Download - Is COPD an inflammatory disease?
Is COPD An Inflammatory Disease?
Gamal Rabie Agmy, MD,FCCP Professor of Chest Diseases, Assiut university
Presentation1.lnk
Global Strategy for Diagnosis, Management and Prevention of COPD
Definition of COPD
◙ COPD, a common preventable and treatable
disease, is characterized by persistent airflow limitation that is usually progressive and associated with an enhanced chronic inflammatory response in the airways and the lung to noxious particles or gases.
◙ Exacerbations and comorbidities contribute to the overall severity in individual patients.
The Real Story
6 6
Angiogenesis in COPD
Reprinted f rom International Journal of COPD, 2, Siafakas NM, et al., Role of angiogenesis and vascular remodeling in
chronic obstructive pulmonary disease, 453-462, Copyright 2007, with permission f rom Dove Medical Press Ltd.
extravasated
plasma proteins
Inflammatory cells (Mac, Neu, Epith, Lymph)
Release of angiogenic
mediators
Fibrinogen products
Inflammation Tissue
hypoxia
Airway
fibrosis
Mechanical
Injury
Increased
blood flow
Vessel growth
Angiogenesis
Vascular remodeling
Up-regulation of
Angiogenic factors
Shear stress
on the endothelium
7 7
Angiogenic and Angiostatic Factors in COPD
Angiogenic CXC Chemokines, CC Chemokines, and Growth Factors:
– CXCL1
– CXCL5
– CXCL8
– CCL2
– VEGF
– bFGF
– Angiopoietin-1
– HGF
– EGF
Angiostatic CXC Chemokines, CC Chemokines, and Growth Factors:
– CXCL10
– CXCL11
Siafakas NM, et al. Int J Chron Obstruct Pulmon Dis. 2007;2:453-462.
8 8
VEGF in COPD
Santos S, et al. Am J Respir Crit Care Med. 2003;167:1250-1256. Reproduced with permission f rom American Thoracic Society.
Copyright © 2003
Moderate COPD Nonsmoker Severe emphysema
a = Pulmonary muscular artery
br = Bronchiole
9 9
VEGF Levels in Stable COPD
Adapted f rom Kanazawa H. Med Sci Monit. 2007;13:RA189-195.
** P<0.05 vs. controls
7000
6000
5000
4000
3000
2000
1000
0
VE
GF
le
ve
ls (p
g/m
l)
Normal
controls
Bronchitis
type
Emphysema
type
COPD patients
**
**
10 10
Serum VEGF Is Elevated in COPD
Exacerbations
Adapted f rom Valipour A, et al. Clin Sci (Lond). 2008;115:225-232.
1,500
1,000
500
0
VE
RG
Fs
er
(pg
/ml)
Exacerbation Recovery
P=0.032
11 11
SIgA Deficiency Is Associated With Airway
Remodeling
Reprinted with permission of the American Thoracic Society. Copyright © 2013 American Thoracic Society. Polosukhin
VV,et al. Am J Respir Crit Care Med. 2011;184:317-327. Of f icial journal of the American Thoracic Society.
SIgA = secretory immunoglobulin A
12 12
Remodeling Is Increased in IgA Deficient
Airways and lower SIgA Is Correlated With Lower FEV1
* P<0.01 compared with lifelong nonsmokers
(never smokers).
** P<0.01 compared with surface SIgA-
positive airways f rom the same clinical group.
Never Smokers
Former Smokers
COPD I-II
COPD III-IV
0.00
0.02
0.04
0.06
0.08
0.10
0.12
0.14
VM
sub (
mm
)
IgA-positive airways
IgA-deficient airways
Average
** **
**
** *
** ** *
*
* *
0.025
0
20
40
60
80
100
120
Inte
nsity o
f Ig
A-s
pecif
ic
Flu
ore
scent
Sig
nal (
ap
v)
Never smokers Former smokers COPD I-II
COPD I-II r = -0.847
p< 0.001
0.050 0.075 0.100 0.125 0.150 0.175
VVsub (mm)
0
0
20
40
60
80
100
Slg
A C
oncentr
atio
n
(g
/ml)
20 40 60 80 100 120
FEV1
140
r = 0.516 p< 0.05
Reprinted with permission of the American Thoracic Society. Copyright © 2013 American Thoracic Society. Polosukhin
VV,et al. Am J Respir Crit Care Med. 2011;184:317-327. Of f icial journal of the American Thoracic Society.
13 13
COPD Is a Disease Characterised
by Inflammation
Reproduced f rom The Lancet, Vol 364, Barnes PJ & Hansel TT, "Prospects for new drugs for chronic obstructive pulmonary disease",
pp985-96. Copyright © 2004, with permission f rom Elsevier.
Cigarette smoke
Epithelial
cells
CD8+ Tc cell
Emphysema
Proteases
Mucous hypersecretion
Macrophage/Dendritic cell
Neutrophil Monocyte
Fibroblast
Obstructive bronchiolitis
Fibrosis
14
COPDforum is
supported by
Inflammatory Cells in Stable COPD
15 15
Neutrophils in COPD
Mucous hypersecretion
Serine proteases Neutrophil Elastase
Cathepsin G
Proteinase-3
O2-
MPO
LTB4, IL-8, GRO-
LTB4, IL-8
Adapted f rom Barnes PJ. N Engl J Med. 2000; 343: 269-280
Adapted f rom Barnes PJ, et al. Eur Respir J. 2003; 22: 672-688
Emphysema
Severe emphysema
Images courtesy R Buhl.
16 16
Sputum Neutrophil Count
Correlates With Declining Lung Function
Reproduced with permission of Thorax f rom “Airways obstruction, chronic expectoration and rapid decline of FEV1 in smokers are
associated with increased levels of sputum neutrophils,” Stanescu et al, Vol 51, Copyright © 1996; permission conveyed through
Copyright Clearance Center, Inc.
