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Is COPD an inflammatory disease?
1.
2. Is COPD An Inflammatory
Disease?
Gamal Rabie Agmy, MD,FCCP
Professor of Chest Diseases, Assiut university
Presentation1.lnk
3. 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.
6. 66
Angiogenesis in COPD
Reprinted from 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 from 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. 77
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.
21. 2121
CD8+ Cells in COPD
Adapted from Berke G. Ann Rev Immunol. 1994; 12: 735-773. Cosio MG, et al. Chest. 2002;121:160S-165S
Adapted from 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-
24. 2424
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. 2525
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 from Majo J, et al. Eur Respir J. 2001;17:946-953.
26. 2626
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 from Hogg JC, et al. N Engl J Med. 2004;350:2645-2653.
PMN = Polymorphonuclear cells
28. 2828
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. 2929
TNF- Has Pro-inflammatory
Actions in COPD
Mukhopadhyay S, et al. Respir Res. 2006;7:125. Reproduced with permission from Biomed Central.
Oxidative stress
Activation of NF-B and AP-1
Activation of proinflammatorymolecules e.g.VCAM-1,ICAM-1 and RAGE
SubcellularROS production
TNF-
Antioxidants
e.g. GSH,
Catalase
Scavenge free radicals,
detoxifycellular
hydrogen peroxideand
inhibit ROS generation
Proinflammation
+
+
+
+
+
+
+
-
-
30. 3030
Levels of TNF-α in Exhaled Breath Condensate
in Stable COPD and Exacerbations
Reprinted from 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 from Dove Medical Press Ltd. Int J Chron Obstruct Pulmon Dis. 2009;4:79-86.
Exacerbation
25
20
15
10
5
0
LevelofTNFαinexhaledBreath
condensate(pg/ml)
Day 5 Day 14 Day 30 Day 60 Stable COPD Normal
P=0.017 P=0.036
P=0.045
P=0.009
31. 3131
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.
36. 3636
Actions of Proteinases in COPD
Reprinted from International Journal of COPD, 3, Owen CA, Roles for proteinases in the pathogenesis of chronic
obstructive pulmonary disease, 253-268, Copyright 2008, with permission from 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
38. 3838
MMP-9 Is Elevated in Patients With COPD
Adapted from 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)
SputumMMP-9Concentration(ng/mL)
P<0.001
50. 5050
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.
55. 5555
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-8Procasp-8
FADDBidtBid
Bax
Bak
Cyt C
ER
stress
DNAfragmentation
1
2
4
3
5
?
Fas
56. 5656
Interaction of Apoptosis and Inflammatory
Pathways in COPD
MMPs / TIMPsMacrophages
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. 5757
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
Lymphocytesapoptosis(%)
p<0.001
0
Stable
COPD
Exacerbation
of COPD
p<0.001 p=0.015
30
25
20
15
10
5
ControlCD8+
apoptosis(%)
p<0.001
0
Stable
COPD
Exacerbation
of COPD
p=0.001 p=0.030
30
25
20
15
10
5
Control
CD4+
apoptosis(%)
p<0.001
0
Stable
COPD
Exacerbation
of COPD
p<0.001 p=0.015
300
250
200
150
100
50
Control
TNF-α(pg/mL)
p<0.001
0
Stable
COPD
Exacerbation
of COPD
p=0.021 p<0.001350
63. 6363
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. 6464
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.
66. 6666
Increased Neutrophils During Exacerbations
of Chronic Bronchitis
* P<0.01 versus stable disease
Adapted from 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. 6767
Increased Eosinophils During Exacerbations
of Chronic Bronchitis
* P<0.001
Adapted from Saetta M, et al. Am J Respir Crit Care Med. 1994;150:1646-1652.
60%
150
100
50
*
EG2(+)cells/mm2
0
200
ExacerbationsStable disease
68. 6868
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 from Hurst JR, et al. Am J Respir Crit Care Med. 2006;174:867-874.
* P<0.001 versus baseline
*
Serumconcentration
*
69. 6969
MMP-9 Is Elevated in Acute Exacerbations
Mercer PF, et al. Respir Res. 2005;6:151. Reproduced with permission from Biomed Central.
P<0.01
MMP-9(µg/gsputum)
Pre-exacerbation
0
20
40
60
80
100
Sputum Sample
120
140
Exacerbation
71. 7171
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 from 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
%ofp16positivecells/
VWFpositivecells
Controls
COPD
*
0
20
40
60
80
%p21positivecells/
VWFposiitivecells
Controls
COPD
*
72. 7272
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 from Amsellem V, et al. Am J Respir Crit Care Med. 2011;184:1358-1356.
The T/S ratio is the ratio of telomere repeatcopy numberoversingle gene copynumber.
* P<0.05 versus controland † P<0.05 versus correspondingvalue atpassage 4
Passage 4
Telomerelength(T/S)ratio
Controls
COPD
1.5
1.0
0.5
0.0
Senescence
* †
†
73. 7373
Decreased Replicative Capacity of Pulmonary
Vascular Endothelial Cells From Patients With COPD
Adapted from Amsellem V, et al. Am J Respir Crit Care Med. 2011;184:1358-1356.
* P<0.01PDL = population doublinglevel
Controls
COPD
CumulativePDL
25
20
15
0
*
5
10
P4
CumulativePDL
25
20
15
0
5
10
P6 P8 P10 P12 P14 P16 P18
Controls
COPD
79. 7979
Clinical Impact of Inflammation in COPD
Tsoumakidou M, et al. Respir Res. 2006;7:80. Reproduced with permission from Biomed Central.
Increased Airway Inflammation
Increased mucous production
Airway wall thickening
Airway wall oedema
Bronchoconstriction
Airway narrowing
V’/Q’ MismatchingHyperinflation
Worsening of gas exchange
Increased work of breathing
Increased oxygen consumption –
Decreased mixed venous oxygen
Cough, sputum, dyspnoea, Respiratory failure
80. 8080
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
81. 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
82. 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.
84. 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 .
86. 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
87. Influencing The Cellular Components
Of Inflammation
Adenosine receptors A2a Agonists
CGS21680; ATL146e; UK371,104; GW328267X;
regadenoson (CVT-3146); 2-(cyclohexylethylthio)-AMP
88. Influencing The Cellular Components
Of Inflammation
Adhesion molecules
Inflammatory processes in COPD are coupled to an increased
recruitmentof neutrophilsto 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
89. 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
92. Drugs that may have indirect anti-
inflammatory actions
Reversing glucocorticoid resistance :
Activation of HDAC2: theophylline;
curcumin; resveratrol
Inhibition of P-glycoprotein
Inhibition of MIF
