Pathophysiology of asthma and chronic obstructive pulmonary disease M. Tatár.

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Pathophysiology of asthma Pathophysiology of asthma and and chronic obstructive pulmonary chronic obstructive pulmonary disease disease M. Tatár M. Tatár

Transcript of Pathophysiology of asthma and chronic obstructive pulmonary disease M. Tatár.

Pathophysiology of asthmaPathophysiology of asthmaand and

chronic obstructive pulmonary chronic obstructive pulmonary diseasedisease

M. TatárM. Tatár

Thyroid cartilage

Cricothyroid ligament

Cricoid cartilage

Connective tissuesheath (cut away)

Intercartilaginousligaments

Mucosa showinglongitudual folds formedby dense collectionsof elastic fibres

Tracheal cartilages

Toupperlobe

Eparterialbronchus

Tomiddlelobe

Tolowerlobe

R. mainbronchus

L. mainbronchus

Intrapulmonary Extrapulmonary Intrapulmonary

Tolowerlobe

Tolingula

Toupperlobe

Trachealis muscle

Oesophageal muscle

Epithelium

Lymph vesselsElastic fibres

Gland

Small arteries

Nerve

Posterior wall

Cross sectionthrough trachea

Anterior wall

Epithelium

Nerve

Lymph vessels

Small artery

Gland

Elastic fibres

Cartilage

Connective tissue sheath

Structure of trachea and major bronchi

© Novartis

OBSTRUCTIVE LUNG DISEASES OBSTRUCTIVE LUNG DISEASES

localized: laryngeal constriction, tracheal and localized: laryngeal constriction, tracheal and bronchial carcinoma, foreign bodiesbronchial carcinoma, foreign bodies

generalized: asthma, COPD, bronchiectasis, cystic generalized: asthma, COPD, bronchiectasis, cystic

fibrosisfibrosis

OBSTRUCTIVE VENTILATORY DISORDER - spirometryOBSTRUCTIVE VENTILATORY DISORDER - spirometry

Airflow limitationAirflow limitation

Cartilage

Segmentalbronchus

Largesubsegmentalbronchi(about 5generations)

Small bronchi(about 15generations)

Terminalbronchioles

Respiratorybronchioles(3 orders)

Alveolarducts andalveolar sacs

Lobule

Acinus

Acinus

Poresof Kohn

Alveolar sacsand alveoli

Alveolar ducts

3rd order

2nd order

1st order

Respiratorybronchioles

Alveolus

Elastic fibres

Smooth muscle

Terminal bronchiole

Subdivisions and structure ofintrapulmonary airways

© Novartis

0.5

End of quiet expirationEnd of quiet expiration

- 0.5- 0.5

00 0 0 0 0

InspirationInspiration

- 2.5- 2.5

0.5

- 2.5- 2.5

0- 1.0 - 0.5- 1.5- 2.0- 2.0

InspirationInspiration

ForcedForcedexpirationexpiration

+ 2.0+ 2.0

0.5

Forced expirationForced expiration

+ 2.0+ 2.0

+ 2.5+ 2.5 0+ 2.0 + 1.5 + 1.0

EPPEPP

ASTHMA - definitionASTHMA - definition

Chronic inflammatory disorder of the airwaysChronic inflammatory disorder of the airways

Mast cells, eosinophils, T-lymphocytes

Recurrent episodes of wheezing, dyspnoea, Recurrent episodes of wheezing, dyspnoea, and cough particularly at night and early and cough particularly at night and early

morningmorning

Symptoms are associated with airflow Symptoms are associated with airflow limitation that is partly reversible either limitation that is partly reversible either

spontaneously or with therapyspontaneously or with therapy

Bronchial hyperresponsiveness is present very often

1 2 3 4 5

Time (seconds)

FEV1

Volume

Normal subject

Asthmatic (after bronchodilator)

Asthmatic (before bronchodilator)

ASTHMA - classificationASTHMA - classification

A. Intrinsic asthma• no environmental causes can be identified• negative skin test to common airborn allergens• rather negative family history

