Lecture 20 - Asthma Flashcards
Describe the normal airway structure
Trachea
Bronchi
Bronchioles
Alveoli
Tissue structure: • Epithelium • Lamina propria • Muscle layer • Serosa • + Cartilage
BALT:
• Bronchial associated lymphoid tissue
• Similar to MALT
Describe the epithelium in the airways.
Pseudostratified columnar epithelium
Cell types:
• Ciliated cells
• Goblet cells
What happens to the thickness of the airway wall in asthma?
Why does this happen?
Normally: very thin wall
Disease: thickened, due to inflammatory cell infiltrate
Which inflammatory cell is the most important in asthma?
Describe the major features of this cell
Mast cells:
• Cytoplasm filled with granules
• Binds IgE with the Fc(e)R
To a lesser extent:
• Neutrophils
• Eosinophils
Which part of the respiratory tract is affected by asthma?
Bronchi
What are the symptoms of asthma?
- Wheeze
- Cough
- Sputum
Give the defining features of asthma.
Give the more resent, more inclusive definition
- Chronic, relapsing
- Inflammatory disorder
- Hyper-reactive airways
- Reversible (episodic) constriction
More inclusive definition:
“Bronchial hyper-reactivity due to inflammation in response to diverse stimuli”
What is atopy?
Increased susceptibility to generation of IgE in response to external allergens
How common is asthma in Australia?
What is the trend in incidence?
What is its importance?
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
Describe the ‘relapsing’ feature of asthma
May be asymptomatic between attacks
NB There may be underlying chronic airway obstruction
What are the classifications of asthma?
Briefly outline both
- Extrinsic:
• Atopy
• Type I hypersensitivity - 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
What is the main treatment for asthma?
Describe how this works
- Inhaled corticosteroids
Function:
• Suppression of Th2 cytokines
- mAbs
• Anti-IL4
• Anti-IL13
etc.
When does atopic asthma begin?
Childhood
What triggers atopic asthma?
Environmental allergens: • Dust • Pollens • Animal fur • Foods
What often precedes asthma?
- Allergic rhinitis
- Urticaria (hives)
- Eczema
These are related allergic diseases w/ similar root causes
Describe the mechanism of Type I Hypersensitivity
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
What are the mediators released in degranulation of Mast cells?
What are the functions of these mediators?
1. Granule associated pre-formed mediators • Histamine • Heparin • Proteases (e.g. tryptase) • Chemotactic factors
- 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
- Late phase reaction
• Chemoattractants: leukocyte recruitment
• Bronchospasm
• Epithelial damage
What are spasmogens?
Factors released by Mast cells once activated
Bring about:
• Contraction of bronchial smooth muscle
• Mucosal oedema & secretion
Ultimately leading to:
→ Airway constriction
Describe the function of chemotactic factors released by Mast cells
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
Compare direct & indirect effects of Mast cell degranulation
Direct:
• Granule contents
→ Airway constriction
→ Oedema
Indirect:
• Chemotactic factors
• Recruit more inflammatory cells
→ Airway inflammation constriction
What are the three phases of asthma?
Outline these phases
- 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 - 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
Describe the acute response
What is the time frame?
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
What mediators do neutrophils & eosinophils release once recruited to the airways?
When are they recruited?
Neutrophils:
• Neutrophil elastase
Eosinophils:
• Major basic protein
• Cationic protein
Function:
• Supposed to be bactericidal
• End up damaging the tissue
Recruited in the late phase
What is one of the effects of damaged tissue in the airways in the late phase response?
Increased access of the allergen to the tissue
What is the role of mucous in the late phase response?
There is a lot of mucous in the airways
Airways are increasingly occluded
What is the effect of histamine?
- Increased VP
* Increased secretion of mucous
What are the enzyme mediators released by Mast cells?
What is their function?
Proteases
Break down of tissue to allow movement of cells
Which inflammatory cells are recruited?
• Eosinophils also: • Neutrophils • Basophils • Monocytes • Lymphocytes
What are the primary mediators released by Mast cells?
Biogenic amine:
• Histamine
Enzymes
• Proteases
Chemotactic factors
What are the secondary mediators released by Mast cells?
Arachidonic acid metabolites:
• Leukotrienes
• Prostaglandin
• PAF
Cytokines:
• Pro-inflammatory & Th2 Cytokines
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
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)
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
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
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
What are Tregs?
Describe their role in healthy airways
- FOXP3 positive
- Suppress Th2 bias in asthma
Healthy airways:
- DC presents antigen to Treg
- Suppression of Th2; no allergic response
Describe why TGF-beta is a double edged sword
- Suppressive cytokine
2. Role in fibrosis
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
Describe its hypothesised role in asthma of the following proteins: • E-cadherin • β-catenin • ADAM-33 • TSLP
- E-cadherin
• Cell-cell adherence molecule
• Mutant forms lead to epithelial damage - β-catenin
• Cell-cell adherence molecule
• Mutant forms lead to epithelial damage - ADAM-33
• A metalloproteinase
• Mutant form increases fibroblast activity - TSLP
• Released in healing
• Stimulates cytokine release from inflammatory cells and drives inflammatory processes
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
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
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
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
What are some possible asthma therapeutics?
- TNF-alpha inhibitors
* mAbs against Th2 cytokines
What are the triggers of non-atopic asthma?
Viral infection:
• Rhinovirus
• Parainfluenza virus
Inhaled pollutants:
• SO2
• NO2
Is family history common in:
• Atopic asthma
• Non-atopic asthma?
Atopic: yes
Non-atopic: no
Which drug is often responsible for drug induced asthma?
Aspirin
What is occupational asthma?
Various occupations involved with inhalation of various chemicals:
• Formaldehyde etc.
Describe the macroscopic morphology in asthma
Lungs overextended
Over-inflation / collapse
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
What is ‘spiral pieces of epithelium’?
Sloughed off epithelium
Found in the mucous in asthma
What are Charcot-Leydon crystals?
Collections of eosinophil membrane
Where are the mucous secreting glands in the airway tissue?
Submucosal: below the mucosa
What does vagal stimulation in the triggering of an asthma attack bring about?
Broncho-constriction
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
What happens to the bronchial epithelium in the early phase reaction?
Opening of tight junctions
→ access to sub-mucosal mast cells
What is the effect of major basic protein?
When is it present in asthma?
Epithelial damage
Present during the late phase reaction
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
What happens to goblet cells in the asthma airway?
Metaplasia
There are normally very few goblet cells
In asthma, there are many
What do leukotrienes bring about?
- Prolonged bronchospasm
- Increased vascular permeability
- Mucous secretion
What is the effect of eotaxin?
Released by endothelial cell
Recruits eosinophils
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
What is the role of acetylcholine in asthma?
Leads to bronchoconstriction, further narrowing the airways