> 30 < 20
100
0
Ne
utr
op
hils in
iIn
du
ce
d s
pu
tum
(%
)
90
20 – 30
80
60
70
50
40
FEV1 decline (mL/year)
P<0.01
17 17
Neutrophils Infiltrating Bronchial Glands
in COPD
Saetta M, et al. Am J Respir Crit Care Med. 1997;156:1633-1639. Reproduced with permission f rom American Thoracic Society.
Copyright © 1997
18 18
Reduction in Neutrophil Apoptosis in COPD
Adapted f rom Brown V, et al. Respir Res. 2009;10:24.
Apoptotic neutrophils
(arrows)
*P<0.05
*P<0.01
Morphology Tunel
NS
HS
COPD
60
50
40
30
20
10
0
Apoptotic
neutrophils [%]
Image courtesy of R Buhl.
NS: nonsmoking controls (n=9) HS:
healthy smoking controls (n=9)
TUNEL: the terminal transferase-
mediated dUTP nick end-labeling method
19 19
Alveolar Macrophages in COPD
Phagocytosis
Cigarette smoke
Wood smoke
Elastolysis MMP-9, MMP-12
Cathepsins K, L, S
Emphysema
Steroid resistance
NO
ROS ONOO-
HDAC Steroid
response
Monocytes
MCP-1
GRO-
Neutrophils
LTB4
IL-8 GRO-
CD8+ Cells
IP-10 Mig I-TAC
Adapted f rom Barnes PJ. J COPD. 2004;1:59-70. Copyright © 2004 f rom "Alveolar Macrophages as Orchestrators of COPD" by
Barnes. Reproduced by permission of Taylor & Francis Group, LLC., www.taylorandfrancis.com
Emphysema
Severe emphysema
Images courtesy of R Buhl.
Numbers
Secretion
20
COPDforum is
supported by
Inflammatory Mediators in Stable COPD
21 21
CD8+ Cells in COPD
Adapted f rom Berke G. Ann Rev Immunol. 1994; 12: 735-773. Cosio MG, et al. Chest. 2002;121:160S-165S
Adapted f rom Grumelli S, et al PLoS Med. 2004;1: 75-83. Majo J, et al. Eur Respir J. 2001;17:946-953
Cytotoxic T-Cell (CD8+: Tc1 Cell)
Macrophage
Bronchiolar epithelial cells
IP-10, Mig, I-TAC
CXCR3
Perforins Granzyme B
Emphysema
(Apoptosis of Type I pneumocytes)
IFN-
22 22
The Greater the CD8+ Infiltration,
the Greater the Airway Obstruction
Saetta M, et al. Am J Respir Crit Care Med. 1998;157:822-826. Reproduced with permission f rom American Thoracic Society.
Copyright © 1998.
1000
P=0.01
rho= –0.63
N=6
0
200
400
600
0 50 60 70 80 90 110
FEV1 (% predicted)
CD
8+ (
ce
lls/m
m2)
100
800
23 23
Increased CD8+ Cell Numbers in the Submucosa
of Large and Small Airways, Vessels and
Alveolar Wall of Smokers Who Develop COPD
Saetta M, et al. Am J Respir Crit Care Med. 1999;160:711-717. Reproduced with permission f rom American Thoracic Society.
Copyright © 1999
L
I
E
Jef fery PK. Chest. 2000; 117: 251S-260S. Courtesy of Dr Marina Saetta
Bro
nch
iole
A
lve
oli B
ron
ch
us
Pu
lmo
na
ry a
rtery
24 24 Siena L, et al. Respir Med. 2011;105:1491-500.
Apoptosis of CD8+ Cell Is Decreased in
Mild-to-Moderate COPD and Is Associated
With Lower FEV1
Background – CD8+ T-lymphocytes are crucial effector and regulatory cells in inflammation and are
increased in the central and peripheral airways in COPD.
Study Information:
– This study assessed the role of apoptosis in the accumulation of CD8+ T-lymphocytes within the airway wall in COPD.
– TUNEL and immunohistochemistry techniques were used to identify apoptosis and cell phenotype, respectively.
Key Results: – The percentage of apoptotic CD8+ T-lymphocytes was significantly lower (P
<0.0001) in smokers with mild-to-moderate COPD than in non-smokers, smokers with normal lung function, and smokers with severe/very severe COPD.
– Level of apoptotic CD8+ cells in central and peripheral airways were positively related to values of FEV1 and FEV1/FVC ratio.
These data suggest that reduced apoptosis of CD8+ T-lymphocytes may be an important mechanism that contributes to the accumulation of these cells in the
airway submucosa in smokers with mild/moderate COPD.
25 25
Emphysema Is Associated With Inflammatory
Cells in the Alveoli
Cells/mm-1
Nonsmokers
N=6
Smokers
without
emphysema
N=5
Smokers with
emphysema
N=10
Elastase+ 2.24 1.61 1.40
CD3+ 0.95 0.75 1.81
CD4+ 0.41 0.25 0.71
CD8+ 0.20 0.26 0.63
Adapted f rom Majo J, et al. Eur Respir J. 2001;17:946-953.
26 26
Numbers of Inflammatory Cells and Mediators
Increase as Disease Progresses
Percent of Airways with Measurable Cells
(%) by GOLD Stage
Cell Type I II III IV
PMNs 67 55 84 100
Macrophages 54 66 73 92
Eosinophils 25 33 29 32
CD4+ 63 87 77 94
CD8+ 85 80 88 98
B cells 7 8 45 37
Adapted f rom Hogg JC, et al. N Engl J Med. 2004;350:2645-2653.
