Asthma: pathophysiology
Asthma is an inflammator disorder of the
airways. Patients suffer from episodes of cough, wheezing, chest tightness
and/or dyspnoea (breath-lessness), which are often worse at night or early in
the morning. Asthma can be usefully define as 'a chronic inflammator disorder
characterized by increased responsiveness of the bronchi to various innocuous
stimuli, manifested by widespread and variable airway narrowing that varies
in severity either spontaneously or with treatment'. The major characteristics
of asthma are (Fig. 24a):
· Narrowing of the airways and impeded airfl w, commonly reversible
spontaneously or following treatment.
· Non-specifi airway hyperresponsiveness to a
range of normally innocuous stimuli (e.g. cold air, irritants and pollutants) and
airway spasmogens leading to bronchoconstriction (Fig. 24b).
· Increased mucosal inflammatio and recruitment of inflammatory
cells (eosinophils, mast cells, neutrophils, T lymphocytes) to the airways.
There is also hypersecretion of
mucus, which can lead to block age of airways with mucus plugs, and
swelling of mucosa due to inflammation-associate vascular leak and consequent oedema
of the airway wall, all of which further limit airflow. Damage to the
epithelium (epithelial shedding) is reflecte by whorls of epithelial
cells (Curschmann's spirals) in the mucus, which also contains eosinophil cell
membranes (Charcot-Leyden crystals). In chronic asthma remodelling of the
airway wall structure occurs, including increased bronchial smooth muscle
content. This causes irreversible narrowing of the airways and limits the
effectiveness of bronchodilators.
Prevalence
Asthma is increasing in prevalence,
particularly in the Western world, where more than 5% of the population may be
symptomatic and receiving treatment. There has been a concomitant increase in
mortality, despite improved treatment. In the UK, one in seven of the
population has allergic disease and over 9 million people will have wheezed in
the last year. The number of teenagers with asthma has nearly doubled over the
last 12 years. Asthma is least common in the Far East and most common in the
UK, Australia and New Zealand. There is some correlation with Westernized
lifestyles, including living conditions that favour house dust mites and
atmospheric pollution. Many factors can precipitate an asthma attack or worsen
symptoms, including exposure to specifix antigens,
tobacco smoke and exhaust fumes, and emotional stress.
Exercise (exercised-induced asthma) and inhalation of cold air often
precipitate wheezing in asthmatics, probably via drying and cooling of the
bronchial epithelium, and is common in children. Certain viral infections (rhinovirus,
parainfluenza respiratory syncy- tial virus) are associated with asthma
attacks. There may also be a genetic component to asthma. Importantly, 20% of
the working population may be susceptible to occupational asthma due
to their working environment (Chapter 33).
Classification
Asthma can be classifie as extrinsic,
having a definit external cause, and intrinsic, where no external cause
can be identified Extrinsic asthma commonly occurs as a result of an allergic
response, with development of IgE antibodies to specifi antigens (allergic
or atopic asthma) and tends to start in childhood with symptoms
becoming less severe with age; approximately 80% of asthmatics are atopic.
Intrinsic asthma generally appears in adults and is IgE-independent.
Atopic asthma
Individuals who readily produce IgE to
common antigens are prone to allergic asthma. Major antigens include proteins
in fecal pellets from house dust mite (Dermatophagoids pteronyssinus;
DerP)-the most common cause of asthma worldwide-grass and tree pollen,
dander (skin f akes) from domestic pets and fungal spores (Fig.
24c). Genetic factors, atmospheric pollution and maternal smoking in pregnancy
all predispose to raised IgE levels and later development of asthma and airway
hyperresponsiveness.
Inhalation of allergens by atopic
individuals initiates an immediate response (bronchoconstriction) that
usually subsides within 2 hours (Fig. 24d); this is reversible with
bronchodilators such as β2-adrenoceptor agonists (Chapter 25). This
is often followed 3-12 hours later by a late-phase response with
bronchoconstriction, airway inflammatio and oedema, and hyperresponsiveness
(Fig. 24d), which is less susceptible to bronchodilators. Some materials (e.g. iso-cyanates) cause only an isolated late phase. The increased hyper-responsiveness may promote recurrent asthma attacks over several days.
The immediate response is an example
of type I hypersensitivity. It is caused by antigen/IgE-induced mast
cell degranulation and release of histamine, prostaglandin D2
(PgD2) and leukotriene C4 and D4
(LTC4, LTD4); these cause bronchoconstriction, increased
mucus production and vascular leak (Fig. 24e). The late phase (an example of type
IV or cell-based hypersensitivity) is primarily due to inflamma
tion. Mast cells and, in particular, activated TH2 lymphocytes release
cytokines (cellular mediators) that attract eosinophils and neutrophils
to the area. TH2 lymphocytes are a specifi type of TH
cell that are also activated by antigen presenting cells (see Chapter
18), but unlike TH1 cells release cytokines such as IL-5 which
recruit eosinophils. Asthma is therefore sometimes described as a TH2-driven
disease, and may involve an imbalance between TH1 and TH2
lymphocytes.
Consequently, eosinophils are present
in large numbers in asthmatic bronchi, and release leukotrienes,
platelet-activating factor (PAF), ma- jor basic protein (MBP) and
eosinophil cationic protein (ECP). MBP and ECP contribute to epithelial
cell damage, causing increased permeability to allergens, release of cytokines
that attract more eosinophils (Fig. 24e), and exposure of C-fibr sensory nerve
endings which release proinflammator tachykinins. Asthmatic smooth muscle also
produces cytokines. Important cytokines involved in asthma include IL-5, IL-
13, eotaxin, RANTES and granulocyte macrophage colony-stimulating factor
(GM-CSF).
Drug-associated asthma
Aspirin and other non-steroidal
anti-inflammator drugs (NSAIDs) promote asthmatic attacks in 5% of asthmatics.
They inhibit the cyclooxygenase (COX) pathway that synthesizes prostaglandins
and shift arachidonic acid metabolism from COX towards the lipoxygenase pathway and production of LTC4 and LTD4. Aspirin-induced
asthma is partially reversed by antileukotriene therapy (Chapter 25).
The bronchi have little sympathetic
innervation, but circulating epinephrine (adrenaline) acting via β2-adrenoceptors
on smooth muscle causes bronchodilatation. Consequently β-adrenoceptor antagonists can cause bronchoconstriction in asthmatics. This may even occur with
nominally β -selective drugs, and their use for cardiovascular disease should
be avoided in asthmatics.
