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This note is really good since it has assisted me to get 1st class for pharmacology module of 1 year of medical school. i believe this would be overly beneficial especially to medical students...
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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’