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The respiratory system in health and disease

Tyra Zetterström tscz@dmu.ac.uk

PHCO2308, 2011

Aim of lectures •  To review the physiology of the lungs and

respiration

•  How this relates to two common respiratory diseases: asthma and chronic obstructive pulmonary disease (COPD)

•  To examine the molecular and cellular events that that relates to lung function and dysfunction

•  How drugs can modify these events

Recommended reading (if you want to do well look in the Kimberlin Library or

Campus book shop !)

•  Rang and Dale’s Pharmacology 6th edition chapter 23, Churchill-Livingstone, 2007

•  Also Rang and Dale’s Pharmacology 7th edition

(2012), chapter 27

•  Widmaier EP, Raff H & Strang KT Vander’s Human Physiology, McGraw-Hill, 2008

•  Fox SI, Fundamentals of Human Physiology,

McGraw-Hill, 2008

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The Respiratory System

Detailed branching of the Bronchial Tree

The respiratory system

Starts at the mouth and nose, where air enters

Terminates in the alveoli, where oxygen and carbon dioxide are exchanged

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Alveoli: terminal parts of the Bronchioles

The diaphragm Role in respiration

•  Major importance for respiration

•  A sheet of muscle that divides the chest cavity from the abdomen

•  Contraction of the diaphragm causes the lungs to expand and air to be drawn in

Anatomical illustration

The Respiratory Centre •  The autonomic nervous

system controls breathing •  The respiratory system is

located in the medulla at the base of the brain (Brain Stem)

•  Connections between the medulla and cerebral cortex makes is possible to influence breathing

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Respiration

Ventilation of the lung

Exchange of O2 and CO2;

- Intake and utilisation of O2

- Elimination of CO2

Respiration and

1.  Route for water loss & heat elimination

2.  Acid base balance (elimination of CO2)

3.  Vocalization

4.  Facilitates sense of smell

Function of the respiratory system

Protective mechanisms in the upper respiratory tract

The lungs are exposed to a range of chemicals microorganisms and dust

•  Tiny hairs within the nose

•  The nose is also lined with mucus producing cells

•  Sticky mucus traps small particles for removal

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Defence mechanism in the lower respiratory tract

•  The tracheobronchial tree is lined with cilia

•  Small projections from cells that sweeps secretion produced by goblet cells and bronchial glands

•  “Sweeping” of secretion (mucus) towards the throat to be swallowed

•  Damage of the cilia is a significant contributor to respiratory disease

Bronchiolar Epithelium

Goblet cells & Ciliated cells

Damage leads to respiratory disease

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Summary Lecture 1

•  The respiratory system terminates in the alveoli where O2 and CO2 are exchanged.

•  Contraction of the diaphragm causes the lungs to expand and air to be drawn in.

•  The autonomic nervous system originates in the brain stem and controls breathing.

•  Connections between the medulla and cerebral cortex can influence breathing.

•  Cilia are small projections from cells that sweep secretion produced by goblet cells and bronchial glands.

Lecture 2

The role of the Alveoli

Bronchiolar smooth muscle control

Function of the Alveoli •  Most distal part of the

bronchioles

•  Alveoli in direct contact with blood vessels

•  Exchange of gases O2 & CO2

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Detailed branching of the Bronchial Tree

Alveoli are in intimate contact with pulmonary capillaries

Note: 90% of alveolar surface* is covered with capillaries. * ~80 m2

Blood and air volume during the respiratory cycle

•  The right ventricle of the heart pumps blood through the pulmonary arteries and arterioles

•  Blood then enters the capillaries surrounding each alveolus

•  At rest approximately 4 litre of air enters and leave the alveoli/minute

•  In comparison 5 litre of blood flows through the pulmonary capillaries

•  During heavy exercise, the air flow can increase 20 fold and the blood flow 5-6 fold

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Smooth muscle and the respiratory tract

•  The trachea & the bronchial tree are surrounded by muscles (wrapped in a double helix).

•  Lower down the tree, muscle amount increases and cartilage decreases.

•  Muscles are innervated by sympathetic and parasympathetic nerves.

•  Sympathetic relaxation and parasympathetic constriction.

