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What is the normal airway structure? Which parts of the normal airway are affected in asthma?

- starts with the trachea and ends in the respiratory bronchioles
- all parts of the airway involved in asthma

4 main layers:
- epithelium
- lamina propria
- muscle layer
- serosa

- all layers involved
- all layers filled with inflammatory cells

- at high power you can see that it is pseudostratified columnar epithelium
- main types of cells are the ciliated cells and goblet cells
- proportions of these cells change in asthma
- in the normal airway the airway wall is very thin but in disease it becomes filled with inflammatory cells and when these inflammatory cells come together in a group they are known as bronchiole associated lymphoid tissue (BALT)


What is an important inflammatory cell involved in asthma?

the mast cell
- has a lot of cytoplasm devoted to granules

also neutrophil, lymphocytes and the eosinophil


For what are granules effective?

- quick way of releasing a lot of a particular substance


How do we define asthma?

- by the part of the lung that is affected (bronchus) and also the symptoms that are involved
- symptoms = wheeze, cough and sputum

related diseases such as emphysema and chronic bronchitis involve dyspnea and perhaps alveolar involvement rather than the airways


What is dyspnea?

shortness of breath


What is a definition of asthma?

- a chronic relapsing inflammatory disorder in which hyperreactive airways undergo reversible (episodic) constriction
- increased responsiveness to variety of stimuli
- Mostly! - increased susceptibility to generation of IgE in response to external allergy = atopy


How is australia affected by asthma?

- 2.2 million
-- in in 4 children (14 - 16%)
-- 1 in 7 teenagers
-- 1 in 10 adults (10 - 12%)

- in 0 - 14 years: boys > girls
- 15+ years: women > men

- 1.2% health expenditure - $606 million in 2004/5
- incidence rising but number of deaths/year falling

- 385 deaths in 2007 (released march 18 2009)
- hospital admissions: declined since 1993-94, 45% among adults, 42% among children


What is the most common chronic disease of childhood?



What are the symptoms of asthma?

- sudden bronchospasm which produce unpredictable attacks of wheezing, cough, sputum production, dyspnea
- triggered by .. ?
- may be asymptomatic in between attacks BUT...
- may be superimposed upon chronic airway obstruction
- incidence of asthma INCREASING - world wide trend


What are the 2 major types of asthma, historically speaking?

- initiated by type 1 hypersensitivity reaction due to exposure to antigen
e.g. atopic (allergic) asthma - most common occupational asthma

- constriction of muscle in the airways
- due to diverse, non-immune mechanisms
e.g. ingestion of aspirin
pulmonary infections (especially viral)
also: cold, exercise, inhaled irritants, stress


What other classifications of asthma have arisen over the years?

- steroid-dependent (steroid is main drug)
- steroid-resistent
- difficult
- seasonal
- exercise induced

- so much variation, overlap and increased IgE levels - no longer clinically applicable
- so a more inclusive definition is:
'bronchial hyper-reactivity due to inflammation in response to diverse stimuli'


What is atopic asthma?

- most common - begins in childhood
- triggered by environmental antigens
-- dusts, pollens, animal fur, foods
-- family history of atopy common

- asthma often preceded by allergic rhinitis, urticaria, eczema


What is type 1 hypersensitivity?

- antigen crosses the epithelium
- binds to APCs (sometimes these can sit in the epithelium)
- APC interacts with Th2 cell
- Th2 tells B-epsilon cell to secrete IgE (immunoglobulin characteristic of allergies)
- when the antigen is encountered again it will cross link antigens sitting on a mast cell, triggering its degranulation
- from this trigger you have an enormous cascade of different events


What are mediators derived from mast cells and their effects?

granule-associated preformed mediators
- contained within the granules

newly formed mediators
- secreted through secretory pathway directly


How do these two types of mediators drive the symptoms of asthma?

preformed and newly formed will mix to some extent

- main functions are as chemo-attractants (attract neutrophils, eosinophils, monocytes), activation (vasodilation and vascular permeability), spasmogens (causing contraction of the bronchial smooth muscle, mucus secretion)


How do mast cell products act directly and indirectly?

- constriction of airway wall directly by spasmogens or by the chronic inflammatory cell response represented by these cells in the airway wall

direct or indirect (via chemo-taxis of other immune cells?)


What is the first period of atopic asthma?

- APCs and T cells in BALT (bronchus associated lymphoid tissue)
- antigen + APC = presented to Th2
- TH2 --> cytokines , IgE B cell,
- recruitment of eosinophils
- IgE antibody bound to mast cells
- may occur sometime before stage II


What is the second period of atopic asthma?

Triggering of attack:
- immediate phase (minutes)
- allergen encountered again, binds to the IgE
- antigen also binds to nerves
- these nerves, with some of the mediators released by mast cells, cause constriction of the airway smooth muscle
- some release of mucus from the goblet cells
- very quick, acute


What do the mediators do?

- tight junctions open - access to sub-mucosal mast cells
- increased vascular permeability leads to oedema
- mucous hyper secretion

- vagal stimulation --> bronchoconstriction via central and local reflexes

- also recruitment of neutrophils, monocytes, lymphocytes, basophils and **eosinophils**

= acute/immediate response: minutes


What is the third phase of atopic asthma?

