lecture 20 Flashcards
Asthma to understand: - the aetiology and pathology of asthma - where asthma fits in to COPD to consider: - some of the questions relating to the aetiology of asthma 1. normal airway structure 2. asthma - definition and types 3. asthma - pathogenesis: - atopic asthma - attempts to explain: data --> hypotheses - other types of asthma 4. Asthma: morphology 5. what you should know
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?
asthma
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…
and - may be superimposed upon chronic airway obstruction
- incidence of asthma INCREASING - world wide trend
What are the 2 major types of asthma, historically speaking?
extrinsic
- initiated by type 1 hypersensitivity reaction due to exposure to antigen
e. g. atopic (allergic) asthma - most common occupational asthma
intrinsic - 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
- etc.*
BUT
- 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?
Sensitisation:
- 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
