COPD Pathogenesis and Inflammatory Mediators

COPD
Gamal Rabie Agmy, MD,FCCP Professor of Chest Diseases, Assiut university

Goal of this learning modules
•To Provide a framework to make informed decisions regarding the diagnosis and treatment of Chronic obstructive pulmonary disease

Learning objectives
After completing this module you should know:
•know the definition of COPD
•Understand the burden of COPD
•know the risk factors of COPD occurrence
•Learn about the pathology, pathogenesis and Pathophysiology of COPD.

History of COPD
•A British medical textbook (1860s )→ C/P of chronic bronchitis as an advanced disease with repeated bronchial infections that ended in right-sided heart failure.
•20th century, Ciba symposium of 1958 proposed definitions of chronic bronchitis and emphysema → concept of airflow obstruction.
•Chronic bronchitis: chronic productive cough for 3 months during each of 2 consecutive years (other causes of cough being excluded).
•Emphysema: an abnormal, permanent enlargement of the air spaces distal to the terminal bronchioles, accompanied by destruction of their walls and without obvious fibrosis

Definition & Overview Common preventable & treatable disease Characterized by persistent airflow limitation that is usually progressive Associated with an enhanced chronic inflammatory response in the airways & the lung to noxious particles or gases Exacerbations & comorbidities contribute to the overall severity in individual patients

COPD is a progressive disease The Downward Spiral in COPD

Burden of COPD COPD is a leading cause of morbidity & mortality worldwide The burden will increase in coming decades due to continued exposure to risk factors & the aging of the world’s population COPD is associated with significant economic burden

Prevalence Buist AS, McBurnie MA, Vollmer WM, et al. International variation in the prevalence of COPD (the BOLD Study): a population- based prevalence study. Lancet. 2007;370:741-750. 11.8% 8.5% 10.1% overall

COPD Misdiagnosis Is Common in Women
Chapman KR, Tashkin DP, Pye DJ. Gender bias in the diagnosis of COPD. Chest. 2001;119:1691-1695

Under diagnosis of COPD in the United States
• Over 12 million people in the United
States have been diagnosed with
COPD; another 12 million are
estimated to be undiagnosed1
• Data from NHANES III indicate that
approximately 24 million US adults
have evidence of impaired lung
function indicative of COPD2,3
• Most (70%) of patients with
undiagnosed COPD are <65 years
70%
<Age 65
30%
≥Age
65
Percent With Undiagnosed COPD
1. NHLBI; available at http://www.nhlbi.nih.gov/health/public/lung/copd/index.html. 3. Mannino DM, et al. Proc Am Thorac Soc. 2007;4:502-306
2. Mannino DM, et al. MMWR Surveill Summ. 2002;51:1-16.

Mortality :
Global burden of Disease study: COPD rank Murray and Lopez Lancet 1997

Mortality :
Global burden of Disease study: COPD rank

Mortality :
Global burden of Disease study
•Almost 90% of COPD deaths occur in low- and middle-income countries.

Economic and social burden
Economic
•USA: Direct costs $ 29.5 billion & Indirect costs $ 20.4 billion
•Europe: 38.6 billion Euros
•In developing countries:
–Workplace & home productivity loss > Medical costs loss
Social
•Disability-Adjusted Life year (DALY)
–1990→ 12th leading cause of DALYs
–2030 → 7th leading cause of DALYs

Risk factors for COPD Influence disease development & progression

Genes
•Gene-environmental interaction are the key for development of COPD.
•Susceptibility to COPD is not dichotomous variable and a range of susceptibility exits.
–Some smokers develop the disease earlier than others.
–Progression in COPD is very heterogeneous

Genes
•In patients with COPD
–emphysema represents accelerated ageing of the lung
–studies showed telomere shortening & dysfunction
•Telomerase null mice with short telomeres
–increased emphysema
–double-strand DNA breaks
•after exposure to chronic cigarette smoke
•with evidence of reduced epithelial repair
•Family with a telomerase mutation
–have early-onset emphysema

Cumulative exposure to noxious particles is the key risk factor for COPD

Airway Responsiveness-Dutch Hypothesis
•Increased airways responsiveness and allergy are clinical phenotypes that predict increased susceptibility to cigarette smoke.
•Methacholine and histamine responsiveness precedes and predicts accelerated decline in lung function, thus a risk factor for COPD.*
•Increased airways responsiveness noted among 1st degree relatives of patients with early onset COPD.^
*Silva, GE et al. Asthma as a risk factor for COPD in a longitudinal study. Chest 2004; 126:59.
^Celedon JC et al. Bronchodilator responsiveness and serum total IgE levels in families of probands with severe early-onset COPD. Eur Respir J 1999; 14:1009.

