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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
Q

What is the role of mucous in the late phase response?

A

There is a lot of mucous in the airways

Airways are increasingly occluded

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26
Q

What is the effect of histamine?

A
  • Increased VP

* Increased secretion of mucous

27
Q

What are the enzyme mediators released by Mast cells?

What is their function?

A

Proteases

Break down of tissue to allow movement of cells

28
Q

Which inflammatory cells are recruited?

A 
• Eosinophils
also:
 • Neutrophils
 • Basophils
 • Monocytes
 • Lymphocytes
29
Q

What are the primary mediators released by Mast cells?

A

Biogenic amine:
• Histamine

Enzymes
• Proteases

Chemotactic factors

30
Q

What are the secondary mediators released by Mast cells?

A

Arachidonic acid metabolites:
• Leukotrienes
• Prostaglandin
• PAF

Cytokines:
• Pro-inflammatory & Th2 Cytokines

31
Q

Describe targeting of mediators to attenuate asthma

Give some examples

A

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
Q

Describe the genetic pre-disposition hypothesis for Asthma

A
  • GWAS have revealed a genetic pre-disposition
  • Inherited condition
Candidate genes:
 • HLA complex
 • TCR
 • Cytokine function
 • Receptors for bronchodilators (beta-2-adrenergic receptors)
33
Q

Describe the Th1 / Th2 hypothesis for Asthma

What is the evidence for this hypothesis?

A

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
Q

Compare cytokine release by Th1 and Th2

A

Th1 cell:
• Secretion of IL-2 and IFN-gamma

Th2 cell:
• Secretion of IL-4, IL-5, IL-13

35
Q

Describe the Hygiene hypothesis

A 
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
Q

What are Tregs?

Describe their role in healthy airways

A
  • FOXP3 positive
  • Suppress Th2 bias in asthma

Healthy airways:

  1. DC presents antigen to Treg
  2. Suppression of Th2; no allergic response
37
Q

Describe why TGF-beta is a double edged sword

A
  1. Suppressive cytokine

2. Role in fibrosis

38
Q

Describe the Airway Remodelling hypothesis

What is the criticism of this hypothesis?

A

“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
Q 
Describe its hypothesised role in asthma of the following proteins:
 • E-cadherin
 • β-catenin
 • ADAM-33
 • TSLP
A
  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
Q

Describe the contribution of Mast cells to airway remodelling

A

Bronchial smooth muscle infiltrated w/ many Mast cells

Effect:
• Release of vasoactive mediators
• GF release
• Smooth muscle proliferation

41
Q

Describe the concept of the Epithelial mesenchymal trophic unit

A

Link between atopic inflammatory part of asthma and airway remodelling

These two factors co-exist in most cases of asthma

42
Q

Is Asthma diverse?

Why / why not?

A

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
Q

Describe the TNF-alpha hypothesis for asthma causation

A

In asthmatics: increased TNF-alpha

Functions:
• Increases adhesion molecules in endothelium → leukocyte recruitment
• Increased mucous secretion
• Increased fibroblasts → fibrosis & remodelling
• Smooth muscle constriction

44
Q

What are some possible asthma therapeutics?

A
  • TNF-alpha inhibitors

* mAbs against Th2 cytokines

45
Q

What are the triggers of non-atopic asthma?

A

Viral infection:
• Rhinovirus
• Parainfluenza virus

Inhaled pollutants:
• SO2
• NO2

46
Q

Is family history common in:
• Atopic asthma
• Non-atopic asthma?

A

Atopic: yes

Non-atopic: no

47
Q

Which drug is often responsible for drug induced asthma?

A

Aspirin

48
Q

What is occupational asthma?

A

Various occupations involved with inhalation of various chemicals:
• Formaldehyde etc.

49
Q

Describe the macroscopic morphology in asthma

A

Lungs overextended

Over-inflation / collapse

50
Q

What is the microscopic morphology in asthma?

A
  • 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
Q

What is ‘spiral pieces of epithelium’?

A

Sloughed off epithelium

Found in the mucous in asthma

52
Q

What are Charcot-Leydon crystals?

A

Collections of eosinophil membrane

53
Q

Where are the mucous secreting glands in the airway tissue?

A

Submucosal: below the mucosa

54
Q

What does vagal stimulation in the triggering of an asthma attack bring about?

A

Broncho-constriction

55
Q

What is the time frame for the early and late phases of the asthma attack?

A

Early phase: minutes

Late phase: hours
• Can mast up to a day

56
Q

What happens to the bronchial epithelium in the early phase reaction?

A

Opening of tight junctions

→ access to sub-mucosal mast cells

57
Q

What is the effect of major basic protein?

When is it present in asthma?

A

Epithelial damage

Present during the late phase reaction

58
Q

Compare skin test result in people with atopic and non-atopic asthma

What does this highlight about non-atopic asthma?

A

Atopic: reaction → allergen sensitisation
Non-atopic: no reaction → no allergen sensitisation

This highlights the fact that non-atopic asthma is not immune mediated

59
Q

What happens to goblet cells in the asthma airway?

A

Metaplasia
There are normally very few goblet cells
In asthma, there are many

60
Q

What do leukotrienes bring about?

A
  • Prolonged bronchospasm
  • Increased vascular permeability
  • Mucous secretion
61
Q

What is the effect of eotaxin?

A

Released by endothelial cell

Recruits eosinophils

62
Q

What is the effect of eosinophil cationic protein?

A

Released by eosinophils once recruited to the asthmatic airways

Supposed to kill extracellular pathogens
In asthma, leads to damage of airways

63
Q

What is the role of acetylcholine in asthma?

A

Leads to bronchoconstriction, further narrowing the airways

PATH30001 - Mechanisms of Disease (34 decks)

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