COPD

WHAT HAS HAPENNED

TO AIRWAY SYSTEM
Amira Permatasari Tarigan
RESPINA-2011
RESPINA 2011

05/12/2011

CHRONIC OBSTRUCTIVE PULMONARY DISEASE

((GOLD, PDPI))

a preventable and treatable disease state

characterised by airflow limitation that is not fully
reversible.
reversible
The airflow limitation is usually progressive and
associated
i d with
i h an abnormal
b
l iinflammatory
fl
response of the lungs to noxious particles or gases,
primarily caused by cigarette smoking

2
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Figure . Diagnosis
Fi
Di
i off chronic
h i obstructive
b
i pulmonary
l
disease
di
(COPD).
(COPD) Diagnosis
Di
i depends
d
d
on clinical suspicion driven by the presence of risk factors and symptoms, followed by
objective testing with spirometry. The most important risk factor for COPD in the
developed world is cigarette smoking , though in the developing world exposure to biomass
fuels is also important . Other factors including occupational exposures , malnutrition ,
genetics , infections in early life , and airway hyperreactivity and asthma also contribute.
3
Currently, a forced expiratory volume in 1 second
(FEV1)/forced vital capacity (FVC) ratio
below the fixed value ofR E0.70
S P I Nis
A ,used
J A K A to
R T define
A 3 D E the
S E M presence
B E R 2 0 1 1 of airflow obstruction.

05/12/2011

Pathogenesis of COPD

Cigarette
g
smoke
Biomass particles
Particulates
Host factors
Amplif in mechanisms
Amplifying
m h ni m

LUNG INFLAMMATION
Anti--oxidants
Anti

Anti--proteinases
Anti

Oxidative
stress

Proteinases
Repair
mechanisms

COPD PATHOLOGY
4

RESPINA,JAKARTA 3 DESEMBER 2011

Source: Peter J. Barnes, MD

5/12/2011
Inflammatory Cells Involved in0 COPD

Cigarette smoke
(and other irritants)

Epithelial
cells
ll

Alveolar macrophage
p g
Chemotactic factors

Fibroblast

CD8+
lymphocyte
Neutrophil

PROTEASES
Fibrosis
Alveolar wall destruction
(Obstructive
(Emphysema)
bronchiolitis)
5

Monocyte
Neutrophil elastase
Cathepsins
MMPs

Mucus hypersecretion

:
R E S P I N A , J A K A R T A 3 D E S E M B E R 2 0Source
11

Peter J. Barnes, MD

05/12/2011

Figure. Connective tissue destruction and fibrosis coexist in chronic obstructive pulmonary
disease (COPD). Matrix metalloproteinase-9 (MMP-9) is the major elastolytic enzyme released
by alveolar macrophages and is generated from an inactive precursor pro-MMP-9. MMP-9
causes elastolysis directly,
directly but also releases chemotactic peptides that attract neutrophils,
neutrophils which
release neutrophil elastase. The elastolytic effect of neutrophil elastase is enhanced as MMP-9
inactivates its specific antiproteinase 1antitrypsin (1AT), resulting in emphysema. MMP-9
also activates transforming growth factor-(TGF-)from a latent precursor, which leads to
the fibrosis of small airways. TGF-also plays a role in activating MMP-9, so the interplay
between these mediators leads to tissue destruction
and fibrosis simultaneously, as observed in
6
COPD lungs.
RESPINA,JAKARTA 3 DESEMBER 2011

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Inflammatory process located in :

Mucosa
Gl d dducts
Gland
Glands of intermediate ( 2-4 mm )
Parenchyma

7
RESPINA,JAKARTA 3 DESEMBER 2011

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THE SITE OF AIRWAYS

OBSTRUCTION

The peripheral airways were the major

site
it off obstruction
b tr ti n in COPD
Smaller conducting airways
(B
(Bronchi
hi andd Bronchioles
B
hi l off less
l than
h
2 mm diameter))
8
RESPINA,JAKARTA 3 DESEMBER 2011

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AIFLOW LIMITATION of COPD due to :

Peribronchial Fibrosis
airway obstruction airflow limitation

Alveoli Destruction
loss of lung elastic recoil
increase intraalveoli pressure when exhalation
decrease intraluminal and loss of alveoli attachment in Emphysema
collaps of small airways expiration airflow limitation

Mucus Hypersecretion
Smooth Muscle Contriction
9

RESPINA,JAKARTA 3 DESEMBER 2011

OverviewofsmallairwaysinCOPD:
schematic view
schematicview

Figure: Smallairwaysinchronicobstructivepulmonarydiseasepatients.Theairwaywallis
thickenedandinfiltratedwithinflammatorycells,predominantlymacrophagesandCD8+
lymphocytes,withincreasednumbersoffibroblasts.InsevereCOPDtherealsoarelymphoid
follicles,whichconsistofacentralcoreofBlymphocytessurroundedbyTlymphocytesand
are thought to indicate chronic exposure to antigens (bacterial viral or autoantigens)
arethoughttoindicatechronicexposuretoantigens(bacterial,viral,orautoantigens).
Similarchangesarealsoreportedinlargerairways.Thelumenisoftenfilledwithan
inflammatoryexudateandmucusandthereisperibronchial fibrosis,resultinginprogressive
05/12/2011
Respina,Jakarta3Desember2011
10
andirreversiblenarrowingoftheairway.