Actions of parasympathetic and sympathetic nervous systems

Anatomy of a bronchiole

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Cross section of a bronchiole

bronchiolar smooth muscle, Innervations control airways

resistance:

Bronchiolar s.m. wrapped around bronchiole

Bronchiolar epithelium

Mucous

Post ganglionic parasympathetic neuron

ACh

Muscarinic m3 acetylcholine receptor

Functional radius reduced by 1. Bronchiolar s.m. contraction 2.  Increased mucous secretion. 3. Tissue inflammation

Stimulation of m3 ACh receptors → s.m contraction

Adrenaline from circulation

β2 adrenoceptor

Stimulation of β2 adrenoceptor → s.m. relaxation

β2AR → Gs → αs-GTP → ↑cAMP

mAChR → Gq → αq-GTP → PLC → IP3 →↑Ca2+

CONTRACTION

DECREASED

INCREASED

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Adrenaline

β2

α β γ

Gs protein

adenylyl cyclase

ATP

↑ cAMP activation of cAMP-dependent kinase

(PKA)

Bronchiolar s.m. membrane

Decreased contraction

β2

α β γ

Summary slide L2 •  Alveoli are in intimate contact with pulmonary capillaries

•  At rest approximately 4 L of air enters and leave the alveoli/minute and 5 L of blood flows through the pulmonary capillaries

•  These volumes changes dramatically during exercise

•  The trachea & the bronchial tree are surrounded by muscles (wrapped in a double helix)

•  Muscles are innervated by sympathetic (relaxes) and parasympathetic (constricts) nerves

•  Β2 adrenergic receptors relaxes and m3 cholinergic type receptors constrict smooth muscles tissue surrounding the bronchi

Lecture 3

Lung Disorders

Airflow obstruction Asthma & COPD

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Airflow Obstruction

•  Seen in: asthma, COPD, chronic bronchitis, emphysema and cystic fibrosis

A reduction in airway diameter •  Increased parasympathetic activity •  Change in bronchial smooth muscle tone

Effects on bronchial secretions •  Increased mucus viscosity and reduced

clearance

Tests of airflow obstruction

•  Peak flow meter, used to test Peak Expiratory Flow (PEF); the greatest airflow that can be sustained for 10 millisec on forced expiration.

•  Spirometer, used to measure Forced Expiratory Volume in 1 sec (FEV1) and Vital Capacity (VC); maximum total volume of air that can be exhaled under force.

With diseases of airways obstruction both PEF and FEV1/VC are decreased.

Normal Peak Expiratory Flow (PEF) depends on: gender, age and height

Handheld peak flow meter

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Spirometry

•  A lung function tests

•  Helps to diagnose various lung conditions, including chronic obstructive pulmonary disease (COPD)

•  Spirometry is also used to monitor the severity of some other lung conditions, and their response to treatment

http://www.aafp.org/afp/2004/0301/p1107.html

Lung Disorders

•  Airflow obstruction – Asthma & COPD

•  Restrictive lung disease (reduced volume and total lung capacity)

•  Abnormalities of diffusion

•  Abnormalities of pulmonary blood vessels

Asthma and COPD

•  Asthma is very common and may be distressing, disabling and dangerous - good drug therapy is the key

•  COPD is increasingly common throughout the world – it kills large numbers of people and is mainly caused by smoking – good drug therapy helps enormously, but doesn’t prevent progression to death

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Asthma Defining signs & symptoms

1.  Widespread narrowing of airways

2.  This narrowing changes spontaneously or as a result of treatment (i.e. it is reversible)

3.  Characterised by increased responsiveness of bronchi to various stimuli (known & unknown).

All 3 are important in diagnosis & treatment

What is it like to have asthma?

GRAB A DRINKING STRAW BLOCK YOUR NOSE

… and TRY TO BREATH IN AND OUT THROUGH THE STRAW.

don’t try this if you actually have asthma!!

Typical triggering stimuli

•  Upper respiratory tract infection

•  Exercise

•  Cold air

•  Inhaled irritants, allergens & drugs (e.g. β-blockers)

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Bronchiolar s.m. wrapped around bronchiole

Bronchiolar epithelium

Mucous

Post ganglionic parasympathetic neuron

ACh

Muscarinic acetylcholine receptor

Functional radius reduced by 1. Bronchiolar s.m. contraction 2.  Increased mucous secretion. 3. Tissue inflammation

Stimulation of m3ACh receptors → s.m contraction

Adrenaline from circulation

β2 adrenoceptor

Stimulation of β2 adrenoceptor → s.m. relaxation

Symptoms of Asthma • Wheezing

• Chest tightness

• Difficulty in breathing

• Coughing

• Blue colour of the lips

Prevalence of Asthma •  8-10% of adults •  10-15% of children (UK and Australia) •  In the UK 5.2 x 106 asthma sufferers •  1.1 x 106 are children •  0.5 X 106 have an asthma attack every day

Indicates unacceptably poor control Leicester city has highest incidence of asthma emergency

admissions per capita in the UK

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•  Peak age of onset ~ 5 years

•  In young children more common in boys (3:2)

•  Later ages equal between sexes

•  1500 patients die each year in UK (5-10 deaths/year in Leicestershire

•  Mortality often due to incorrect management

•  Incidence increasing in developed countries.