Pathogenesis Noxious agents Biomass particles Occupational agents Pollutants Genetic factors Resp. infection

These data are communicated for scientific purpose only. Confidential slide set
23
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
COPD Pathogenesis

25
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
COPD Pathogenesis

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
Siafakas NM, et al. Int J Chron Obstruct Pulmon Dis. 2007;2:453-462.
COPD Pathogenesis

Pathogenesis
Obstructive Bronchiolitis
Emphysema

Inflammatory Cells in Stable COPD
Gamal Agmy 2-5-2014
Inflammation in COPD

29
Neutrophils in COPD
Mucous hypersecretion
Serine proteases
Neutrophil Elastase
Cathepsin G
Proteinase-3
O2-
MPO
LTB4, IL-8, GRO-
LTB4, IL-8
Adapted from Barnes PJ. N Engl J Med. 2000; 343: 269-280
Adapted from Barnes PJ, et al. Eur Respir J. 2003; 22: 672-688
Emphysema
Severe emphysema
Images courtesy R Buhl.

30
Sputum Neutrophil Count Correlates With Declining Lung Function
Reproduced with permission of Thorax from “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
Neutrophils in iInduced sputum (%)
90
20 – 30
80
60
70
50
40
FEV1 decline (mL/year)
P<0.01

31
Neutrophils Infiltrating Bronchial Glands in COPD
Saetta M, et al. Am J Respir Crit Care Med. 1997;156:1633-1639. Reproduced with permission from American Thoracic Society. Copyright © 1997

32
Reduction in Neutrophil Apoptosis in COPD
Adapted from 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

33
Alveolar Macrophages in COPD
 Phagocytosis
Cigarette smoke
Wood smoke
Elastolysis
MMP-9, MMP-12
Cathepsins K, L, S
Emphysema
Steroid resistance
NO
ONOO- ROS
 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.taylorandf rancis.com
Emphysema
Severe emphysema
Images courtesy of R Buhl.
 Numbers
 Secretion

34
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.

35
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

36
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 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
+
+
+
+
+
+
+
-
-

Modulation of Inflammation by Histone Deacetylase (HDAC)
Gamal Agmy 2-5-2014

38
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.

39
Pulmonary HDAC Levels Decrease With COPD Severity
Adapted from 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
HDAC2 expression (vs. lamin A/C)
P=0.04
P<0.001
P<0.001
S4
N=6
S0
N=9
S1
N=10
S2
N=10
■
■
■
■
■

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.

41
Inflammation and Airway Destruction
Normal
COPD
Reproduced from The Lancet, Vol 364, Hogg JC. "Pathophysiology of airflow limitation in chronic obstructive pulmonary disease," pp709-721. Copyright © 2004, with permission from Elsevier.

42
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

43
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’ Mismatching
Hyperinflation
Worsening of gas exchange
Increased work of breathing
Increased oxygen consumption –
Decreased mixed venous oxygen
Cough, sputum, dyspnoea, Respiratory failure

44
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

Inflammatory cells and mediators in COPD

The site of pathology in COPD
Mucus gland hyperplasiaGoblet cellhyperplasiaMucus hypersecretionNeutrophilsin sputumSquamousmetaplasiaof epithelium↑MacrophagesNo basement membrane thickeningLittle increase inairway smooth muscle↑CD8+lymphocytesChanges in Large Airways of COPD PatientsChanges Patients Source: Peter J. Barnes, MD

Chronic bronchitis
Hyperplasia of mucous
glands and infiltration of the
airway wall with
inflammatory cells

The site of pathology in COPD
Disrupted alveolar attachmentsInflammatory exudatein lumenPeribronchialfibrosisLymphoid follicleThickened wall with inflammatory cells-macrophages, CD8+ cells, fibroblastsChanges in Small Airways in COPD Patients Source: Peter J. Barnes, MD

The site of pathology in COPD Endothelial dysfunctionIntimalhyperplasiaSmooth muscle hyperplasia↑Inflammatory cells(macrophages, CD8+lymphocytes) Changes in Pulmonary Arteries in COPD Patients Source: Peter J. Barnes, MD

Emphysema
•Centriacinar
–Focal destruction limited to the respiratory bronchioles and the central portions of the acini.
–associated with cigarette smoking
–most severe in the upper lobes
•Panacinar
–involves the entire alveolus distal to the terminal bronchiole.
–most severe in the lower lung zones
–AAT deficiency
•Distal acinar or paraseptal
–least common form and involves distal airway structures, alveolar ducts, and sacs.
loss of alveolar walls and dilatation of airspaces in emphysema

Natural History of Emphysema
•In non-smokers, maximal lung function
–attained at age 15 - 25 years
–after a variable plateau phase, declines ~ 20 -25 mL/year
•Lung Health Study (large longitudinal study)
–smoking is associated with an accelerated decline in lung function
•Females are at higher risk of lung damage
–related to smoke exposure than males

Fletcher C et al. 1977
FEV1 (% of value at age 25)
100
25
50 75 Never smoked or not susceptible to smoke Age (years)
Disability
Smoked regularly and susceptible to its effects
Death
0
25 50 75 Stopped at 65
Stopped at 45 Classical View of “Disease Progression” & “Disease Modification”

Pathogenic mechanisms
Pathological changes in COPD Physiological abnormalities: Mucous hypersecretion & ciliary dysfunction Airflow obstruction & hyperinflation Gas exchange abnormalities Pulmonary hypertension & systemic effects Pathophysiology

COPD Pathogenesis and Inflammatory Mediators

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