Figure. Mechanismsofairflowlimitationinchronicobstructivepulmonarydisease(COPD).The
y
j
y
,
airwayinnormalsubjectsisdistendedbyalveolarattachments,whichcontainelastinfibers
duringexpiration,allowingalveolaremptyingandlungdeflation.InCOPDtheseattachmentsare
disruptedduetoemphysema,thuscontributingtoairwayclosureduringexpiration,trappinggas
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Respina,Jakarta3Desember2011
11
inthealveoliandresultinginhyperinflation.

AIR TRAPPING AND

HYPERINFLATION IN COPD
05/12/2011

Normal
Inspiration

Mild - Moderate
COPD

Severe Very Severe

COPD

small
airway

alveolar attachments

loss of elasticity

loss of alveolar attachments

Expiration

closure
12
RESPINA,JAKARTA 3 DESEMBER 2011

Courtesy of Barnes P

AIR TRAPPING AND

HYPERINFLATION IN COPD
05/12/2011

Normal
Inspiration

Mild - Moderate
COPD

Severe Very Severe

COPD

small
airway

Air trapping and Hyperinflation

loss of elasticity

Residual volume (RV)

Expiration
FRC
Inspiratory capacity (IC)
Inspiratory reserve volume (IRV)
TLC
alveolarattachments

Exertional
loss of alveolar
attachments
dyspnoea
Exercise
tolerance

closure

13
RESPINA,JAKARTA 3 DESEMBER 2011

Courtesy of Barnes P

05/12/2011
DYNAMIC HYPERINFLATION
IN COPD

Exercise
IRV

TLC

Healthy
IC

VC
EELV
RV
Exercise

TLC

IC

COPD

VC
EELV
RV

Decreases in inspiratory capacity (IC) &

inspiratory reserve volume (IRV) during
exercise is dynamic hyperinflation
14

DE Eur Respir Rev 2006; 15:37-41

R E S P I N A , J A K A R T A 3 D E S E M B E R 2 0 1ODonnell
1

05/12/2011

15
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16
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Figure. Left, Scanning electron micrograph of a patient with emphysema showing the
enlargement of alveoli and destruction of the alveolar walls. Right, Changes in lung parenchyma
in chronic obstructive p
pulmonaryy disease. There is loss of elasticityy and alveolar wall
destruction, as well as accumulation of inflammatory cells, predominantly macrophages and
17
CD8+ lymphocytes. The destructive changes reduce
the pulmonary capillary bed.
RESPINA,JAKARTA 3 DESEMBER 2011

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Figure. Mucus hypersecretion in chronic obstructive pulmonary disease. Mucus gland secretion
may be stimulated via neural mechanisms and the release of acetylcholine (ACh) from cholinergic
nerves and of substance P (SP) from sensory nerves. It is likely that the most important stimulants
of mucus secretion are neutrophil elastase (NE) from activated neutrophils and epithelial growth
factor receptor ligands such as transforming growth factor- (TGF-). Several stimulants of mucus
18
hypersecretion, such as cigarette smoke and reactive
oxygen species (ROS), also appear to activate
RESPINA,JAKARTA 3 DESEMBER 2011
epidermal growth factor receptors
.

05/12/2011

Figure. Changes in large airways of chronic obstructive pulmonary disease patients. The epithelium
often shows squamous metaplasia and there is goblet cell and submucosal gland hyperplasia,
resultingg in mucus hypersecretion.
yp
The airwayy wall is infiltrated with macrophages
p g and CD4+ and
CD8+ lymphocytes, whereas neutrophils predominate in the airway lumen and around submucosal
19
glands. Airway smooth muscle and basement membrane
are minimally increased compared to the
RESPINA,JAKARTA 3 DESEMBER 2011
findings in asthma.