Asthma Epidemiology

Why? Possible explanations

•  Overuse of β2-bronchodilators

•  Childhood environment too clean

•  Changes in diagnostic practice:

Previous under diagnosis? Current over diagnosis?

Summary L3 •  Airflow obstruction seen in: asthma, COPD

chronic bronchitis, emphysema and cystic fibrosis

•  Spirometry is used to diagnose various lung conditions including COPD

•  Common reasons for lung disorders: reduction in airway diameter and/or effects on bronchial secretions

•  In the UK 5.2 x 106 asthma sufferers •  High mortality; 1500 patients die each year

in UK

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Lecture 4 Lung Disorders II

Asthma & inflammation

Central to asthma:

Bronchial s.m. hyper-responsiveness

Inflammation

Airflow obstruction

QUESTION: IS ASTHMA PRIMARILY AN INFLAMMATORY DISEASE?

Inflammation-Introductory comments

•  A common set of responses to infections (viral or bacterial) tissue damage (bruises) or allergens

•  A protective mechanism; removes infections and damaged tissue

•  Helps to repair tissue

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Inflammation; mediators and drug treatment •  Mediators of inflammation: histamine prostaglandins and leukotrienes

•  Antiinflammatory drugs: stereoids such as, hydrocortisone, prednisolone and betamethasone

•  Also non-steroidal antiinflammatory drugs-NSAIDS: aspirin, diclofenac and ibuprofen

Inflammation involves; •  Attracting a type of white blood cells (eosinophils) which

remove bugs and damaged tissue

•  Activation of inflammatory cells (mast cells) by allergen binding to antibodies (IgE) on mast cell surface

•  Releasing mediators of inflammation from mast cells and eosinophils

•  Protein leakage from blood vessels causing swelling (oedema)

•  Increasing local blood flow, stimulation of pain nerve terminals-pain and itching

Histamine a mediator of inflammation and bronchoconstriction

•  Histamine derives from mast cells

•  Acts at H1 receptors and causes bronchoconstriction

•  Drugs: H1 ANTAGONISTS (the antihistamines)

Antihistamines are NOT used in the treatment of asthma

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Mast Cells & IgE

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Mast Cell

IgE from sensitized

Release of mediators of inflammation histamine, prostaglandins and leukotrienes

IgE receptors in mast cell membrane

More mediators of inflammation and bronchoconstriction

1. From mast cells and eosinophils

•  Prostaglandins (e.g. PGD2) Precursor - arachidonic acid Acts at PG receptors → BRONCHOCONSTRICTION

DRUGS: Antiinflammatory steroids reduce synthesis

•  Leukotrienes, especially cysteinyl leukotrienes (cysLTs) - LTC4, LTD4, & LTE4. Precursor arachidonic acid.

Act at cysLT receptors → bronchoconstriction & eosinophilia

DRUGS: 1. Antiinflammatory steroids reduce synthesis 2. cysLT receptor antagonists (LTRAs)

More mediators of inflammation and bronchoconstriction - 2

2. from eosinophils

•  Eosinophil derived proteins. These cause epithelia damage, enhancing disease progression.