Late phase
- occurs over a period of hours
- effector inflammatory cells are coming into the tissue in great numbers, mainly eosinophils and neutrophils (also basophil, which is similar in eosinophil in function)
- release their various proteins e.g. neutrophil elastase, from eosinophils: major basic protein, eosinophil cationic protein
- these proteins are designed to kill bacteria etc but they also damage the epithelium
- this can let more allergens and microorganisms into the tissue
- overactive immune response

- starts 4 - 12 hours, persists for 24 hours
- due to highly increased numbers of leukocytes attracted by mast cell mediators
- + mediators from other cells, inflammatory cells, endothelial cells, epithelial cells --> eotaxin
- major basic protein --> epithelial damage
- eosinophil cationic protein --> brings eosinophils


What are primary mast cell mediators to be aware of?

- biogenic amines e.g. histamine, adenosine
-- increased vascular permeability
-- increased secretion of mucus
-- increased mediator release

- enzymes - proteases

- chemotactic mediators
-- eosinophil chemotactic f.
-- neutrophil chemotactic f.


What are secondary mast cell mediators to be aware of?

- leukotrienes C4, D4
- prostaglandin D2

- TNF-alpha
- IL-1, 3, 4, 5, 6


For what mediators have therapies to treat asthma been developed that were effective?

- leukotriene C4, D4, E4 - prolonged bronchospasm, increased vascular permeability, increased mucus secretion

- acetylcholine: bronchospasm, muscarinic receptors


For what mediators have therapies to treat asthma been developed that were ineffective?

- histamine
- prostaglandin
- PAF (platelet activating factor)

- maybe because of redundancy?


For what mediators could therapies to treat asthma be developed?

no effective antagonists (as yet)
- IL-1
- IL-6
- chemokines e.g. eotaxin
- neuropeptides
- bradykinin
- endothelins


What is asthma due to? (possibly)

- genetic predisposition to type 2 hypersensitivity (atopy)
- acute and chronic airway inflammation
-- many cell types
-- many mediators
- airway hyperresponsiveness

- TH2 cells of particular importance

- unknown how we get from acute and chronic airway inflammation to airway hyperresponsiveness


What is the genetic predisposition hypothesis for the pathogenesis of asthma?

Genetic pre-disposition
- possible candidate genes - confer pre-disposition to atopy
- antigen presentation (HLA complex)
- T cell activation (T-cell receptor, IFN-gamma)
- regulation of cytokine production/function (Il-4/5)
- receptors for bronchodilators (Beta2-adrenergic receptors)

Hypothesis 1: asthma is related to a predisposition to develop atopy


What is the Th1/Th2 hypothesis for the pathogenesis of asthma?

Th1 and Th2 cells
- CD4+ T cells
- differentiate into Th1 with IL-12, Th2 with IL-4
- Th1 --> IL-2, IFN-gamma --> cell mediated immune R inflammation (activate macs and Tc cells)
- Th2 --> IL-4, 5, 6, 9, 13 + B cells --> IgE --> allergic, antibody mediated

- bronchial lymphocytes from patients with asthma lack T-bet, a transcription factor required for production of IFN-gamma by Th1 cells
- IFN-gamma normally inhibits Th2
- these cells normally in balance

- decreased IFN-gamma: takes restraint from Th2 cells --> airway inflammation
- in asthma T cell differentiation >> Th2 +++
- Th1 differentiation needs transcription factor Tbet
- Tbet absent from asthmatic T cells, present in controls
- Tbet -/- mice spontaneously develope asthma like disease

Hypothesis 2:
- Asthma is related to an imbalance between Th1 and Th2 cells


What is the Hygiene Hypothesis?

- the importance of balance: Th1- and Th2-type response
- neo-nate skewed to TH2, needs appropriate stimuli to create a balance
- 'Eat dirt - the hygiene hypothesis and allergic disease'


What are factors favouring the Th1 phenotype?

- presence of older siblings
- early exposure to day care
- tuberculosis, measles, or hepatitis A infection
- rural environment


What are factors favouring the Th2 phenotype?

- widespread use of antibiotics
- western lifestyle
- urban environment
- diet
- sensitisation to house dust mites and cockroaches


What is the role of Th2 cytokines in asthma?

- extensive role
- could debate whether it was the mast cell or the Th2 cell that had the most important role in asthma
- produces lots of different cytokines
- IgE production --> Il-4 via B-cells
- mast cell degranulation (IL-9)
- recruitment of eosinophils and basophils
- structural components of the airway wall (IL-13) --> secretion of mucus, remodelling (goblet cell metaplasia)


What are regulatory T cells?

- T cells that are FoxP3 positive
- these cells suppress Th2 bias (in the context of asthma)
- therapeutic potential

- dendritic cell presents allergen to Treg which suppresses Th2
- note: TGF-beta = double-edged sword


What is the lineage of regulatory T cells?

- IL-10 ....


What is the third hypothesis to explain pathogenesis in asthma?

