Air pollution: Systemic effects?

Presented by : Stephan van Eeden MD PhDRespirologist, Pacific Lung Health Centre, St Pauls HospitalInvestigator, Institute for Heart and Lung Health

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

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

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)

PM10 in alveolar macrophages and epithelial cells

Van Eeden et al Proc Am Thorac Soc 2005

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

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

HypothesisPM10 induced lung inflammation

Systemic Inflammatory Response

Lung Macrophages

Lung Epithelial cells

Pro-inflammatory mediators

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

South-East Asia

haze of 1997

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

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

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

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

arterial blood

venous blood

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

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

HypothesisPM10 induced lung inflammation

Bone marrow Stimulation

(leukocytes and platelets)

Systemic Inflammatory Response

Development and destabilization of

atheroscrelotic plaques

Cytokines production

Heart attacks

Strokes

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

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

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

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

Air Pollution and blood vessel

responses (endothelial dysfunction)

Wire Myograph

Carotid artery

Tamagawa et al AJP 2008

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

-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

-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

Air Pollution where you live:Atherosclerosis

Kunzli et al. Environ Health Perspect. 2005

Living near a heavy traffic route:

Coronary Heart Disease

Hoffmann B et al., Circulation,2007

Coronary Plaque

Admission for acute myocardial infarctions and PM2.5 levels

Peters et al Circ 2001;103;2810

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)

How air pollutants aggravate heart and lung disease

Blood stream inflammation

Air pollution

Lung inflammation

Heart Attacks & Strokes

Pneumonia

Asthma Attacks

COPD Attacks

What can we do to attenuate the impact of PM air pollution on blood

vessels?

Pleiotropic Effects of Statins

Nf-kB

Rho

Cholesterol

Rac 1

TXA2 Platelet Activation

Anti-inflammatory

Immunomodulatory

Endothelial FunctionHMG-CoA Reductase

Inhibitors

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)

Statins reduce Lung Inflammation

Miyata et al Chest. 2013;143(2):452-460

Cell Differential Counts in BAL Fluid

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

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

Saline Saline + Lovastatin PM10 PM10 + Lovastatin

Oil-red-O

Statins attenuates PM-induced Atherocslerosis

Miyata et al Tox Appl Pharm 2013

***

##

***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

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.

Policy Implications

•Size of air pollution particles matter

•Rethink urban development

•Should work on near-term solutions to mitigate adverse effects of PM

Breathing Clean Air Promotes Heart & Lung Health