No drugs directly relating to this process, but steroids attenuate recruitment and activation of eosinophils

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Pathology of chronic-late phase asthma •  Hypertrophy (increased size) and

hyperplasia (increased number) of the s.m. surrounding the bronchial tree

•  Increased number of blood vessels, resulting in thickening of the airway wall

•  Increased number of goblet cells, resulting in increased mucous secretion and mucous plugging

•  Infiltration by leukocytes ie eosinophils

White Blood Cells •  Leukocytes from leuco Ancient Greek

white •  Cells of the immune system, defending the

body against infections, disease and foreign materials

•  Five different types exist: neutrophil, eosinophil, basophil, lymphosite (T lymphocyte and B cells) and monocyte

•  All produced and derived from the bone marrow

Eosinophils •  A type of white blood cells not present in healthy

lungs but in lungs of asthma sufferer •  Attracted to lungs by interleukins (from T

lymphocytes) •  Once present in lungs they release meditators of

inflammation – These include leukotrienes – Leukotrienes cause bronchoconstriction – They attract more eosinophils into the lungs

which then release more leukotrienes Eosinophils contribute to both early and late

phases of asthma

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Pathogenesis of asthma ~ 70% of asthmatics are atopic i.e. specific reactions to environmental stimuli

Allergen Lymphocytes

Mast cells & eosinophils

IgE antibodies from B cells Interleukins

from T lymphocytes Protect and activate mast cells Recruitment, infiltration and activation of eosinophils

Mediators of inflammation and bronchoconstriction

Summary L4

•  Asthma is primarily an inflammatory disease

•  Mediators of inflammation: histamine prostaglandins and leukotrienes •  Mast cells release histamine which causes

inflammation and bronchoconstriction •  Eosinophils contribute to both early and

late phases of asthma •  Pathology and pathogenesis of asthma

Lecture 5

Drug treatment of Asthma

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Recommended reading (if you want to do well look in the Kimberlin Library or

Campus book shop !)

•  Rang and Dale’s Pharmacology 6th edition chapter 23, Churchill-Livingstone, 2007

•  Also Rang and Dale’s Pharmacology 7th edition

(2012), chapter 27

•  Widmaier EP, Raff H & Strang KT Vander’s Human Physiology, McGraw-Hill, 2008

•  Fox SI, Fundamentals of Human Physiology,

McGraw-Hill, 2008

Phases of asthma acute/chronic Acute/immediate phase 1.  Bronchoconstriction 2.  Mediator release – histamine and leukotriene B4. 3.  Infiltration of eosinophils –more LTB4.

RESULTS IN AIRWAYS NARROWING

Late/chronic phase •  Mediator release from eosinophils •  Long term inflammation •  Long term structural changes to airways

Receptors •  Proteins on the cell surface

•  Agonists bind to the receptor and change the function of the cell

•  For example, by stimulating enzymes e.g., adenylate cyclase and the formation of cyclic AMP

•  Antagonists bind and block the receptors without activating them

•  Agonists cannot bind in the presence of an antagonist

• 

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Drugs used in treatment of asthma

1. Bronchodilators

2. Anti-inflammatory Steroids

1. BRONCHODILATORS

•  β2-adrenoceptor agonists

•  Xanthines

•  Muscarinic receptor antagonists

•  cysLT receptor antagonists (LTRAs)

β2-adrenoceptor agonists

Act on bronchiolar s.m. β2-adrenoceptors → relax → bronchodilaton

Also: •  inhibit mediator release from mast cells

•  Increase mucus clearance by an action on cilia

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Administration of β2-adrenoceptor agonists

•  Most commonly by aerosol

•  Also by powder or nebulisor

•  Sometimes orally or i.v (eg in status asthmaticus) .

Ways to administrate β2-adrenoceptor agonists

Nebuliser (liquid) Aerosol (powder)

β2-adrenoceptor agonists; two classes

Short acting Salbutamol, terbutaline.

Rapid onset use on demand to relieve symptoms, lasts 4-6 h.

Long-acting Salmeterol Slow onset, lasts 12 hours. Used regularly to prevent symptoms.

Skeletal muscle tremor- A side effect of both types Side effects are reduced by keeping dose low and by using in combination with steroids Note: These drugs relieve symptoms but they leave the underlying disease process unchecked

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Short and long-lasting β2-agonists

Xanthines Weaker brochodilators than salbutamol Phosphodiesterase inhibitors (i.e. inhibit cyclic AMPbreakdown)

… and … some anti-inflammatory effects

Side effects: 1. CNS stimulant 2. Stimulate the heart 3. Weak diuretic

Main clinical drugs: Theophylline & aminophylline NB Caffeine is a xanthine

Used orally, with inhaled steroids in β2 agonist unresponsive patients.