- asthmatic airway characterised by remodelling of wall = hypertrophy and hyperplasia of airway smooth muscle, sub-epithelial fibrosis, epithelial remodelling and angiogenesis

- ??? secondary - but recent studies: remodelling observed years before symptom onset

hypothesis 3:
- abnormal genetically-determined micro-environment in airway wall is necessary for asthma to develop

BUT genome wide association study:
contribution of ADAM-33
- A Disintegrin And Metalloproteinase
- ADAM-33 gene linked to asthma
- ADAM-33 protein related to matrix metalloproteinases e.g. collagenases
- expressed by lung smooth muscle and fibroblasts

hypothesis 3:
- ADAM-33 polymorphisms increase rate of proliferation of airway fibroblasts and smooth muscle - adding to airway hyperreactivity and re-modelling


What is the contribution of mast cells to airway remodelling?

Bronchial biopsies
- smooth muscle infiltrated with mast cells ++++
- mast cells --> vasoactive mediators, cytokinse
- growth factors (PDGF) and proteins increase smooth muscle proliferation
- stem cell factor


How can an inherent defect in epithelial protection and repair lead to airway remodelling?

epithelial damage
- barrier loss
- macromolecular permeability

Immediate response
- cell migration
- formation of temporary barrier

Interim repair
- barrier restored
- secretory cell function

Proliferation and differentiation
- ciliagenesis
- secretory function

if this process goes awry then there is increased fibroblast/myofibroblast proliferation in the airway wall

MMPs, collagaen increased
junctional proteins decreased

fibroblast proliferation, myofibroblast activation

differentiation 1
- matrix remodelling
- myofibroblast apoptosis

differentiation 2
- resolution

- polymorphisms in e-cadherin and beta-catenin (proteins that hold epithelium together)
- polymorphisms in genes involved in protection and repair


What is TSLP?

- Thymic stromal lymphopoietin
- TSLP made by activated epithelial cells stimulates cytokine release
- links remodelling changes to inflammatory changes


What is the epithelial mesenchymal trophic unit?

- link between atopic/inflammatory part of asthma to the airway remodelling
- proposed by Stephen T Holgate


What candidate genes are associated with the role of epithelium in asthma?

asthma is a very diverse heterogeneous disease
there are many different genes and proteins involved
makes it almost impossible to target all these different genes

e.g. ADAM33, GPRA (both remodelling, ADAM33 also BHR), DDP10 (inflammation), ETS 2 & 3, Muc 8 (mucus), HLA-G, PCDH1 (barrier/host defence)


What is effective in suppressing Th2 cytokines (and other cytokines) ?

- corticosteroids


Have antibodies been developed for use in asthma?

- yes
- to various interleukins, mainly IL-4, IL-13 (a third of funding?)


What is the fourth hypothesis attempting to explain the pathogenesis of asthma?

Tumour necrosis factor-alpha
- NEJM 354,7, Feburary 16th 2006
- 'evidence of role of TNF-alpha in refractory asthma'
- TNF-alpha
-- released from mast cells and macs during allergic response
-- increase adhesion molecules --> migration of WBCs --> mediators
-- increase mucus secretion by epithelial cells
-- increase fibroblasts --> matrix production
-- increase smooth muscle response to contractile stimuli

- patients with refractory asthma have increased TNF-alpha
- TNF-alpha inhibitors may be a useful in therapy and reduce symptoms


So in summary, what are four general mechanisms for atopic asthma pathogenesis?

1. genetic pre-disposition
2. Th1/Th2 cell imbalance
3. Airway remodelling: ADAM-33, Mast cells
4. TNF-alpha: widespread roles, boost imbalance and remodelling


What is non-atopic asthma?

- triggered by viral infection e.g. rhinovirus, parainfluenza virus
- family history uncommon
- serum IgE normal
- ?? virus-induced inflammation lowers threshold of subepithelial vagal irritant receptors
- inhaled pollutants (SO2, NO2, O3)- role??


What is drug-induced asthma?

- due to aspirin - uncommon
- in patients with recurrent rhinitis and nasal polyps
- asthma + urticaria

- ?? aspirin
- inhibits cyclooxygenase pathway
- increases broncho-constrictor leukotrienes


What is occupational asthma?

- stimulated by fumes
-- e.g. epoxy resins, plastics, organic and chemical dusts, gases, penicilllins, formaldehyde etc
- after repeated exposure

?? mechanisms
- type 1 mediated reactions
- hypersensitivity of unknown origin
- release of bronchoconstrictors??


What is the morphology of asthma?

- lungs over extended - over inflation/collapse

- occlusion of bronchi/bronchioles – thick mucus
- mucus contains spiral pieces of epithelium AND
- collections of eosinophil membrane - crystals (Charcot-Leydon)
- thickened basement membrane
- oedema and inflammatory infiltrate - eosinophils +++
- increase in mucous secreting gland
- hypertrophy of smooth muscle


What is the airway morphology in asthma?

- occluded lumen
- mucus and inflammatory cells
- muscle constricted into tight bundles
- mucosa with large submucosal glands, inflammatory cells


What is COPD?

- chronic bronchitis/emphysema/asthma
- these conditions form a spectrum - symptoms overlap

- tobacco smoking