From Bench to Bedside; What Should a Physician Know About Air Pollution

and How to Help the Patient

Hasan Bayram, MD, PhD.Department of Chest Diseases, School of

Medicine, University of GaziantepE-posta: bayram@gantep.edu.tr

TTS 10th Annual Congress, Antalya, 25-29 April 2007

Contents• Air pollution; definition• Effects on health

– Epidemiological studies– In vivo studies– In vitro data

• Intervention and effects• Suggestions

– Informing patients; authorities, press, physician– Medication

What is Air Pollution?

• Presence of pollutants in the environment, where can have negative effects on nature and public health

• Outdoor air pollution; particulate matter (PM0.5, 2.5, 10), ozone, NOx, SO2

Indoor Air Pollution

• NOx, Ozone, CO• PM, volatile organic compounds,• Poly aromatic hydrocarbons,• Formaldehyde,• Radon,• Biological agents,• Asbestos • Lead etc

Contents• Air pollution; definition• Effects on health

– Epidemiological studies– In vivo studies– In vitro data

• Intervention and effects• Suggestions

– Informing patients; authorities, press, physician– Medication

Effect of a 10g/m3 PM2.5 Increase on Cardiovascular and Respiratory Mortality in Metropolitan Cities in USA (1979-83, 99-00)

Pope CA,et al. Circulation 2004.

Ozone - Mortality, APHEA-2 (23 Cities in Europe)

1h Ozone – Daily Mortality in Summer Period

Gryparis A et al, Am J Respir Crit Care Med, 2004

Total Mortality

Resp Mortality

Association of Total and Respiratory Mortality withNO2 Over 6 days Over All Cities in Europe-APHEA-2.

Samoli E, et al. Eur Respir J 2006.

Association of 10g/m3 increase in PM10-13/TSP With Emergency Room Visits Due to Asthma+COPD (>65y) -APHEA-2.

Atkinson RW, et al. Am J Respir Crit Care Med 2001.

Effect of Air Pollution on Emergency Room Visits in Denizli City Centre

0

0,5

1

1,5

2

2,5

3

3,5

4

1 2 3 4 5 6 7 8 9 10 11 12

Admission Number

•Assoc. of Previous wk SO2 (r = 0,25) and PM (r=0,1) levels with emerg. visits

•Effect of 100g/m3/day SO2 (1.38;1.13- 1.63) and PM (1.14;1.03-1.25)

İncrease on risk of emergency room visits

Fişekçi et al Eur Respir J. (Suppl 30) 1999

Berktaş M ve Bircan A,Tüberküloz ve Toraks Dergisi 2003

Monthly Emergency Room Visits Due to Asthma and Levels of SO2 and PM in Ankara

PM - AB

SO2 - AB

0

20

40

60

80

100

120

140

160

Sep Oct Nov Dec Jan Feb Mar April May June July Aug

SO2

PM

Admis.

Hospital.

Bayram H, et al. Proc Am Thorac Soc 2006; 3: A389.

Association Between Respiratory Outpatients Visits and Hospitalisation and levels of SO2 (g/m3) and PM (g/m3) in

Diyarbakır 2004.

Exercise and Asthma and Ozone- A Children Cohort

• 3535 Children (9-16yr) without asthma• 5 years follow up in Southern California• Newly diagnosed asthma in 265 children• In presence of ozone,

– The risk of asthma in children having exercise 2-3 times/day was 3.3 (1.9-5.8)

– No effects of exercise– Time spent outside has effect

McConnel R, et al. Lancet 2002

Prevalence of All. Rhinitis Symptoms in High School Students in Bayrampaşa and Beykoz

• N=386

• Bayrampaşa; All Rinitis= 22.8 %

• Beykoz; 6%,

• The risk of living in Bayrampaşa= OR:4.6 (2.3-9.0)

Keleş N, et al. Am J Rhinol, 1999.

FEV1 Growth in Girls/Boys Living in S Californiaand Mean NO2 Levels in 1993-2001

Gauderman WJ, et al. N Engl J Med 2004

Air Pollution and Life Quality in Asthmatics in Gaziantep

• Air pollution • Use of bronchodilators in moderate

persistent asthma • Night symptoms

Bozkurt Aİ, TTS 2. Congress Abstract Book, 1998

Epidemiological Data-Summary

• Mortality: Heart, lung and others

• Hospital visits: Asthma, COPD, cardiac diseases

• Increase in prevalence of allergic rhinitis, asthma, lung cancer, COPD,

• Effect on lung growth in children

• Effects on medication

Contents• Air pollution; definition• Effects on health

– Epidemiological studies

– In vivo data– In vitro data

• Intervention and effects• Suggestions

– Informing patients; authorities, press, physician– Medication

A human exposure hood developed for aerosol exposureKarolinska University Hospital, Stockholm (Liden et al, 1998)

Air Pollutants – Clinical Effects

• Irritation in mouth and nose,

• Dyspnoea, wheezing, chest tightness,

• Decrease in lung function tests (FEV1, FVC, FEF25-75)

• Increase in airway hyperresponsivenessBrunekreef B, Holgate ST. Lancet 2002; 360: 1233-42.

