BRONCHIAL ASTHMA

Dr. Eilís Dowd

TODAY AND TOMORROW’S LECTURES

Æ Today’s lecture
- Overview of the normal
regulation of respiration
(breathing)

- The pathophysiology of
bronchial asthma

Æ Tomorrow’s lecture
- Drugs used to treat
bronchial asthma
LOCAL REGULATION OF THE AIRWAYS
The airway’s muscles, glands and blood vessels

Æ The following features of the

airways are regulated:
- Airway smooth muscle tone
- Airway glandular secretions
- Airway blood vessel tone

Æ These are variously regulated by:

- Parasympathetic innervation
- Sympathetic innervation
- Circulating catecholamines
- Non-adrenergic, non-cholinergic
mediators
LOCAL REGULATION OF THE AIRWAYS
The airway’s muscles, glands and blood vessels

Parasympathetic (cholinergic) control of the airways

Æ Airway smooth muscle

- Parasympathetic innervation causes contraction of airway smooth muscle via
muscarinic M3 receptors

Æ Airway glandular secretions

- Parasympathetic innervation causes mucus secretion from airway glands via
muscarinic M3 receptors

Æ Airway blood vessel tone

- Not affected by parasympathetic stimulation
LOCAL REGULATION OF THE AIRWAYS
The airway’s muscles, glands and blood vessels

Sympathetic (noradrenergic) control of the airways

Æ Airway smooth muscle

- No direct sympathetic innervation of the airway smooth muscle

Æ Airway glandular secretions

- Sympathetic innervation inhibits mucus secretion from airway glands (via β
adrenoceptors?)

Æ Airway blood vessel tone

- Sympathetic innervation causes airway blood vessel constriction (via α
adrenoceptors?)
LOCAL REGULATION OF THE AIRWAYS
The airway’s muscles, glands and blood vessels

Circulating catecholamine control of the airways

Æ Airway smooth muscle

- Circulating adrenaline causes relaxation of airway smooth muscle via B2
adrenoceptors

Æ Airway glandular secretions

- Not relevant

Æ Airway blood vessel tone

- Not relevant
LOCAL REGULATION OF THE AIRWAYS
The airway’s muscles, glands and blood vessels

NANC control of the airways

Æ Airway smooth muscle

- Nitric oxide causes relaxation of airway smooth muscle

Æ Airway glandular secretions

- Not relevant

Æ Airway blood vessel tone

- Not relevant
LOCAL REGULATION OF THE AIRWAYS
The airway’s muscles, glands and blood vessels

Summary of the local factors controlling the airways

Parasympathetic Sympathetic Catecholamines NANC

Airway
smooth Contraction - Relaxation Relaxation
muscle

Airway Stimulates Inhibits

- -
glands secretion secretion

Airway
- Constriction - -
blood vessels
Bronchial asthma
What is asthma?

Æ Asthma is a disease in which there is recurrent ‘narrowing’ of the airways

Æ This narrowing causes the classical symptoms of asthma:
- Wheezing
- Shortness of breath
- Chest tightness
- Coughing

Æ In asthma, the bronchi become hyper-responsive to certain stimuli (see

next slide)

Æ This bronchial hyper-responsiveness leads to:

- Bronchospasm, inflammation & increased mucus production
- Leading to … airway obstruction
Bronchial asthma
What triggers an asthma attack?

Æ Asthmatics suffer recurrent acute exacerbations of their symptoms (an

asthma attack). In between attacks, most patients feel fine.

Æ Numerous factors can trigger an asthma attack:

- Exposure to an allergen
- Exercise
Of these, attacks induced by
- Air pollutants allergens are best understood
- Certain drugs
- Cold air Thus, ‘allergic asthma’ will be
- Emotional stress discussed in more detail
- Some childhood infections
- Some industrial chemicals
 Allergic asthma
Triggers of allergic asthma

Æ Numerous allergens can trigger an The house dust mite

asthma attack in hypersensitive
individuals:
- Dust (i.e. waste from dust mites)
- Animals (i.e. pet epithelial cells)
- Grass pollen
- Mould spores

Æ Exposures to these allergens

causes bronchial constriction,
followed by inflammation with
excessive mucus production
Allergic asthma
How does hypersensitivity develop in the first place?