PMN = Polymorphonuclear cells
27 27
Inflammatory Mediators in COPD – Summary
Cell
Neutrophils
Macrophages
T-cell
Epithelial cell
IL-8, TGF- 1, IP-10, Mig, I-TAC, LTB4, GRO- , MCP-1, MMP-9
Granzyme B, perforins, IFN-, TNF-
IL-8, IL-6, TGF-1 TGF-, IP-10, Mig, I-TAC, LTB4, GRO-, MCP-1, ROS, MMP-9
Serine proteases, TNF-, ROS, IL-8, MPO, LTB4
Selected Mediators
Barnes PJ, et al. Eur Respir J. 2003;22:672-888.
28 28
Examples of Chemotactic Factors in COPD
Barnes PJ. Curr Opin Pharmacol. 2004;4:263-272.
Hill AT, et al. Am J Respir Crit Care Med. 1999;160: 893-898.
Montuschi P, et al. Thorax. 2003;58:585-588.
MCP-1
GRO-
Elastin
fragments
LTB4
IL-8
GRO-
Elastin
fragments
IP-10
Mig
I-TAC
Neutrophil Monocyte T-cell
29 29
TNF- Has Pro-inflammatory
Actions in COPD
Mukhopadhyay S, et al. Respir Res. 2006;7:125. Reproduced with permission f rom Biomed Central.
Oxidative stress
Activation of NF-B and AP-1
Activation of proinflammatory molecules e.g. VCAM-1, ICAM-1 and RAGE
Subcellular ROS production
TNF-
Antioxidants
e.g. GSH, Catalase
Scavenge free radicals,
detoxify cellular hydrogen peroxide and inhibit ROS generation
Proinflammation
+
+ +
+
+
+
+
-
-
30 30
Levels of TNF-α in Exhaled Breath Condensate
in Stable COPD and Exacerbations
Reprinted f rom International Journal of COPD, 4, Ko FW, et al., Measurement of tumor necrosis factor-alpha, leukotriene B4, and
interleukin 8 in the exhaled breath condensate in patients with acute exacerbations of chronic obstructive pulmonary disease, 79-86,
Copyright 2009, with permissions f rom Dove Medical Press Ltd. Int J Chron Obstruct Pulmon Dis. 2009;4:79-86.
Exacerbation
25
20
15
10
5
0
Le
ve
l of
TN
F α
in
exh
ale
d B
rea
th
co
nd
en
sa
te (p
g/m
l)
Day 5 Day 14 Day 30 Day 60 Stable COPD Normal
P=0.017 P=0.036
P=0.045
P=0.009
31 31
COPD Inflammatory Mediators:
TGF-1
TGF-1 is elevated in airways of patients with COPD1
TGF-1 expression is partly responsible for small airway fibrosis1,2
TGF-1 mRNA correlates positively with pack-years of tobacco abuse and degree of small airway obstruction3
Several studies to show that TGF- 1 reduces -agonist receptors and function3
1. de Boer WI, et al. Am J Respir Crit Care Med. 1998;158:1951-1957.
2. Vignola AM, et al. Am J Respir Crit Care Med. 1997;156:591-599.
3. Takizawa H, et al. Am J Respir Crit Care Med. 2001;163:1476-1483.
32 32
Increased TGF-1 in COPD
Small Airway Epithelium
de Boer WI, 1998, “Transforming growth factor beta1 and recruitment of macrophages and mast cells in airways in chronic
obstructive pulmonary disease,” American Journal of Respiratory and Critical Care Medicine, Vol 158:1951-1957.
Off icial Journal of the American Thoracic Society © American Thoracic Society, Christina Shepherd, Managing Editor, 9/18/08.
Bronchiole
Macrophage
Fibrosis
33 33
IL-6 Concentrations in Exhaled
Breath Condensates
Reproduced f rom Respiratory Medicine, Vol 97, Bucchioni et al. "High levels of interleukin-6 in the exhaled breath condensate of patients
with COPD," pp1299-1302, Copyright © 2003, with permission f rom Elsevier.
Control COPD
10.0
7.5
5.0
2.5
IL-6
(p
g/m
L)
0.0
P<0.0001
34 34
Increased Bronchiolar Expression
of the T-Cell Chemokine Receptor CXCR3
Saetta M, et al. Am J Respir Crit Care Med. 2002;165:1404-1409. Reproduced with permission f rom American Thoracic Society.
Copyright © 2002
COPD
(Smoker)
Smoker
(Normal lung
function)
Non-smoker
(Normal lung
function)
Arrows indicate CXCR3+ cells. Nuclei counterstained with nuclear fast red (x40) be = Bronchiolar epithelium; bs = Bronchiolar submucosa
35 35
Elastins in the Development of Emphysema
Reproduced with permission of Nature Med, f rom “Antielastin autoimmunity in tobacco smoking-induced emphysema,” Lee et al, Vol 13,
Copyright © 2007; permission conveyed through Copyright Clearance Center, Inc.
ROS
Antigen-presenting cell
B cell Macrophage
Elastase
Cigarette smoke
Neutrophil
elastase
Macrophage
MMP12
MMP9
Cigarette smoke
Innate immunity Adaptive immunity
CD25 TRC
Tr
CXCR3
Neutrophil
TCR/MHC-11
Elastin peptides
IFN-
1AT
MMP12
MMP9 CXCL10
CXCR3
TH1 cell
CXCL9
Emphysema Normal lung
36 36
Actions of Proteinases in COPD
Reprinted f rom International Journal of COPD, 3, Owen CA, Roles for proteinases in the pathogenesis of chronic
obstructive pulmonary disease, 253-268, Copyright 2008, with permission f rom Dove Medical Press Ltd.
