Air pollution: Systemic effects? · 10 exposure causes a systemic inflammatory response that...
Transcript of Air pollution: Systemic effects? · 10 exposure causes a systemic inflammatory response that...
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Air pollution: Systemic effects?
Presented by : Stephan van Eeden MD PhDRespirologist, Pacific Lung Health Centre, St Pauls HospitalInvestigator, Institute for Heart and Lung Health
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Overview
• Introduction statements
• Effect of air pollution on the lung
• Systemic inflammation induced by air pollution
• Impact of air pollution on blood vessels
• What can we do to attenuate theses systemic effects
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Effect of ambient air pollution on mortality
Dockery et al. New Engl J Med, 1993 Laden et al Am J Respir Crit Care Med. 2006
Deaths predominantly cardiopulmonary
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Deposition of Particles into the lungs
Nemmar A et al. Circulation. 2003
a, Aggregates of particles of 20-50 nm in diameter
b, Most of these aggregates are <2.5 µm in largest diameter
2.5 µm
Nemmar A et al. Circulation. 2003
Particulate Matter:Carbon nucleus
Polycyclic aromatic hydrocarbons
Transition metals (iron, copper)
Biologic’s (LPS etc)
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PM10 in alveolar macrophages and epithelial cells
Van Eeden et al Proc Am Thorac Soc 2005
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IL-8 IL-6 GM-CSF MIP-1a MIP-1b IL-1a IL-1b IL-10 TNF-a0
10
20
30
40
PM10
Control
*
*
***
*p<0.01**p<0.05
Cyto
kin
e c
on
cen
trati
on
Cytokine produced by human AM
exposed to PM
Van Eeden et al Am J Respir Crit Care Med. 164:826-30. 2001
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IL-8 IL-6 GM-CSF IL-1b
0
500
1000
1500
2000
0
50
100
150
200
Cyt
oki
ne
pg
/ml
Control
PM10(100ug)
PM10(500ug)
Control
PM10(100ug)
PM10(500ug)
*
*
**p<0.01
*
Bronchial Epithelium
Cytokines produced by human bronchial
epithelium following exposure to PM
10 mm
Fujii et al Am J Respir Cell Mol Biol. 27:34-41. 2002
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HypothesisPM10 induced lung inflammation
Systemic Inflammatory Response
Lung Macrophages
Lung Epithelial cells
Pro-inflammatory mediators
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Smoke Exposure Causes bloodstream
inflammation
Baseline Exercise Exposure0
25
50
75*p<0.001
*
Changes in circulating IL-8 induced by fire fighting
n=9
IL-8
pg
/ml
Swiston et al Eur Resp J 2008
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South-East Asia
haze of 1997
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Jan Febr March Apr May June July Aug Sept Oct Nov Dec
0
50
100
150
200
250
300
PM
10
mcg
/m3
Air pollution levels in Singapore 1997
Tan & van Eeden 2001, AJRCCM
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Blood Stream inflammation causes
by Woodsmoke
Haze Post-haze0
1
2
3
4
5
6
7
8
9
10
Ban
ds %
*
*p<0.001
Sep 26 Oct 6 Oct 13 Oct 20 Oct 27 Nov 21 Nov 28 Dec50
1
2
3
4
5
6
7
8
9
10
% B
an
d C
ell
s
0
60
120
180
240
300
PM
10
(u
g/m3 )
* ***
**
# ##
##
Tan & van Eeden 2001, AJRCCM
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Blood Stream inflammation causes
by Woodsmoke
0
5
10
0 50 100 150 200
PM10 (mg/m3)
IL-6
pg
/ml
Haze
Post-haze
0
5
10
15
0 50 100 150 200
PM10 (mg/m3)
IL-1
pg
/ml
Post-haze
Haze
IL-6, p<0.09
PM10, p<0.001
IL-1, p<0.05
PM10, p<0.001
Tan & van Eeden 2001, AJRCCM
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Possible Biological Mechanisms for PM10 adverse health effects
Seaton hypothesis: PM10 induces inflammation in the
lung that have systemic effects
Particles hypothesis: Particles themselves are toxic to