Peden DB. Allergy 1997; 52 (suppl 38): 37-44.

Ozone – Human Exposure

• Airway permeability; LDH, total protein, albumine

• BAL;– PMN leukocytes ↑– IL-6, IL-8, GM-CSF and fibronectin ↑

• Asthmatics; increase in eosinophils and MPO Scannell C, et al.Am J Respir Crit Care 1996; 154: 24-9.Balmes JR, et al. Res Rep Health Eff Inst 1997; 78:1-37.

Ozone – Bronchial Epithelial GM-CSF Expression in Mild Asthmatics

Hava 0.2ppm O3 (2h)

Bosson J, et al. Clin Exp Allergy 2003;33:777-82.

Nitrogen Doxide (NO2) Exposure

• Healthy subjects; Increase of neutrophils, IL-6, IL-8, and decreases in mucociliary cleareanceDevlin RB,et al. Inhal Toxicol 1999; 11:89-109.

• Asthmatics; Increases in Thromboxane B2 and prostaglandin D2 in BALJörres R, et al. Eur Respir J 1995; 8: 416-24.

Devalia JL, et al. Lancet 1994; 344: 1668-1671.

Effects of NO2 and SO2 on Airway Response of Asthmatics to Allergens

1010

66

55

44

33

22

11

Allergen (CBU x 103)

Air NO2 SO2 NO2 +SO2

p<0.05

Diesel Exhaust Exposure (PM10=108g/m3- 2h) – Normals

• Bronchial lavage;

– Neutrophil,

– Lymphocyte,

– IL-8

• Bronchial biopsy;

– IL-8 mRNA,

– p selectine,

– VICAM-1

Stenfors N, et al. Eur Respir J 2004;23:82-6

Effect of Nasal DEP (0.3mg) on Allergen Induced IgE

Diaz-Sanchez D. Allergy 1997; 52 (suppl 38): 52-56.

0

40

80

120

160

Day 0 Day 1 Day 4 Day 8 Day 8

allergen + DEP

allergen

IgE (U/ml)

CH Technologies(USA) Inc. http://www.toxics.com/expose/expose.html

Single Animal Exposure Units for Rodents

Effect of Diesel Exhaust (30-1000g/m3

PM, 7 days) on RSV Infection in Mice

Harrod KS, et al. Am J Respir Cell Mol Biol 2003;28:451-63.

Summary: In Vivo Laboratory Studies

• Bronchospasm, airway reactivity and related clinical symptoms

• Airway inflammation

• Enhances effects of allergens

• Potentiates effects of each others

• Tendency to viral airway disease (animal studies)

Contents• Air pollution; definition• Effects on health

– Epidemiological studies– In vivo studies

– In vitro data• Intervention and effects• Suggestions

– Informing patients; authorities, press, physician– Medication

Cells outgrow from tissue explant

(Hoffman Modulation Contrast Light Microscope, x300)

Cell Cultures (Humans, Animal)• Cell line

• Primary cell cultures

• Nasal, tracheal, bronchial, alveolar epithelial cells

• Smooth muscle cells

• Fibroblasts

• Alveolar macrophages

t2 t6 t240

1

2

3

4

501050100

Time (hours)

Ozone (ppb)

**

** *

****

**

*

##

#

14C

-BSA

% in

med

ium

t2 t6 t240

1

2

3

4

5

Time (hours)

14C

-BSA

% in

med

ium

Ozone – BEC Culture Permeability of Asthmatics and Non-asthmatics

Non-asthmatics Asthmatics

Bayram H, et al. Clin Exp Allergy 2002.

0

0,5

1

1,5

2

2,5

3

3,5

Air 10 50 100Concentration of Ozone

(ppb)

NS

Non-asthmaticsGM-CSFpg/ug cell protein

NS

NS

0

0,5

1

1,5

2

2,5

3

3,5

Air 10 50 100Concentration of Ozone

(ppb)

NS

p=0.035

p=0.015

AsthmaticsGM-CSFpg/ug cell protein

*

Bayram H, et al. J Allergy Clin Immunol 2001.

Effect of ozone on release of GM-CSF from BEC of non-asthmatics and asthmatics

Bayram H, et al; J Allergy Clin Immunol 1999.

Effect of Loratadine on 400ppb NO2-induced release

of RANTES and sICAM-1 from HBEC

Air 400ppb NO2 0.25M 2.5M 25M Loratadine[M]+NO2

Air 400ppb NO2 0.25M 2.5M 25M Loratadine[M]+NO2

Incubation of BEC with DEP

Bayram H, et al. Am J Respir Cell Mol Biol 1998.