MMP
Inflammation
MMP SP ADAMs MMP SP ADAMs
T Cells Structural
Cells
CP CP GRZ
MMP SP CP
SP ADAMs
Proteinases Growth factor
activation
Small Airway
Fibrosis
Septal Cell
Apoptosis ECM
Degradation
Airspace Enlargement
Mucous Secretion
Bacterial Infection
Elastin Fragments
Cytokine Production or Activation
Defective Repair
IP-10
MAC PMN
COPD
37 37
Elevation of Matrix Metalloproteinase in COPD
Counts of MMP-2-Positive Macrophages
100
80
60
40
20
0 Severe COPD
(GOLD III–IV)
Mild/moderate
COPD
(GOLD I–II)
Control
smokers
Non-
smokers
MM
P-2
+ m
acro
ph
age
s (%
)
P=0.002 P=0.003
P=0.001
P=0.01
P=0.0001
Reproduced with permission of Chest, f rom “Matrix metalloproteinase-2 Protein in Lung Periphery is Related to COPD Progression,”
Baraldo et al, Vol 132, Copyright © 2007; permission conveyed through Copyright Clearance Center, Inc.
38 38
MMP-9 Is Elevated in Patients With COPD
Adapted f rom Beeh et a l. Respir Med. 2003;97:634-639.
914
44
0
100
200
300
400
500
600
700
800
900
1000
1100
COPD (N=12) Control (N=14)
Sputu
m M
MP
-9 C
on
ce
ntr
atio
n (
ng
/mL
)
P<0.001
39 39
Cathepsins Are Elevated in Smokers
0
1
2
3
4
NS
Smoking
FS
Status
S
IHC
score
* *
Nonsmoking Smoking
Elias JA, et al, 2006, “State of the art. Mechanistic heterogeneity in chronic obstructive pulmonary disease: insights f rom transgenic mice.”
Proceedings of the American Thoracic Society, Vol 3:494-498. Off icial Journal of the American Thoracic Society © American Thoracic
Society, Christina Shepherd, Managing Editor, 9/18/08.
* P=0.01
40 40 Andresen Eet al. PLoS One. 2011;6:e21898.
Defensin Gene Is Elevated in COPD and Is
Associated With Decreased FEV1
0.0
-0.5
-1.0
-1.5
-2.0
-2.5
healthy controls
COPD patients
DE
FB
1 m
RN
A e
xp
ressio
n p<0.0001
0.0
-0.5
-1.0
-1.5
-2.0
-2.5
healthy controls
COPD 3+4
DE
FB
1 m
RN
A e
xp
ressio
n
p<0.0001
COPD 1+2
0.0
-0.5
-1.0
-1.5
-2.0
-2.5
20
DE
FB
1 m
RN
A e
xp
ressio
n
Pearson r = -0.43
p = 0.0024
40 60 80 100 120
FEV1 (% predicted)
0.0
-0.5
-1.0
-1.5
-2.0
-2.5
20
DE
FB
1 m
RN
A e
xp
ressio
n
Pearson r = -0.49
p = 0.0005
40 60 80 100 120
FEV1/VC ratio (% predicted)
p = 0.0014
41 41
let-7c MicroRNA Expression and Pulmonary
Function
Reprinted with permission of the American Thoracic Society. Copyright © 2013 American Thoracic Society. Pottelberge GR, et al.
Am J Respir Crit Care Med. 2011;183:898-906. Of f icial journal of the American Thoracic Society.
7
6
5
4
3
2
Never Smokers
COPD ex-smokers
rela
tive
exp
ressio
n (L
og
2)
*
1
0
*
Smokers without COPD
COPD current
smokers
*
1250
1000
750
500
250
Never Smokers
Sp
utu
m s
TN
FR
-II
(pg
/mL
)
*
0
Current Smokers without
COPD
COPD current
smokers
-5
r = -0.43; p = 0.025
-4 -3 -2 -1 2
sputum let-7C
1250
1000
750
500
250
Sp
utu
m s
TN
FR
-II
(pg
/mL
)
0
0 1
50 75 100 125 150
FEV1 post (% pred)
5
4
3
2
1
rela
tive
exp
ressio
n (L
og
2)
0
6
42
COPDforum is
supported by
Modulation of Inflammation by Histone Deacetylase (HDAC)
43 43
Decreased HDAC Expression May Promote
Inflammation and Decrease Response to ICS
in COPD
Normal
Histone acetylation
Stimuli
Steroid sensitive
Histone hyperacetylation
nitration ubiquitination
oxidation
↑TNF
↑IL-8
↑GM-CSF
Stimuli
Steroid resistant
HAT
TF
HAT
TF
TNF IL-8 GM-CSF
Glucocorticoid
receptor
COPD
HDAC2
HDAC2
Glucocorticoid
peroxynitrite
Reproduced f rom Pharmacol Ther, Vol 116, Ito et al, “Impact of protein acetylation in inf lammatory lung diseases,” pp249-265.
Copyright © 2007, with permission f rom Elsevier.
44 44
Pulmonary HDAC Levels Decrease With
COPD Severity
Adapted f rom Ito K, et al. N Engl J Med. 2005;352:1967-1976.
S = COPD Stage
0
.5
1.0
1.5
2.0
Non-
smoker
N=11
P<0.001
HD
AC
2 e
xp
ressio
n (vs. la
min
A/C
)
P=0.04
P<0.001
P<0.001
S4
N=6
S0
N=9
S1
N=10 S2
N=10
■ ■
■
■
■
45
COPDforum is
supported by
Oxidative Stress
46 46
Airway Epithelium in COPD: Reactive Oxygen
Species and Polymorphonuclear Cells
Reproduced f rom Clin Applied Immunol Rev, Vol 5, Daheshia M, “Pathogenesis of chronic obstructive pulmonary disease (COPD)",
pp339-351. Copyright © 2005, with permission f rom Elsevier.
