Asthma (medical School)

BRONCHIAL ASTHMA Dr. Eilís Dowd

TODAY AND TOMORROW’S LECTURES

Æ Today’s lecture - Overview of the normal regulation of respiration (breathing) - The pathophysiology bronchial asthma

of

Æ Tomorrow’s lecture - Drugs used to bronchial asthma

treat

LOCAL REGULATION OF THE AIRWAYS The airway’s muscles, glands and blood vessels Æ The following features airways are regulated:

of

the

- 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, mediators

non-cholinergic

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 muscle

Contraction

-

Relaxation

Relaxation

Airway glands

Stimulates secretion

Inhibits secretion

-

-

Airway blood vessels

-

Constriction

-

-

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 Thus, ‘allergic asthma’ will be - Cold air discussed in more detail - Emotional stress - Some childhood infections - Some industrial chemicals

Allergic asthma Triggers of allergic asthma

Æ Numerous allergens can trigger an 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

The house dust mite

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 An overview

Induction phase Effector phase

Pathogen detected

MHC Class I APCs present to CD8+ T cells

MHC Class II APCs present to CD4+ T cells

Proliferation

Proliferation of T helper 1 cells

Proliferation of T helper 2 cells

Develop into cytotoxic T cells

Develop into macrophage-activating T cells

Interact with B cells to control 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 In normal individuals, the CD4+ T cells will ‘check’ and ignore the presented antigen

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In genetically susceptible individuals, presentation of the antigen will lead to activation of the T helper type 2 wing of the immune response

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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

Æ

The 2 phases of asthma after inhalation of grass pollen in a hypersensitive individual 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’