Effect of DEP on Ciliary Beat Frequencyof Bronchial Epithelial Cells

Effect of DEP on Release of IL-8 from Bronchial Epithelial Cells of Non-asthmatics and Asthmatics After 24hrs

Non-asthmatics AsthmaticsBayram H, et al. J Allergy Clin Immunol 1998.

Effect of DEP (10g/ml) onA549 cell proliferation

G0/1 S G2/M0

25

50

75

100Serum Free

DEP (10g/ml)

FCS (10%)***

***

*

**

*****

Cell cycle compartments

Per

cent

of

cells

Channels (FL2-H)0 50 100 150 200 250

Num

ber

020

040

060

080

010

00

Sync Wizard Model File: Data.002Date acquired: 06-Jun-03Date analyzed: 6-Jun-2003

G0G1: 75.81 % Mean: 53.79 CV: 4.94 %G2M: 10.98 % Mean: 97.36 G2/G1: 1.81S-Phase: 13.21 % Mean: 76.25 Compartment 1: 4.03 % Compartment 2: 4.70 % Compartment 3: 4.47 % Modeled Events: 8835RCS: 4.671

G0G1G2MS-Phase

SF

•NAC (10mM)•JNK inh. (33M)

Bayram H et al, Eur Respir J 2006

LL(A-/P-) LR(A+/P-) UR(A+/P+) UL(A-/P+)0

10

20

30

40

70

100 **

*

FCS(10%)SF

DEP (10g/ml)

*

*

Kuadrantlar

Hüc

rele

rin %

'si

*P<0.05 and**P<0.005 vs SF

Effect of DEP (10g/ml) on A549cell apoptosis

SF

Bayram H et al, Eur Respir J 2006

permeability

IL-8 RANTES GM-CSF ICAM-1

Adhesion molecule)ICAM-1VCAM-1

E-selectin EosinophilChemotaxis

SurvivalEndothelial cell

Allergen

Mast Cell

O3, NO2, DEPCBF

Apoptosis Prolif.

(Starvation)

•NAC•JNK inh.•NF-kB inh.

•Anti-infl agn

Contents• Air pollution; definition• Effects on health

– Epidemiological studies– In vivo studies– In vitro data

• Intervention and effects• Suggestions

– Informing patients; authorities, press, physician– Medication

The Death Rates in Dublin 6yrs Before and After Ban (1990) on Coal Sales

*Adjusted for temperature, humidity, resp epidemics and standard death rates

Clancy L et al, Lancet 2002

Acute Asthma Attacks Before and During Atlanta 1996 Summer Olympics

* 21 June-18 July and 5 August -1 September 1996† 19 July - 4 August 1996.

Friedman MS et al. JAMA, 2001.

Effect of Natural Gas Instillation on Symptoms of Rhinitis in High School Students in Istanbul

Rhinitis Symptoms: 62.5% (n=125)* 51% (n=102)OR : 1.6 (1.08-2.58)

*p<0.05

Keleş N, et al. Arch Environ Health 1999.

(Doğal gazdan sonra)(Doğal gazdan önce)

Effects of Home Preventative Measures (allerg,smoke) on Asthmatic Symptoms of Children (n=937)

Morgan WJ, et al. New Eng J Med 2004

Chapman RS, et al,BMJ 2005; 331: 1050-56

Effects of Improvement in Household Stoves on Risk of COPDin China (Xuanwei) (Retrospektive cohort, 1976-92)

Contents• Air pollution; definition• Effects on health

– Epidemiological studies– In vivo studies– In vitro data

• Intervention and effects

• Suggestions– Informing patients; authorities, press, physician– Medication

Legislative Measures

• 1930; Umumi Hıfzısıhha K, Gayrı Sıhhi M, regulation on environmental health

• 1961; Monitory of SO2 and smoke in Ankara

• 1983; Environmental protection law

• 1986; Turkish Law of Air Quality Protection

Ministry of Envronment and Forestry (www.cevreorman.gov.tr) and Health (www.rshm.gov.tr), Republic of Turkey.

Emergency Measures; Alarming Levels*

**SO2 (g/m3) **PM (g/m3)

1. Step 700 400

2. Step 1000 600

3. Step 1500 800

4. Step 2000 1000

Ministry of Health, Turkey (www.rshm.gov.tr)

*Measures to be taken by local authorities**24h average

What Can We Do for Our Patients?

• Measures to reduce indoor air pollution

• Ventilation at suitable time periods

• Stay indoor when level of pollution is high outside

• Close monitorisation for attacks when air pollution is high.

• Increase dose of medication if needed

SUMMARY• Air pollution has negative effects on heart and lungs

• Shows these effects by directly influence airways (airway

narrowing etc)

• By increasing oxidative stress or altering other cellular

functions leading to– Inflammation and

– Changes in cell proliferation and death

• Measures reducing air pollution have positive impact on

health

• Patients should be more closely monitored in periods

when level of pollution is high.

Thank You For Your Interest