05/12/2011

Figure. Epidermal growth factor receptor (EGFR) in chronic obstructive pulmonary disease.
EGFR play
EGFRs
l a key
k role
l in
i the
h regulation
l i off mucus hypersecretion,
h
i with
i h iincreased
d expression
i off
mucin genes (MUC5AC, MUC5B) and differentiation of goblet cells and hyperplasia of mucussecreting cells. These effects are mediated via the activation of mitogen-activated protein (MAP)
kinases. EGFR are activated byy transformingg growth
g
factor- ((TGF-),
), which is in turn activated byy
the tumor necrosis factor- converting enzyme (TACE), which is activated via release of oxidants
from cigarette smoke and neutrophils. EGFR may20also be activated by epidermal growth factor
RESPINA,JAKARTA 3 DESEMBER 2011
(EGF).

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PATHOPHYSIOLOGY
OF COPD:
VAGAL NERVE SYSTEM

Central
nervous
system

Airway smooth muscle

constriction

Inflammatory
cell mediators

Vagus nerve
ACh

Parasympathetic
ganglion
ACh

Cholinergic
Ch
li
i
receptors

ACh

Submucosal
gland

Airway epithelium

Irritants
(e.g. cigarette smoke, bacteria, viruses
)
21

Mucus
Hypersecretion

from:
R E S P I N A , J A K A R T A 3 D Adapted
ESEMB
E R Hansel
2 0 1 1T/Barnes P. An Atlas of COPD. 2004

ANTICHOLINERGICS BLOCK
VAGAL TONE
TONE IN THE AIRWAYS
05/12/2011

Normal

COPD

Vagal
tone

Resistance
~ 1/radius4

Cholinergic
Ch
li
i
blocker
Post-ganglionic
g g
nerve
Acetylcholine
22
R E S P I N A , J A K A R T A 3 DAdapted
E S E Mfrom:
B E RHansel
2 0 1 1T/Barnes P. An Atlas of COPD. 2004

05/12/2011

Figure. Transforming growth factor- (TGF-) in chronic obstructive pulmonary disease.

TGF- is released in a latent form that is activated by matrix metalloproteinase-9 (MMP-9). It
may then cause fibrosis directly through the effects on fibroblasts or indirectly via the release of
connective tissue growth factor (CTGF). TGF- may also downregulate 2-adrenoceptors on
cells such as airway smooth muscle to diminish the bronchodilator response to -agonists
agonists.
23
RESPINA,JAKARTA 3 DESEMBER 2011

05/12/2011

Figure. Vascular changes in chronic obstructive pulmonary disease. Chronic hypoxia results in
hypoxic pulmonary vasoconstriction and, over time, leads to structural changes in pulmonary
vessels that result in secondary pulmonary hypertension. An inflammatory response similar to
that found in airways is also seen in the vessel wall. Over time, this may lead to right-sided heart
failure (cor pulmonale), which has a poor prognosis,
with most patients surviving only 6 to 12
24
months.
RESPINA,JAKARTA 3 DESEMBER 2011

05/12/2011

Fig. - Pulmonary muscular artery from a patient with chronic obstructive pulmonary disease,
showing
h i prominent
i
t iintimal
ti l thi
thickening
k i and
d lluminal
i l narrowing.
i
a)) Immunostaining
I
t i i with
ith
monoclonal antibody against a-smooth muscle actin, showing abundant proliferation of
25
smooth muscle cells in the intima. b) Orcein stain showing abundant deposition of elastic
R E S P Iscale
N A , J bar=42.2
A K A R T A mm.
3 DESEMBER 2011
fibres in the intimallayer. Internal

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CONCEPTS
OF DISEASE
PROGRESSION

Clinical Manifestations
(Patient-Centered Outcomes)

Severity

Physiological (Functional)
Abnormalities
Radiographic Abnormalities

Pathological (Structural) Evidence

Induction
Genetic
Predisposition

Biochemical and Cellular Events

L
Latency
Exposure

Advanced
Disease

Disease
Onset

Time (age)
26

RESPINA,JAKARTA 3 DESEMBER 2011

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FEV1 MODEL
OF DISEASE
PROGRESSION IN COPD

COPD
Stages

FEV1 (% of value aat age 25)

100%

Diagnosis

75%

Moderate

Treatment

50%

S
Severe
25%

Very
Severe
0%
25

50
Age (years)

75

27
Adapted
1:1645-1648.
R E S P from
I N AFletcher
, J A K ACRand
T APeto
3 R,
D BMJ
E S E1977;
MBE
R 2 0 1 1 Imagery courtesy ODonnell D

UNDERDIAGNOSIS AND MISDIAGNOSIS:

PATIENT PERCEPTIONS
Patients
Patients may
misunderstand or
minimize symptoms,
y p
such as fatigue, dyspnoea
and cough
As a result, they may
not mention these
symptoms to their
h i
physicians

Ive been coughing when I

wake up each morning, but
its just smokers cough. This
is normal and not harmful to
my health

I dont need meds

for my breathing
because its not a
serious problem

Carrying
Carrying these
groceries is harder
than it used to be.
I must be old and
out of shape

