33Asthma and COPD 2

8/11/2019 33Asthma and COPD 2

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Pathophysiology of asthmaandchronic obstructive pulmonary disease

M. Tatr


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OBSTRUCTIVE LUNG DISEASES

localized: laryngeal constriction, tracheal and bronchialcarcinoma, foreign bodies

generalized: asthma, COPD, bronchiectasis, cystic fibrosis

OBSTRUCTIVE VENTILATORY DISORDER - spirometry

Airflow limitation


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0.5

End of quiet expiration

- 0.5

0 0 0 0 0Inspiration

- 2.5


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0.5

- 2.5

0-1.0 -0.5-1.5- 2.0

Inspiration

Forced

expiration

+ 2.0


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0.5

Forced expiration

+ 2.0

+ 2.5 0+ 2.0 + 1.5 + 1.0

EPP


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ASTHMA - definition

Chronic inflammatory disorder of the airways

Mast cells, eosinophils, T-lymphocytes

Recurrent episodes of wheezing, dyspnoea, andcough particularly at night and early morning

Symptoms are associated with airflow limitation thatis partly reversible either spontaneously or with

therapy

Bronchial hyperresponsiveness is present very often


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1 2 3 4 5

Time (seconds)

FEV

1

Volume

Normal subject

Asthmatic after bronchodilator)

Asthmatic before bronchodilator)


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ASTHMA - 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


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Development of asthma

Risk factors

Predisposing: atopy, gender

Causal: allergens, aspirin, chemicals

Contributing: respiratory infections, diet,air pollution, smoking

Factors that exacerbate asthma - triggers

allergens, respiratory infections,exercise, emotions


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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


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Asthma - bronchial hyperresponsiveness

Instability of the airways =

exaggerated bronchoconstrictorresponse to a wide variety of stimuli

Key factor - airway inflammation

Mechanisms: direct and indirect


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Direct agonists

e.g. methacholine

Airway with

limited airflow

Mediators

Nerve

SO2, bradykinin

Indirect agonists

e.g. exercise, adenosine, hypotonic

or hypertonic aerosols

Mast cell

Airway hyperresponsiveness


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balance

antihyperreactiv factors prohyperreactiv factors

Normal airway reactivity

2-adrenergic

VIP/PHM

anticholinergic

NEP

antioxidants

corticoids

-adrenergic

cholinergic

SP/NK

oxygen-free radicals

peptidases

Airway hyperresponsiveness

im


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Pathological changes in chronic asthma

Normal airway Airway wall remodeling

Epithelium

Basement membrane

Smooth muscle

Mucus plug

Mucus glands


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Mechanisms of asthma

1. 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


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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


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Asthma - airflow limitation

1. Acute bronchoconstriction

2. Swelling of the airway wall

3. Chronic mucus plug formation

4. Airway wall remodeling


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Relaxation Constriction

Normal

Asthma

Airway

narrowing

Exaggerated

airwaynarrowing

R = 1 R = 10

R = 2 R = 40

muscle constriction

35 %

muscle constriction

35 %


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INFLAMMATION

Risk factors

for development of asthma)

Airway

hyperresponsiveness

Airflow limitation

Risk factors

for exacerbations)

Symptoms


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Asthma is a highly variable disease

Asthma is a chronic inflammatory disease of variableseverity. Worsening and exacerbations of asthma areassociated with episodes of acute inflammation, whichdevelop on top of persistent underlying chronicinflammation.

This acute inflammation causes an increase in symptomsand may also lead to an increased sensitivity to triggers anda worsening in airway hyperresponsiveness.

The variability and severity of real life asthma isdependent on a number of factors, including a patientsadherence to the prescribed treatment.


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COPD - definition

Chronic airflow limitation( maximum expiratory flow, slow forced

emptying of the lungs)

Airflow limitation is slowly progressiveand irreversible

Due to varying combinations of:

airway diseaseemphysema


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COPD

Chronic bronchitis

defined in clinical terms

chronic cough with

sputum production- (3 months a year,

2 successive years)

- excluded cardiac orother pulmonary causes

Emphysema

defined anatomically

permanent, destructive

enlagrement of airspacesdistal to the terminalbronchioles withoutobvious fibrosis


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COPD i k f t


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COPD - risk factors

Cigarette smoking

1- antitrypsin deficiency

Solid fuel used for indoor heating or

cooking without adequate ventilation

Heavily polluted environments


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100

75

50

25

0

25 50 75

Age yrs

FEV1

%

Disability

Death

Never smoked

Stopped atage 45 yrs

Stopped at

age 65 yrs

Smoked regularly

COPD - cellular and biochemical mechanisms


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Inflammation: alveolar macrophages, neutrophils

Neutrophil and macrophage enzymes and oxidantsdestroy 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


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Destruction of lung

parenchyma

Imbalance

proteases antiproteases system

oxidantsantioxidants

Small airways

disorder


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COPD - pathology of peripheral airways

mucus plugging

goblet cell metaplasia fibrosis

smooth muscle hypertrophy


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10 2 3 4 5

Volume from TLC ( l )

- 6

0

6

12

V(l.s-1)

Maximal

expiratory effort

Spontaneous

breath


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0 20 40

40

60

80

100

Lungvo

lume(%T

LC)

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

Normals

VT

IRV

VT

IRV

Airflow limit


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Relatively normal

lung region,

normal PAO2

Emphysema

Pulm.vein

Pulm.artery Normal CaO2

CaO2

Airway

narrowing

Emphysematous

region PAO2

Destruction

of capillary

VV

QQ

Relatively

normal CaO2


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Relatively normal

lung region, normal PAO2

normal

CaO2

Airway narrowing

Pulm. v.Pulm. a.

Bronchitis

PAO2

CaO2

V

norm

V

normQ norm Q

CaO2


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04

6

10

0,5 1,0 1,5 2,0 2,5 3,0

FEV1 ( l )

PaCO2(

kPa)


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Sleep period

20

40

60

80

100

O

xygensaturation

(%)

REM REM REM

C t f h i b t ti l di


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Components of chronic obstructive pulmonary disease

Airflow limitation

by spirometry

Chronic bronchitisEmphysema

Asthma

Simple bronchitis

Emphysema

but no COPD

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33Asthma and COPD 2