Toxin exposure
Alveolar macrophage
Mucous secretion
Airway epithelium
TNF
+
Neutrophil
IL-8, LTB4, MCP-1, MIP-1
Proteinase
Connective tissue destruction
TNF
Macrophage
Chemoattraction
Oxidant
E-Selectin upregulation
Tissue damage and Chromatin alteration
Proteinase
Connective tissue destruction
Tissue damage
and chromatin alteration
Perforin Granzyme TNF
Cell death
CD8+ T cell
+ +
+
+
+
+
+
+
Oxidant
+
+
+
+
47 47
Potential Reason for Limited ICS Efficacy in
COPD
Reprinted with permission of the American Thoracic Society. Copyright © 2013 American Thoracic Society. Adcock IM,
Ito K. Proc Am Thorac Soc. 2005;2:313-319. Of f icial journal of the American Thoracic Society.
HDAC2
O2-+ NO
Unknown kinases
Enhanced inflammation
Steroid sensitivity
Reduced inflammation
Steroid sensitivity
phosphorylation
phosphorylation ubiquitination
phosphatase
nitration Pl3K/Akt
peroxynitrite
Oxidative stress
48
COPDforum is
supported by
Tissue Destruction and Remodeling
49 49 Barnes PJ. N Engl J Med. 2000;343:269-280. Copyright © 2000 Massachusetts Medical Society. All rights reserved.
Histopathological Features of COPD
Normal lung
parenchyma
Chronic obstructive
bronchiolitis Emphysema
50 50
Inflammation Leads to Small
Airway Narrowing
Acute and chronic inflammation suspected to contribute to COPD-related small airway narrowing
Airway narrowing leads to airway obstruction
Narrowing results from several factors:
– Collagen deposition and increased lymphoid follicles in outer airway wall
– Mucosal thickening of airway lumen
– Inflammatory exudate in airway lumen
Barnes PJ, et al. Eur Respir J. 2003;22: 672-688.
51 51
Inflammation and Airway Destruction
Normal COPD
Reproduced f rom The Lancet, Vol 364, Hogg JC. "Pathophysiology of airf low limitation in chronic obstructive pulmonary
disease," pp709-721. Copyright © 2004, with permission f rom Elsevier.
52 52
Mucous Glands Are Enlarged in COPD
Hogg JC. Int J Tuberc Lung Dis. 2008;12:467-479. Reprinted with permission of the International Union Against Tuberculosis and
Lung Disease. Copyright © The Union.
53 53
Mucous Plugging Obstructs Small Airways
in COPD
Reproduced f rom The Lancet, Vol 364, Hogg JC. "Pathophysiology of airf low limitation in chronic obstructive pulmonary
disease,” pp709-721. Copyright © 2004, with permission f rom Elsevier.
Normal COPD
Mucous Plug
54 54
Volume of Airway Wall Tissue Correlates
Significantly With Disease Progression
Hogg JC, et al. N Engl J Med. 2004;350:2645-2653. Copyright © 2004 Massachusetts Medical Society.
All rights reserved.
0 20 40 60 80 100 120
0.25
0.20
0.15
0.10
0.05
0
GOLD
Stage 4
FEV1
V:S
A (m
m)
GOLD
Stage 3
GOLD
Stage 2
GOLD
Stages 0 and 1
55 55
Apoptotic Pathways in COPD
Demedts IK, et al. Respir Res. 2006;7:53. Reproduced with permission from Biomed Central.
Survival factor Granzyme B Perforin
TNF-α sFasL
cytoplasm
nucleus
ER Stress
Apoptosome
Apaf 1 Procasp-9
Procasp-9 Casp-9
Casp-8 CAD CAD
ICAD
Casp-8
Procasp-8 Procasp-8
FADD Bid tBid
Bax
Bak
Cyt C
ER stress
DNA fragmentation
1 2
4
3
5
?
Fas
56 56
Interaction of Apoptosis and Inflammatory
Pathways in COPD
MMPs / TIMPs Macrophages
Neutrophils
Impaired clearance of apoptotic cells
Phosphatidylserine receptor
CD8+ T-cells
Perforins
VEGF
Epithelial cell injury
Survival signals
Degradation of BM
Activation of FasL
Granzyme B
OXIDATIVE STRESS
INFLAMMATION
APOPTOSIS
NE
NE/1-AT
PROTEASE/ANTI-PROTEASE IMBALANCE
Demedts IK, et al. Respir Res. 2006;7:53. Reproduced with permission from Biomed Central.
57 57 Lim SC, et al. Yonsei Med J. 2011;52:581.587. Permission granted.
Apoptotic Lymphocytes and Exacerbation
of COPD
Compared to stable COPD, circulating apoptotic lymphocytes, CD 4+ and CD 8+ T cells were significantly increased in patients with exacerbation of COPD.
TNF-α presented a positive correlation with apoptotic lymphocytes in patients with exacerbation of COPD.
30
25
20
15
10
5
Control
Lym
ph
ocyte
s a
po
pto
sis
(%
)
p<0.001
0
Stable COPD
Exacerbation of COPD
p<0.001 p=0.015
30
25
20
15
10
5
Control C
D8
+ a
po
pto
sis
(%
)
p<0.001
0
Stable COPD
Exacerbation of COPD
p=0.001 p=0.030
30
25
20
15
10
5
Control
CD
4+ a
po
pto
sis
(%
)
p<0.001
0
Stable COPD
Exacerbation of COPD
p<0.001 p=0.015
300
250
200
150
100
50
Control
TN
F-α
(p
g/m
L)
p<0.001
0
Stable COPD
Exacerbation of COPD
p=0.021 p<0.001 350
58 58 Elias JA, et al. Proc Am Thorac Soc. 2006;3:494-498. Reproduced with permission f rom American Thoracic Society.