Mannino DM and Braman S. Proc Am Thoracic Soc 2007;4:5026

THE BENEFITS OF EARLIER DIAGNOSIS

AND INTERVENTION

The
curve isisan
anopportunity
opportunity
Thearea
areaunder
under the curve
to:to :
-Improve
symptoms
Improve
symptoms
-Improve
Improveexercise
exercisecapacity
capacity
-Reduce
function
Reducerate
rateofofdecline
decline in
in lung
lung function
-Reduce
Reducefrequency
frequencyof
of exacerbations
exacerbations
-Prevent
Preventcomplications
complications
-Reduce
Reducemortality
mortality

Graph represents an typical profile of a patient with COPD (smoker from age of 16)
RESPINA,JAKARTA 3 DESEMBER 2011

Adapted from: Fletcher C, Peto R.29

BMJ 1977; 1: 16458.

05/12/2011

THE

BENEFITS OF SMOKING CESSATION

30
C, Peto R. BMJ 1977; 1: 16458.
R E S P I N A , J A K A R T A 3 D E S EAdapted
M B E Rfrom:
2 0 Fletcher
11

KEY INDICATORS FOR CONSIDERING

A DIAGNOSIS OF COPD
Dyspnea
y p
thatis

Progressive(worsenovertime)
g
(
)
Usuallyworsewithexercise
Persistent(presenteveryday)
Describedbypatientsas:increasedeffortto
breath,heaviness,airhungerorgasping

Chroniccough
g

Maybeintermittentandmaybe
y
y
unproductive

Chronicsputumproduction

Anypatternofchronicsputumproduction
mayindicateCOPD

Historyofexposuretorisk
factors,especially

Tobaccosmoke
Occupationaldustsandchemicals
Smokefromhomecookingandheating
k f
h
k
dh
fuels
Rabe KF et al. GOLD 2007. Am J Respir Crit Care Med 2007;176:532-555

KEY INDICATORS FOR CONSIDERING

A DIAGNOSIS OF COPD
Dyspnea
y p
thatis

Progressive(worsenovertime)
g
(
)
Usuallyworsewithexercise
Persistent(presenteveryday)
Describedbypatientsas:increasedeffortto
breath,heaviness,airhungerorgasping

Spirometry isneededtoestablishadiagnosisof
Maybeintermittentandmaybe
y
y
COPD
COPD.
unproductive

Chroniccough
g

Chronicsputumproduction

Anypatternofchronicsputumproduction
mayindicateCOPD

Historyofexposuretorisk
factors,especially

Tobaccosmoke
Occupationaldustsandchemicals
Smokefromhomecookingandheating
k f
h
k
dh
fuels
Rabe KF et al. GOLD 2007. Am J Respir Crit Care Med 2007;176:532-555

COPD POPULATION SCREENER (COPD-PS)

Simple,validatedquestionnaire

Canhelpidentifypeopleage35
yearsinthegeneralpopulationwho
areatriskofCOPD

IdentifiesCOPDsymptomsand
risksandconsidersageasa
screeningfactor
f

Thistoolmay:
IncreaseawarenessofCOPD
Helpwithearliersymptom
recognition
Facilitatecaseidentification
Leadtotheuseofspirometry for
diagnosis
Martinez FJ et al. J COPD 2008;5:8595.

COPD POPULATION SCREENER (COPD-PS)

Simple,validatedquestionnaire

Canhelpidentifypeopleage35
yearsinthegeneralpopulationwho
areatriskofCOPD

IdentifiesCOPDsymptomsand
risksandconsidersageasa
screeningfactor
f

Thistoolmay:
IncreaseawarenessofCOPD
Helpwithearliersymptom
recognition
Facilitatecaseidentification
Leadtotheuseofspirometry for
diagnosis
Martinez FJ et al. J COPD 2008;5:8595.

COPD: IMPACT ON QUALITY OF LIFE

Airflow
Limitation

Decreased
Exercise Capacity

Exacerbations

Insomnia,
F i
Fatigue

Quality of Life

Burden of
M di l C
Medical
Care

Loss of
Independence

Social Isolation,
Depression,
Anxiety

Dyspnea,
Cough

What can we do ???

05/12/2011

CONCLUSION
1. Cholinergic
g tone is one of the basic of COPD
patophysiology
2 Airflow limitation in COPD due to : perinbronchial
2.
fibrosis, alveoli destruction, mucus hypersecretion
and smooth muscle airway constriction.
3. Simple, easy-to-use and inexpensive questionnaires
and handheld devices are useful for screening (PDPI
V i )
Version)
4. Diagnose
g
earlier - treat earlier
37
RESPINA,JAKARTA 3 DESEMBER 2011

05/12/2011

38
RESPINA,JAKARTA 3 DESEMBER 2011