate * Hypertrophy of smooth muscle * Increase in mucous secreting glands
51
What is 'spiral pieces of epithelium'?
Sloughed off epithelium Found in the mucous in asthma
52
What are Charcot-Leydon crystals?
Collections of eosinophil membrane
53
Where are the mucous secreting glands in the airway tissue?
Submucosal: below the mucosa
54
What does vagal stimulation in the triggering of an asthma attack bring about?
Broncho-constriction
55
What is the time frame for the early and late phases of the asthma attack?
Early phase: minutes Late phase: hours • Can mast up to a day
56
What happens to the bronchial epithelium in the early phase reaction?
Opening of tight junctions | → access to sub-mucosal mast cells
57
What is the effect of major basic protein? When is it present in asthma?
Epithelial damage Present during the late phase reaction
58
Compare skin test result in people with atopic and non-atopic asthma What does this highlight about non-atopic asthma?
Atopic: reaction → allergen sensitisation Non-atopic: no reaction → no allergen sensitisation This highlights the fact that non-atopic asthma is not immune mediated
59
What happens to goblet cells in the asthma airway?
Metaplasia There are normally very few goblet cells In asthma, there are many
60
What do leukotrienes bring about?
* Prolonged bronchospasm * Increased vascular permeability * Mucous secretion
61
What is the effect of eotaxin?
Released by endothelial cell | Recruits eosinophils
62
What is the effect of eosinophil cationic protein?
Released by eosinophils once recruited to the asthmatic airways Supposed to kill extracellular pathogens In asthma, leads to damage of airways
63
What is the role of acetylcholine in asthma?
Leads to bronchoconstriction, further narrowing the airways

PATH30001 - Mechanisms of Disease (34 decks)

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