Copyright © 2006
Multiple Pathways Lead to
Emphysema in a Murine Model
Protease-Antiprotease abnormalities
MMP-12
Cathepsins
Apoptosis
Emphysema
Inflammation
IFN-/IL-13
Injury
59 59
Macroscopic Emphysema
60 60
Alveolar Septal Cell Apoptosis and
Emphysema
Kasahara Y, et al. Am J Respir Crit Care Med. 2001;163:737-744. Reproduced with permission f rom American Thoracic Society. Copyright © 2001
Increased level of apoptosis Reduced VEGF expression
25
20
15
10
5
0
P<0.02
P<0.01
Nonsmokers Smokers Emphysema
No
. T
UN
EL
+ c
ells/N
ucle
ic a
cid
(
g)
P<0.01 300
250
200
150
100
50
0
Normal Emphysema
N=11 N=12
VE
GF
(p
g/m
L)
VEGF = Vascular endothelial growth factor.
61 61 Saetta M, et al. Am Rev Respir Dis. 1985;132:894-900. Reproduced with permission f rom American Thoracic Society. Copyright © 1985
The Greater the Airway Inflammation, the
Greater the Destruction of Alveolar Attachments
0
20
40
60
80
0 10 15 25
Number of intact attachments
Air
wa
y in
fla
mm
atio
n s
co
re (
%)
20
Smokers’ lungs
Surgical smokers’ lungs
P<0.001
r = –0.80
62
COPDforum is
supported by
Inflammation in Acute Exacerbations
63 63
Exacerbations of Chronic Bronchitis
and Inflammatory Cell Types
Saetta M, et al. Am J Respir Crit Care Med. 1994;150:1646-1652.
Maestrelli P, et al. Am J Respir Crit Care Med. 1995;152:1926-1931.
Barnes PJ. N Engl J Med. 2000;343:269-280.
COPD Exacerbation
Eosinophils
Eosinophils
T-Cells
Neutrophils
Cells Predominant in:
Induced sputum
Biopsy
Neutrophils
64 64
Increase in Neutrophils During
COPD Exacerbations
Chronic lower airway bacterial colonisation is common in stable COPD patients1
During exacerbations, bacterial numbers increase in association with an inflammatory response2
Exacerbations may be associated with isolation of new bacterial strains3
Neutrophil products can further impair the mucosal defenses4
1. Monsó E, et al. Am J Respir Crit Care Med. 1995;152:1316-1320.
2. Sethi S, et al. Am J Respir Crit Care J Med. 2007;176:356-361.
3. Sethi S, et al. Am J Respir Crit Care Med. 2004;169:448-453.
4. White AJ, et al. Thorax. 2003;58:73-80.
65 65
Exhaled 8-Isoprostane in Exacerbations
Reproduced with permission of Thorax f rom “Increased leukotriene B4 and 8-isoprostane in exhaled breath condensate of patients with
exacerbations of COPD,” Biernacki et al, Vol 58, Copyright © 2003; permission conveyed through Copyright Clearance Center, Inc.
Treated with antibiotics
Exh
ale
d 8
-iso
pro
sta
ne
(p
g/m
L)
FEV1 51% predicted
P<0.0001
0
5
10
15
20
25
Exacerbation 2 weeks Normal
n=21 subjects n=12
66 66
Increased Neutrophils During Exacerbations
of Chronic Bronchitis
* P<0.01 versus stable disease
Adapted f rom Saetta M, et al. Am J Respir Crit Care Med. 1994;150:1646-1652.
Exacerbations
*
Stable disease
300
0
250
200
100
150
50
67 67
Increased Eosinophils During Exacerbations
of Chronic Bronchitis
* P<0.001
Adapted f rom Saetta M, et al. Am J Respir Crit Care Med. 1994;150:1646-1652.
60%
150
100
50
*
EG
2 (+
) cells
/mm
2
0
200
Exacerbations Stable disease
68 68
1.55
4 3.25
15.6
0
2
4
6
8
10
12
14
16
18
IL-6 (pg/mL) CRP (g/dL)
Baseline
Exacerbation
Elevation of Serum Markers for Systemic
Inflammation in Acute Exacerbations
Adapted f rom Hurst JR, et al. Am J Respir Crit Care Med. 2006;174:867-874.
* P<0.001 versus baseline
*
Se
rum
co
nce
ntr
atio
n
*
69 69
MMP-9 Is Elevated in Acute Exacerbations
Mercer PF, et al. Respir Res. 2005;6:151. Reproduced with permission f rom Biomed Central.
P<0.01
MM
P-9
(µ
g/g
sp
utu
m)
Pre-exacerbation
0
20
40
60
80
100
Sputum Sample
120
140
Exacerbation
70
COPDforum is
supported by
Clinical Consequences of Inflammation
71 71
Telomere Dysfunction Results in Sustained
Inflammation in COPD
In situ lung specimen studies showed a higher percentage of senescent pulmonary vascular endothelial cells stained for p16 and p21 in patients with COPD than in control subjects
Adapted f rom Amsellem V, et al. Am J Respir Crit Care Med. 2011;184:1358-1356.
p16 p21
Arrowheads show p16- and p21-positive cells. Scale bar = 25 μm * P<0.0001
0
20
40
60
80
100
% o
f p
16
po
sitiv
e c
ells/
VW
F p
ositiv
e c
ells
Controls COPD
*
0
20
40
60
80
% p
21
po
sitiv
e c
ells/
VW
F p
osiitive
ce
lls
Controls COPD
*
72 72
Telomere Dysfunction Results in Sustained
Inflammation in COPD
Telomerase activity was detectable only at early cell passages and was significantly lower in patients with COPD than in control subjects at passage 4
Adapted f rom Amsellem V, et al. Am J Respir Crit Care Med. 2011;184:1358-1356.
The T/S ratio is the ratio of telomere repeat copy number over single gene copy number.
* P<0.05 versus control and † P<0.05 versus corresponding value at passage 4
Passage 4
Te
lom
ere
le
ng
th (
T/S
) ra
tio
Controls
COPD
1.5
1.0
0.5
0.0
Senescence
* †
†
73 73
Decreased Replicative Capacity of Pulmonary
Vascular Endothelial Cells From Patients With COPD
Adapted f rom Amsellem V, et al. Am J Respir Crit Care Med. 2011;184:1358-1356.