B. Extrinsic asthma• atopy, genetic predisposition IgE, mast cells and eosinophils response to

allergens

C. Occupational asthma• sensibilisation of airways to inhalant chemicals

Development of asthmaDevelopment of asthma

Risk factorsRisk factors

Predisposing: atopy, gender

Causal: allergens, aspirin, chemicals

Contributing: respiratory infections, diet, air pollution, smoking

Factors that exacerbate asthma - triggersFactors that exacerbate asthma - triggers

allergens, respiratory infections, exercise, emotions

Respiratory infections• epithelial damage• airway inflammation

Exercise reflex airflow limitation• cooling of mucosa• osmolarity changes of fluid lining

epithelium

Emotions (laughing, crying, anger, fear)• hyperventilation• hypocapnia

Triggers Triggers

Asthma - bronchial hyperresponsivenessAsthma - bronchial hyperresponsiveness

Instability of the airways =Instability of the airways =

exaggerated bronchoconstrictor exaggerated bronchoconstrictor response to a wide variety of response to a wide variety of

stimulistimuli

Key factor - airway inflammation

Mechanisms: direct and indirect

Direct agonistsDirect agonists e.g. methacholine

Airway with limited airflow

Mediators

Nerve

SO2, bradykinin

Indirect agonistsIndirect agonists e.g. exercise, adenosine, hypotonic

or hypertonic aerosols

Mast cell

Airway hyperresponsivenessAirway hyperresponsiveness

balancebalance

antihyperreactiv factorsantihyperreactiv factors prohyperreactiv factorsprohyperreactiv factors

Normal airway reactivityNormal airway reactivity

2-adrenergic

VIP/PHM

anticholinergic

NEP

antioxidants

corticoids

-adrenergic

cholinergic

SP/NK

oxygen-free radicals

peptidases

Airway hyperresponsivenessAirway hyperresponsiveness

imim

Pathological changes in chronic asthma

Normal airway Airway wall remodeling

Epithelium

Basement membrane

Smooth muscle

Mucus plug

Mucus glands

Mechanisms of asthmaMechanisms of asthma

1. Airway inflammation1. Airway inflammation

- recruitments of inflammatory cells from circulation

- endothelial adhesion molecules

- activation of T lymphocytes (Th2 clone)

- production of IgE, leukotriens, prostanoids

- cytokines (CD4+ Th subtype)

2. Neural control of airways

Antigen etc.

Macrophage

T-lymphocyte Neutrophil

Mast cell

Eosinophil

Mucus plug

Vasodilation

Plasma leak

Oedema

Epithelial shedding

Subepithelial fibrosis

Sensory nerve

Efferent nerve

Airway constriction and smooth muscle hypertrophy/hyperplasia

Neurogenic inflammation

Asthma - airflow limitationAsthma - airflow limitation

1. Acute bronchoconstriction1. Acute bronchoconstriction

2. Swelling of the airway wall2. Swelling of the airway wall

3. Chronic mucus plug formation

4. Airway wall remodeling

Relaxation Constriction

Normal

Asthma

Airway narrowing

Exaggeratedairway

narrowing

R = 1R = 1 R = 10R = 10

R = 2R = 2 R = 40R = 40

muscle constriction

35 %

muscle constriction

35 %

INFLAMMATIONINFLAMMATION

Risk factors(for development of asthma)

Airwayhyperresponsiveness Airflow limitation

Risk factors(for exacerbations)

Symptoms

Asthma is a highly variable diseaseAsthma is a highly variable disease

Asthma is a chronic inflammatory disease of variable Asthma is a chronic inflammatory disease of variable severity. Worsening and exacerbations of asthma are severity. Worsening and exacerbations of asthma are associated with episodes of acute inflammation, associated with episodes of acute inflammation, which develop on top of persistent underlying which develop on top of persistent underlying chronic inflammation.chronic inflammation.

This acute inflammation causes an increase in This acute inflammation causes an increase in symptoms and may also lead to an increased symptoms and may also lead to an increased sensitivity to triggers and a worsening in airway sensitivity to triggers and a worsening in airway hyperresponsiveness.hyperresponsiveness.

The variability and severity of „real life“ asthma is The variability and severity of „real life“ asthma is dependent on a number of factors, including a dependent on a number of factors, including a patient´s adherence to the prescribed treatment.patient´s adherence to the prescribed treatment.

