BRONCHIAL ASTHMABRONCHIAL ASTHMA

Dr. Eilís Dowd

Today’s lecture- Overview of the normal

regulation of respiration (breathing)

- The pathophysiology of bronchial asthma

Tomorrow’s lecture- Drugs used to treat

bronchial asthma

TODAY AND TOMORROW’S LECTURES

The following features of the airways are regulated:

- Airway smooth muscle tone

- Airway glandular secretions

- Airway blood vessel tone

These are variously regulated by:

- Parasympathetic innervation

- Sympathetic innervation

- Circulating catecholamines

- Non-adrenergic, non-cholinergic mediators

LOCAL REGULATION OF THE AIRWAYSThe airway’s muscles, glands and blood vessels

Parasympathetic (cholinergic) control of the airways

Airway smooth muscle

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

Airway glandular secretions

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

Airway blood vessel tone

- Not affected by parasympathetic stimulation

LOCAL REGULATION OF THE AIRWAYSThe airway’s muscles, glands and blood vessels

Sympathetic (noradrenergic) control of the airways

Airway smooth muscle

- No direct sympathetic innervation of the airway smooth muscle

Airway glandular secretions

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

Airway blood vessel tone

- Sympathetic innervation causes airway blood vessel constriction (via αadrenoceptors?)

LOCAL REGULATION OF THE AIRWAYSThe airway’s muscles, glands and blood vessels

Circulating catecholamine control of the airways

Airway smooth muscle

- Circulating adrenaline causes relaxation of airway smooth muscle via B2adrenoceptors

Airway glandular secretions

- Not relevant

Airway blood vessel tone

- Not relevant

LOCAL REGULATION OF THE AIRWAYSThe airway’s muscles, glands and blood vessels

NANC control of the airways

Airway smooth muscle

- Nitric oxide causes relaxation of airway smooth muscle

Airway glandular secretions

- Not relevant

Airway blood vessel tone

- Not relevant

LOCAL REGULATION OF THE AIRWAYSThe airway’s muscles, glands and blood vessels

LOCAL REGULATION OF THE AIRWAYSThe airway’s muscles, glands and blood vessels

Summary of the local factors controlling the airways

--Constriction-Airway blood vessels

--Inhibits secretion

Stimulates secretion

Airway glands

RelaxationRelaxation-ContractionAirway smooth muscle

NANCCatecholaminesSympatheticParasympathetic

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

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

In asthma, the bronchi become hyper-responsive to certain stimuli (see next slide)

This bronchial hyper-responsiveness leads to:- Bronchospasm, inflammation & increased mucus production- Leading to … airway obstruction

Bronchial asthmaWhat is asthma?

Asthmatics suffer recurrent acute exacerbations of their symptoms (an asthma attack). In between attacks, most patients feel fine.

Numerous factors can trigger an asthma attack:- Exposure to an allergen- Exercise- Air pollutants- Certain drugs- Cold air- Emotional stress- Some childhood infections- Some industrial chemicals

Bronchial asthmaWhat triggers an asthma attack?

Of these, attacks induced by allergens are best understood

Thus, ‘allergic asthma’ will be discussed in more detail

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

Exposures to these allergens causes bronchial constriction, followed by inflammation with excessive mucus production

Allergic asthmaTriggers of allergic asthma

The house dust mite

Allergic asthma is thought to be due to an abnormal activation of adaptive immune response in response to allergic stimuli in certain individuals

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

Allergic asthmaHow does hypersensitivity develop in the first place?

THE ADAPTIVE IMMUNE RESPONSEAn overview

Pathogen detected

MHC Class I APCspresent to CD8+ T cells

MHC Class II APCspresent to CD4+ T cells

Proliferation of T helper 1 cells

Proliferation of T helper 2 cells

Proliferation

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

Induction phase

Effector phase

In both normal and asthmatic individuals, allergens are ingested, digested and subsequently presented to uncommitted CD4+ T helper lymphocytes

Allergic asthmaHow does hypersensitivity develop in the first place?

In normal individuals, the CD4+ T cells will ‘check’ and ignore the presented antigen

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

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

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

Subsequent re-exposure to the allergen thus causes activation of mast cells and eosinophils leading to an asthma attack

Allergic asthmaHow does hypersensitivity develop in the first place?

Allergic asthmaHow does hypersensitivity develop in the first place?

Re-exposure to the allergen causes an asthma attack

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

Allergic asthmaWhat happens upon re-exposure to the antigen?

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)

Symptomatically, the first event of an allergic asthma attack is bronchospasm

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 asthmaThe early phase - bronchospasm

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

These attract inflammatory leucocytes into the area thereby ‘setting the stage’ for the inflammatory late phase

- Lymphocytes

- Eosinophils

- Monocytes/macrophages

Allergic asthmaThe early phase – mediator release

The late phase of an allergic asthma attack occurs at a variable time after re-exposure to the allergen

It is a progressive inflammatory reaction which initiated during the early phase

In the late phase, various mediators released from the inflammatory leucocytes cause airway inflammation and airway hyper-reactivity

Allergic asthmaThe late phase – progressing inflammation

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 asthmaThe late phase – mediators released

Allergic asthmaThe late phase – consequences

The various mediators released from the inflammatory leucocytes cause airway inflammation and airway hyper-reactivity

This leads to:

Further bronchospasm

Wheezing

Coughing

FURTHER READING

Pathophysiology of asthma:

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