* P<0.01 PDL = population doubling level
Controls
COPD
Cu
mu
lative
PD
L
25
20
15
0
*
5
10
P4
Cu
mu
lative
PD
L
25
20
15
0
5
10
P6 P8 P10 P12 P14 P16 P18
Controls
COPD
74 74
Levels of Cytokines Are Increased in
Pulmonary Vascular Endothelial Cells From
Patients With COPD
Reprinted with permission of the American Thoracic Society. Copyright © 2013 American Thoracic Society. Amsellem V,
et al. Am J Respir Crit Care Med. 2011;184:1358-1356. Of f icial journal of the American Thoracic Society.
*P<0.05 and ***P<0.0001 versus control values; † P<0.05 and †† P<0.01 versus corresponding value at passage 6. FGF-2 = f ibroblast growth
factor-2; MCP-1 = monocyte chemotactic factor-1; PAI-1 = plasminogen activator inhibitor-1; PDGF = platelet-derived growth factor;
RANTES = regulated upon activation, normal T-cell expressed and secreted; sICAM-1 = soluble intercellular adhesion molecule-1.
100 6000 10
80
60
40
20
Passage 6
IL6 p
g/m
L
0
*
Senescene
† 4000
2000
Passage 6
MC
P-1
pg
/mL
0
***
Senescene
†
4
2
Passage 6
0
*
Senescene
††
6
8
sIC
AM
-1 n
g/m
L
††
5000
4000
3000
2000
1000
Passage 6
IL8 p
g/m
L
0
*
Senescene
†
15
10
5
Passage 6
RA
NTE
S p
g/m
L
0
Senescene
† † 6000
4000
2000
Passage 6
PD
GF
ng
/mL
0
Senescene
†
Controls
COPD
75 75
Levels of Cytokines Are Increased in
Pulmonary Vascular Endothelial Cells From
Patients With COPD
*P<0.05 and ***P<0.0001 versus control values; † P<0.05 and †† P<0.01 versus corresponding value at passage 6. FGF-2 = f ibroblast growth
factor-2; MCP-1 = monocyte chemotactic factor-1; PAI-1 = plasminogen activator inhibitor-1; PDGF = platelet-derived growth factor;
RANTES = regulated upon activation, normal T-cell expressed and secreted; sICAM-1 = soluble intercellular adhesion molecule-1.
800
600
400
200
Passage 6
Hu
-GR
O p
g/m
L
0
*
Senescene
†
250
150
100
Passage 6
PA
I-1
pg
/mL
0
Senescene
† †
25
15
5
Passage 6
FG
F-2
pg
/mL
0
Senescene
200
50
20
10
*
Controls
COPD
Reprinted with permission of the American Thoracic Society. Copyright © 2013 American Thoracic Society. Amsellem V,
et al. Am J Respir Crit Care Med. 2011;184:1358-1356. Of f icial journal of the American Thoracic Society.
76 76
Inflammation Predicts Mortality in Patients
With COPD
Reprinted with permission of the American Thoracic Society. Copyright © 2013 American Thoracic Society. Celli BR,
et al. Am J Respir Crit Care Med. 2012;185:1065-1072. Of f icial journal of the American Thoracic Society.
100%
95%
90%
85%
80%
75%
0 6 12 18 24 30 36
IL-6 <4.5 pg/mL
(n=1462)
IL-6 >4.5 pg/mL
(n=504)
p<0.001
IL -6
100%
95%
90%
85%
80%
75%
0 6 12 18 24 30 36
Neutrophils <5.8x10^9/L
(n=1386)
Neutrophils >5.8x10^9/L
(n=593)
p<0.001
Neutrophils
100%
95%
90%
85%
80%
75%
0 6 12 18 24 30 36
Fibrinogen <518 mg/dL
(n=1534)
Fibrinogen >518 mg/dL
(n=490)
p<0.001
Fibrinogen
Time Observed (Months)
Pe
rce
nt S
urv
ival
77 77
Inflammation Predicts Mortality in Patients
With COPD
100%
95%
90%
85%
80%
75%
0 6 12 18 24 30 36
hsCRP <8.7 pg/mL
(n=1572)
hsCRP >8.7 mg/dL
(n=404)
p<0.001
hsCRP
100%
95%
90%
85%
80%
75%
0 6 12 18 24 30 36
CCL-18 <153 ng/mL
(n=1432)
CCL-18 >153 ng/mL
(n=278)
p<0.001
CCL-18/PARC
100%
95%
90%
85%
80%
75%
0 6 12 18 24 30 36
SP-D <165 ng/mL
(n=1461)
SP-D >165 ng/mL
(n=524)
p<0.001
SP-D
Time Observed (Months)
Pe
rce
nt S
urv
ival
Reprinted with permission of the American Thoracic Society. Copyright © 2013 American Thoracic Society. Celli BR,
et al. Am J Respir Crit Care Med. 2012;185:1065-1072. Of f icial journal of the American Thoracic Society.
78 78
Progression From Molecular to Clinical
Events in COPD Inflammation
Chung KF, et al. Eur Respir J. 2008;31:1334-1356.
Aetiology
Cigarette smoke
Environmental pollutants
Amplifying processes
• Innate immunity
• Acquired immunity
• Oxidative stress
• Stress response
• Cellular activation
• Extrapulmonary effects
• Somatic mutations
• Genetics
• Epigenetics
Cellular processes
• Inflammatory cell recruitment/ activation
• T-cell activation
• Autoimmunity
• Transcriptional activation
• Mediator release
• Tissue repair
• Apoptosis
• Cell proliferation
• Senescence
• Systemic Inflammation
• Skeletal muscle
Death
GOLD stage IV: severe
Exacerbations
Mild
Asymptomatic
Clinical outcomes
• Mucous gland hyperplasia
• Small airways obstruction
• Centrilobular emphysema
• Corticosteroid resistance
• Bacterial colonisation
• Respiratory virus infections
Pathological processes
79 79
Clinical Impact of Inflammation in COPD
Tsoumakidou M, et al. Respir Res. 2006;7:80. Reproduced with permission f rom Biomed Central.