COPD - definitionCOPD - definition

Chronic airflow limitation Chronic airflow limitation ( ( maximum expiratory flow, slow maximum expiratory flow, slow

forcedforcedemptying of the lungs) emptying of the lungs)

Airflow limitation is slowly progressive

and irreversible

Due to varying combinations of:• airway disease• emphysema

COPDCOPD

Chronic bronchitisChronic bronchitis

• defined in clinical terms

• chronic cough with sputum production

- (3 months a year, 2 successive years)

- excluded cardiac or other pulmonary causes

EmphysemaEmphysema

• defined anatomically• permanent,

destructive enlagrement of airspaces distal to the terminal bronchioles without obvious fibrosis

Chronic obstructive pulmonary disease

Interrelationship of chronic bronchitis and emphysema

Normal

Chronicbronchitis

Mixed(in variable

degree)

Emphysema

© Novartis

Centriacinar(centrilobular)emphysema

Magnified section.Distended, inter-communicating,sac-like spacesin central areaof acini

Microscopic section.Distention of airspaceswith rupture ofalveolar walls

Gross specimen.Involvement tends tobe most marked inupper part of lung © Novartis

Panacinar (panlobular) emphysema

Gross section of lung.Dilated, saccular airspaces.In cases of disease dueto a1-antitrypsin deficiency,lower part of lung tendsto be more affected

Magnifiedsection.Diffuseinvolvementof allportionsof acini

© Novartis

COPD - risk factorsCOPD - risk factors

Cigarette Cigarette smoking smoking

11 - antitrypsin deficiency - antitrypsin deficiency

Solid fuel used for indoor heating or cooking without adequate

ventilation

Heavily polluted environments

100

75

50

25

0

25 50 75

Age yrs

FE

V1

%

Disability

Death

Never smokedNever smoked

Stopped atStopped at age 45 yrsage 45 yrs

Stopped atStopped atage 65 yrsage 65 yrs

Smoked regularlySmoked regularly

COPD - cellular and biochemical mechanismsCOPD - cellular and biochemical mechanisms

Inflammation: alveolar macrophages, neutrophilsInflammation: alveolar macrophages, neutrophils

Neutrophil and macrophage enzymes and oxidants

destroy components of extracellular matrix (collagen, elastin, fibronectine, proteoglycans)

Loss of cellular components of lung parenchyma:- elastase can induce apoptosis

- cells exposed to oxidants may undergo apoptosis or necrosis

oxidative stress in smokers and in COPD patients

production of elastase, cathepsine G, collagenase

COPD - cellular and biochemical mechanismsCOPD - cellular and biochemical mechanisms

Destruction of lung parenchyma

Imbalance Imbalance

proteases antiproteases system

oxidants antioxidants

Small airwaysdisorder

COPD - pathology of peripheral COPD - pathology of peripheral airwaysairways

• mucus plugging• goblet cell metaplasia• fibrosis• smooth muscle hypertrophy

ChronicbronchitisLargecartilaginousairways

Mucous glandhyperplasia(elevatedReid index)

Dilatedduct ofgland

Thickenedbasementmembrane

Squamousmetaplasia

Inflammatoryinfiltrate

Hyperemia

Oedema

Fibrosis

Profuseexudatein lumen

Epithelialdesquamation

Cartilageintact

Small airways

Goblet cell hyperplasia

Thickened basementmembrane

Hyperemia

Inflammatory infiltrate

Exudate in lumen

Oedema

Squamous metaplasia

Fibrosis

Airways partially orcompletely blocked or‘one-way’ valve effectby mucoid or muco-purulent secretions,with impaired or non-uniform distributionof ventilation

© Novartis

10 2 3 4 5

Volume from TLC ( l )

- 6

0

6

12

( l.

s-1 )

Maximalexpiratory effort

Spontaneousbreath

0 20 40

40

60

80

100

Lu

ng v

olu

me

(%

TL

C)

Oxygen consumption (ml.min-1.kg-1)

Normals

VT

IRV

VT

IRV

Airflow limit

Relatively normal lung region, normal PAO2

Emphysema

Pulm. vein

Pulm. artery Normal CaO2

´

CaO2

Airway narrowing

Emphysematous region PAO2

Destruction of capillary

V´ V´

Q´ Q´

Relatively normal CaO2

Relatively normal lung region, normal PAO2

normalCaO2

Airway narrowing

Pulm. v.Pulm. a.

Bronchitis

PAO2

CaO2

V´norm

norm Q´ norm Q´

CaO2

04

6

10

0,5 1,0 1,5 2,0 2,5 3,0 FEV1 ( l )

PaC

O2 (

kP

a )

Sleep period

20

40

60

80

100

Oxy

gen

sat

ura

tion

(

% )

REM REM REM

Components of chronic obstructive pulmonary disease

Airflow limitationby spirometry

Chronic bronchitisEmphysema

Asthma

Simple bronchitis

Asthma with no airflow limitation

Emphysema but no COPD