Æ Allergic asthma is thought to be due to an abnormal activation of adaptive

immune response in response to allergic stimuli in certain individuals
Æ In particular the so-called T helper Type 2 wing which leads to activation
of B cells and subsequent production of antibodies generated against the
allergenic antigen
 THE ADAPTIVE IMMUNE RESPONSE Induction phase

An overview Effector phase

Pathogen detected

MHC Class I APCs MHC Class II APCs

present to present to
CD8+ T cells CD4+ T cells

Proliferation of Proliferation of
Proliferation
T helper 1 cells T helper 2 cells

Develop into Interact with B cells

Develop into
macrophage-activating to control
cytotoxic T cells
T cells antibody production

Destruction of infected cells Phagocytosis of pathogen Antibody mediated effects

Allergic asthma
How does hypersensitivity develop in the first place?

Æ In both normal and asthmatic individuals, allergens are ingested, digested

and subsequently presented to uncommitted CD4+ T helper lymphocytes

Æ In normal individuals, the Æ In genetically susceptible

CD4+ T cells will ‘check’ and individuals, presentation of the
ignore the presented antigen will lead to activation of the
antigen T helper type 2 wing of the immune
response
Allergic asthma
How does hypersensitivity develop in the first place?

Æ Activation of the T helper type 2 wing of the immune response causes:

- Generation of cytokines (e.g. IL-4) which cause B cells / plasma cells to
produce the IgE type of antibody against the antigen
- Generation of cytokines (e.g. IL-5) which promote differentiation and
activation of eosinophils
- Generation of cytokines (e.g. IL-4, IL-13) that induce expression of IgE
receptors on mast cells and eosinophils

Æ IgE antibodies then bind to IgE receptors on mast cells and eosinophils

Æ Subsequent re-exposure to the allergen thus causes activation of mast

cells and eosinophils leading to an asthma attack
Allergic asthma
How does hypersensitivity develop in the first place?
Allergic asthma
What happens upon re-exposure to the antigen?

Æ Re-exposure to the allergen causes an asthma attack

Æ The asthma attack in response to allergens is typically biphasic and
consists of an ‘early’ and a ‘late’ phase

Æ The 2 phases of asthma

after inhalation of grass
pollen in a hypersensitive
individual

Æ Asthma severity is measures

by the forced expiratory
volume in 1 second (FEV1)
Allergic asthma
The early phase - bronchospasm

Æ Symptomatically, the first event of

an allergic asthma attack is
bronchospasm

Æ Bronchospasm occurs when allergen

binds to mast cell-fixed IgE causing
the release of several spasmogens:
- Histamine
- The cysteinyl-leukotrienes
(e.g. LTC4, LTD4)
- Prostaglandin D2
Allergic asthma
The early phase – mediator release

Æ In addition to bronchospasm,
activation of mast cells causes the
release of other mediators, as well as
various chemotaxins and chemokines

Æ These attract inflammatory leucocytes

into the area thereby ‘setting the
stage’ for the inflammatory late phase
- Lymphocytes
- Eosinophils
- Monocytes/macrophages
Allergic asthma
The late phase – progressing inflammation

Æ The late phase of an allergic asthma attack occurs at a variable time

after re-exposure to the allergen
Æ It is a progressive inflammatory reaction which initiated during the early
phase
Æ In the late phase, various mediators released from the inflammatory
leucocytes cause airway inflammation and airway hyper-reactivity
Allergic asthma
The late phase – mediators released

Æ Mediators released from:

- T lymphocytes
- Cytokines
- B lymphocytes
- IgE
- Eosinophils
- Cysteinyl-leukotrienes
- Cytokines (e.g. IL-3, IL-5)
- Chemokines (e.g. Il-8)
- Eosinophil cationic protein
- Eosinophil major basic protein
Allergic asthma
The late phase – consequences

Æ The various mediators released from the

inflammatory leucocytes cause airway
inflammation and airway hyper-reactivity

Æ This leads to:

Æ Further bronchospasm
Æ Wheezing
Æ Coughing
FURTHER READING

Æ Pathophysiology of asthma:

Rang et al. Chapter 22. ‘The respiratory system’