Problem: Narrow therapeutic window: plasma 10ug for therapy, over 20ug gives side effects – monitor plasma levels

Muscarinic receptor antagonists •  Cholinergic muscarinic (m3) receptors → s.m

contraction & mucus secretion •  Muscarinic receptor antagonists are used as

bronchodilators (ipratropium and tiotropium) •  Both are nonselective also blocks the m2

autoreceptor (bad news, why?) •  Quaternary nitrogen compound with minimal

absorption into the circulation (few side effects) •  Used in combination with β2 agonists for aerosol

inhalation (mainly COPD) •  Tiotropium more long acting than ipratropium

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Leukotriene Receptor Antagonists (LTRAs)

Antagonise the action of all leukotrienes.

• Particularly effective in exercise-induced asthma

• Increasing role in general asthma therapy

Used with β2 agonists and inhaled steroids

Examples: Montelukast & Zafirlukast

2. Anti-Inflammatory Steroids

•  Work by inhibiting expression of pro-inflammatory genes and inducing expression of anti-inflammatory genes.

•  E.g. inhibit production of pro-inflammatory cytokines

•  Increase production of β2 adrenoceptors

•  Reduce numbers of eosinophils, T-lymphocytes & mast cells in airway tissues

Pathogenesis of asthma ~ 70% of asthmatics are atopic i.e. specific reactions to environmental stimuli

Allergen Lymphocytes

Mast cells & eosinophils

IgE antibodies from B cells Interleukins

from T lymphocytes Protect and activate mast cells Recruitment, infiltration and activation of eosinophils

Mediators of inflammation and bronchoconstriction

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Steroids & Asthma (cont) •  Usually administered by inhalation. Also used

orally in acute severe attacks

•  Do NOT alleviate symptoms in short term

•  Used in prophylaxis (PREVENTER) of asthma. Attacks underlying inlammatory disease

•  Beclometasone is usual inhaler choice for mild asthma

•  Fluticasone is more potent – for more persistent conditions

•  Administered routinely – NOT on demand – typically twice/day

STRATEGY IN TREATMENT OF ASTHMA

•  Recognise that symptoms may be treated (with β2 agonist) while leaving the disease process unchecked.

•  This means that, except perhaps in the most occasional forms, asthma should always be treated with steroids.

Summary Lecture 5

•  Bronchodilators •  Anti-inflammatory Drugs •  Symptoms are treated with β2 agonist •  Steroids are treating the cause of the

disease •  Steroids are prophylactics (PREVENTER)

of asthma. Attacks underlying inflammatory disease

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Lecture 6

COPD and its treatment

COPD •  Chronic obstructive pulmonary disease •  30,000 deaths/year in UK •  6th most common cause of death in UK •  Most patients die after years of struggle •  Epidemic of COPD spreads across the world

following the spread of the smoking epidemic. •  In USA COPD is the only major cause of death

to increase significantly in recent years •  COPD becoming the 4th leading cause of death

in Europe

COPD MORTALITY – GETTING WORSE

1. !In 2002 2.75 million people died from In 2002 2.75 million people died from COPD

2. !A substantial number of these were A substantial number of these were in South East Asia where the tobacco epidemic is only just beginning to hit

3. !Here COPD is still predominantly a Here COPD is still predominantly a male disease

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Treatment of COPD •  Stop smoking! •  Short acting β2 agonists (salbutamol) •  Short acting muscarinic agonist -

ipratropium often helpful as well •  Steroids often help too - oral

prednisolone and inhaled •  Also, oxygen, mucolytics,

antibacterials as necessary

Additional Lung Disorders

1. Chronic bronchitis

2. Emphysema

These disorders often co-exist with COPD

Chronic bronchitis •  Productive cough on most days.

•  Excess mucous formation

•  Mucous plugs

•  Inflammation of small airways

•  Commonly with secondary infections.

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Emphysema •  Proteolytic destruction of tissue

•  Damage to alveolar septa

•  Elastin destruction

•  Loss of elasticity

•  Loss of capillary bed

Illustration of damaged Alveoli

Overlapping symptoms of lung diseases

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Course Assessment The Respiratory System

Name :

P number :

PLEASE ANSWER THE FOLLOWING MULTIPLE CHOICE QUESTIONS BY WRITING THE NUMBER OF THE ANSWER WHICH YOU THINK IS CORRECT IN THE BOX.

ATTEMPT TO ANSWER ALL QUESTIONS.

HAND IN YOUR ANSWERS TO THE LECTURER AT THE END OF THE TEST.

Q1. Asthma is a disease of:

1.  The brain 2.  The respiratory System 3.  The liver 4.  The skin 5.  The heart