tissue
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arterial blood
venous blood
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Arterial and Venous IL-6 At 4 Hours
**: P<0.01, * :P<0.05
**
*
*
Saline Low dose PM10 High dose PM10**
0
1
2
3
4
5
UntreatedLo
g s
eru
m I
L-6
(p
g/m
l)
4.5
5.0
5.5
4.0
Lo
g-I
L6 (
pg
/ml)
Artery
Vein
Kido et al Am J Respir Cell Mol Biol Vol 44. pp 197–204, 2011
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BAL versus Arterial IL-6
Log BALF IL-6 (pg/ml)
P<0.0001
-1
0
1
2
3
4
5
6
7
-2 -1 0 1 2 3 4 5 6 7 8
R2 = .234
Lo
g A
ort
ic S
eru
m I
L-6
(p
g/m
l)
Kido et al Am J Respir Cell Mol Biol Vol 44. pp 197–204, 2011
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HypothesisPM10 induced lung inflammation
Bone marrow Stimulation
(leukocytes and platelets)
Systemic Inflammatory Response
Development and destabilization of
atheroscrelotic plaques
Cytokines production
Heart attacks
Strokes
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First direct evidence that air pollutioncauses blood vessel disease
Suwa et al. J Am Coll Cardiol. 2002
•Lacks LDL Receptor
•Hyperlipidemia
•Hypercholesterolemia
•Rapid development of AS-lesions
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Air pollution stimulate lipid uptake in Atherosclerosis plaques
0
10
20
30
40
(%)
Control
n=6
PM10
n=9
* 34.2
21.1
*p<0.05
Suwa JACC 2001
Lipids in Plaques
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A trichrome stained AS lesions. The arrow delineating border between the fibrous cap and atheromatous core.
(%)
Control
4 segments
3 animals
PM10
13 segments
4 animals
24.6
4.7
*
0
10
20
30 *p<0.05
% fibrous cap thinner than 10 mm
Fibrous cap in advanced lesions in aorta
Suwa et al, JACC 2002
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Fibrous Cap
Lipid Core
Foam Cell
Inflammatory cell
Control WHHL Rabbits
Effect PM10 on plaque morphology
Thinner Fibrous Cap
Increased and redistribution of lipids Increase Inflammatory cells
PM10
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Air Pollution and blood vessel
responses (endothelial dysfunction)
Wire Myograph
Carotid artery
Tamagawa et al AJP 2008
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Circulating IL-6 and vessels vasodilation
R2= 0.406 , p-value= 0.014
-0.020 -0.015 -0.010 -0.005 0.000 0.005
50
60
70
80
90
100
AC
h s
tim
ula
ted
max
imu
m v
aso
dila
tio
n
Circulating IL-6 Levels
Tamagawa et al AJP 2008
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-9 -8 -7 -6 -50
25
50
75
100
Control (n=11)
PM10 (n=8)
Log[ACh](M)
% R
ela
xati
on
-8 -7 -6 -5 -40
25
50
75
100
ControlPM10
Log[ACh](M)
% D
ilati
on
** **
Normal Mice IL-6 deficient mice
Impact of IL-6 on PM-induced vascular dysfunction
Suda et al AJCMB 2010
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-0.5
-0.4
-0.3
-0.2
-0.1
0
0.1
0.2
0.3
0.4
Exposure Type
Bra
ch
ial
Art
ery
Dia
me
ter
Ch
an
ge
(m
m)
Filtered Air CAP + Ozone
2. (a)CAP + O3 - BAD
-0.092
0.003
Brook et al. Circulation 2002
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Air Pollution where you live:Atherosclerosis
Kunzli et al. Environ Health Perspect. 2005
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Living near a heavy traffic route:
Coronary Heart Disease
Hoffmann B et al., Circulation,2007
Coronary Plaque
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Admission for acute myocardial infarctions and PM2.5 levels
Peters et al Circ 2001;103;2810
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Cardiovascular Morbidity and Mortality associated with Air Pollution
• Mortality due to PM exposure is predominantly cardiovascular in nature (Pope et al 2002)
• Hospital admission within hours of an increase in PM (Schwartz et al
1994).