Increased Airway Inflammation
Increased mucous production
Airway wall thickening
Airway wall oedema
Bronchoconstriction
Airway narrowing
V’/Q’ Mismatching Hyperinflation
Worsening of gas exchange
Increased work of breathing
Increased oxygen consumption –
Decreased mixed venous oxygen
Cough, sputum, dyspnoea, Respiratory failure
80 80
Inflammation:
Clinical Consequences
Systemic
Nutritional abnormalities and weight loss
Hypoxaemia
Skeletal muscle dysfunction
Cardiovascular disease
Depression
Osteoporosis
Anaemia
Agusti AG, et al. Eur Respir J. 2003;21:347-360.
Agusti AG. Proc Am Thorac. 2006;3:478-483.
Barnes PJ, Cell BR. Eur Respir J. 2009;33:1165-1185.
Pulmonary
Dyspnoea
Cough
Sputum production
Exacerbations
Influencing the bronchial tone
Inhibitory NANC (iNANC) system is considered to be
the main neural mechanism mediating ASM relaxation
by releasing of vasoactive intestinal peptide (VIP), VIP
structure-related peptides and nitric oxide (NO) .
On the other hand, excitatory NANC (eNANC) system
mediates bronchial contraction activating the efferent
functions of bronchopulmonary-sensitive sensory
nerves. These nerves release tachykinins, such as
substance P and neurokinin A, which in turn activate
neurokinin-1 (NK-1) and NK-2 receptors located on the
ASM membrane, thus inducing bronchoconstriction
Influencing the bronchial tone
Bronchodilation may, therefore, be
obtained either by directly relaxing the
smooth muscle through stimulation of the
b2-AR with b2-AR agonists, or/and by
inhibiting the action of ACh at mAChRs.
Furthermore, an alternative approach
could be the modulation of the NANC
system.
Bronchodilators
Indacterol
Olodaterol
Vilanterol
Glycopyrronium bromide
Aclidinium bromide
Xanthines
Influencing The Cellular Components
Of Inflammation
Phosphodiesterase Inhibitors
The PDE4 isoenzyme is a major therapeutic target
because it is the predominant isoenzyme in the majority
of inflammatory cells, including neutrophils, which are
implicated in the pathogenesis of COPD. Inhibition of
PDE4 in inflammatory cells influences various specific
responses, such as the production and/or release of pro-
inflammatory mediators including cytokines and active
oxygen species , with a well-documented efficacy in
animal models of COPD .
Influencing The Cellular Components
Of Inflammation
Phosphodiesterase Inhibitors
Oral PDE4 inhibitors: roflumilast; GRC-3886;
ELB353; GRC 4039; MEM1414; oglemilast;
OX914; ASP3258; TAS-203; Zl-n-91; NIS-
62949; tetomilast
Inhaled PDE4 inhibitors; GSK256066;
SCH900182; Compound 1; tofimilast;
AWD12-281; UK500001
PDE3/4 inhibitors: RPL554
PDE4/7 inhibitors: TPI 1100
Influencing The Cellular Components
Of Inflammation
Adenosine receptors Agonist
Some evidence suggests the involvement of adenosine
receptors in inflammation. Four subtypes (A1, A2A, A2B, A3) of
adenosine receptors have been characterized. The anti-
inflammatory effect of adenosine is due to a short-term
activation of A2A receptor that elevates cAMP and,
consequently, modulates key pro-inflammatory neutrophil
functions such as superoxide generation, degranulation and
adhesion. Furthermore, adenosine A2A receptor activation
induces a shift in the profile of lipid mediator production from
leukotrienes to prostaglandin E2.This shift may contribute to
prevent the subsequent neutrophil-elicited inflammatory
events
Influencing The Cellular Components
Of Inflammation
Adenosine receptors A2a Agonists
CGS21680; ATL146e; UK371,104; GW328267X;
regadenoson (CVT-3146); 2-(cyclohexylethylthio)-AMP
Influencing The Cellular Components
Of Inflammation
Adhesion molecules Inflammatory processes in COPD are coupled to an increased
recruitment of neutrophils to the lung in response to a release of IL-8
and leukotriene B4 (LTB4) by activated epithelial cells and
macrophages . Migration of inflammatory cells from the vascular
compartment to the surrounding tissue is partly regulated by
selectins (L-, P- and E-selectin) . Selectins mediate transient adhesive
interactions pertinent to inflammation through the recognition of the
carbohydrate epitope, sialyl Lewisx (sLex), expressed on circulating
leukocytes. The rapid turnover of selectin--ligand bonds mediates the
cell tethering and rolling in shear flow. Several studies suggest that
selectins are involved in the inflammatory processes of COPD .
Therefore, targeting these molecules might reduce the inflammation
in COPD
Influencing The Cellular Components
Of Inflammation Drugs that interfere with adhesion molecules
Carbohydrate-based inhibitors: sLex antagonists
(bimosiamose); heparins and heparinoids (PGX-
100, PGX-200); synthetic glycomimetic molecule
(GMI-1070) mAb inhibitors: EL246
Influencing The Inflammatory mediators
1-TNF-a
2-Chemokines
3-NF-kB
4-p38 MAPK and MK2
5-PI3K
6-LTB4
7-PPAR
Targeting protease activity at the
enzymatic level
Drugs that may have indirect anti-
inflammatory actions
Reversing glucocorticoid resistance :
Activation of HDAC2: theophylline;
curcumin; resveratrol
Inhibition of P-glycoprotein
Inhibition of MIF