• Cardiovascular admissions for arrhythmia’s, unstable angina, MI’s and heart failure (Dockery et al 1993).
• Hospitalization and mortality form Stroke Haidong 2003
• Predominantly the elderly at risk(Schwartz J 1994)
• M & M correlates the best with particle levels (Bates DJ 1992)
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How air pollutants aggravate heart and lung disease
Blood stream inflammation
Air pollution
Lung inflammation
Heart Attacks & Strokes
Pneumonia
Asthma Attacks
COPD Attacks
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What can we do to attenuate the impact of PM air pollution on blood
vessels?
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Pleiotropic Effects of Statins
Nf-kB
Rho
Cholesterol
Rac 1
TXA2 Platelet Activation
Anti-inflammatory
Immunomodulatory
Endothelial FunctionHMG-CoA Reductase
Inhibitors
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Animals : New Zealand White rabbits
(12-week-old, female)
Interventions : i) +/- Lovastatin (5 mg/kg, 8 weeks)
ii) PM10 or saline instillation
(direct intratracheal instillation; 1.0 mg/kg,
3 days a week. 4 weeks)
Study design
Day 1 29 36 43 50 57
+/- Lovastatin
PM10 exposure 4 hr later
Euthanasia
Saline exposure
or
(Miyata, Chest 2013)
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Statins reduce Lung Inflammation
Miyata et al Chest. 2013;143(2):452-460
Cell Differential Counts in BAL Fluid
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Statins reduces cytokines in airspaces
†
IL-6 IL-8
pg
/mL
Saline
Saline + Lovastatin
PM10
PM10 + Lovastatin
***
*
###
#
Miyata et al Chest. 2013;143(2):452-460
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Transit times of PMN through bone marrow
Group Transit Time (hrs)
Saline 47.9 0.7
Saline + Lovastatin 42.7 3.7
PM10 21.3 4.3 ***
PM10 + Lovastatin 38.2 0.5 ###
Two-way factorial analysis of variance (ANOVA) with PM10 exposure and statin treatment as
independent variables, followed by Bonferroni post-hoc test. Transcripts with a significant PM10
exposure statin treatment interaction (p < 0.05) were additionally analyzed with a one-way ANOVA
followed by Newman-Keuls post-hoc test for comparison of individual treatment groups. ***p < 0.001
compared to saline; ### p< 0.001 compared to PM10
Statins attenuates the systemic inflammatory response
Miyata et al Am J Physiol 2012
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Saline Saline + Lovastatin PM10 PM10 + Lovastatin
Oil-red-O
Statins attenuates PM-induced Atherocslerosis
Miyata et al Tox Appl Pharm 2013
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***
##
***P < 0.001 vs. saline; ## P < 0.01 vs. PM10,
Two-way factorial ANOVA
Maximum vasoconstriction at PE 10-4 mM
Statins attenuates PM-induced endothelial dysfunction
Miyata et al Tox Appl Pharm 2013
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Summary• Overwhelming epi-evidence that PM10 air pollution is
associated with heart and vascular disease
• PM10 exposure causes a systemic inflammatory response that increases CRP/IL-6 which stimulates the bone marrow.
• This systemic response activate blood vessels (endothelial dysfunction) and enhanced the development of atherosclerosis and induced instability in plaques.
• Statins attenuate the effects PM air pollution on blood vessels.
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Policy Implications
•Size of air pollution particles matter
•Rethink urban development
•Should work on near-term solutions to mitigate adverse effects of PM
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Breathing Clean Air Promotes Heart & Lung Health