PPT

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PPT

  1. 1. Health Effects of Air PollutionHealth Effects of Air Pollution March 17, 2010 Presented by David B. Peden, M.D., M.S. Professor of Pediatrics, Medicine & Microbiology/Immunology Director, UNC Center for Environmental Medicine, Asthma and Lung Biology
  2. 2. 2 DisclosuresDisclosures • CORPORATE • GlaxoSmithKline • Funxional Therapeutics • FEDERAL • US EPA • NHLBI • NIEHS • NCCAM
  3. 3. Sources of Common Environmental Contaminants Which Modify Asthma
  4. 4. National Ambient Air Quality StandardsNational Ambient Air Quality Standards (NAAQS)(NAAQS) Pollutant Primary Stds. Averaging Times Carbon Monoxide 9 ppm (10 mg/m3 ) 8-hour(1) 35 ppm (40 mg/m3 ) 1-hour(1) Lead 1.5 µg/m3 Quarterly Average Nitrogen Dioxide 0.053 ppm (100 µg/m3 ) Annual (Arithmetic Mean) Particulate Matter (PM10 ) Revoked(2) Annual(2) (Arith. Mean) 150 µg/m3 24-hour(3) Particulate Matter (PM2.5 ) 15.0 µg/m3 Annual(4) (Arith. Mean) 35 µg/m3 24-hour(5) Ozone 0.075 ppm 8-hour(6) 0.12 ppm 1-hour(7) (Applies only in limited areas) Sulfur Oxides 0.03 ppm Annual (Arith. Mean) 0.14 ppm 24-hour(1)
  5. 5. Pollutants and AsthmaPollutants and Asthma
  6. 6. Environmental Agents Which InduceEnvironmental Agents Which Induce Asthma, Allergies and Lung DiseaseAsthma, Allergies and Lung Disease • Probable » Diesel Exhaust » ETS • Possible » O3 » NO2 » Other Particulates • Plausible » Low dose endotoxin (Gauderman et al NEJM, 2004, 351:1057-1067)
  7. 7. Environmental Agents Which WorsenEnvironmental Agents Which Worsen Asthma and AllergiesAsthma and Allergies • Ozone • SO2 • NO2 • Diesel Exhaust • Particulates • Environmental Tobacco Smoke • Endotoxin Burnett, RT et al. Am J Epidemiol. 2001 Mar 1;153(5):444-52
  8. 8. 0 10 20 30 40 50 60 70 80 1985 1986 1987 1988 Steel Mill Closed 0 25 50 75 100 125 150 1985 1986 1987 1988 Steel Mill Closed Impact of steel mill closing on PM 2.5 (left,Impact of steel mill closing on PM 2.5 (left, µµg/mg/m33 ) and Bronchitis admissions (right) in the) and Bronchitis admissions (right) in the Utah Valley (Pope, et al)Utah Valley (Pope, et al)
  9. 9. Endotoxin exposure is a risk factor for asthma: theEndotoxin exposure is a risk factor for asthma: the national survey of endotoxin in United States housing.national survey of endotoxin in United States housing. Am J Respir Crit Care Med. 2005 Dec 1;172(11):1371-7Am J Respir Crit Care Med. 2005 Dec 1;172(11):1371-7 9
  10. 10. Pollutants shown to enhance recallPollutants shown to enhance recall response to allergenresponse to allergen • Ozone • NO2/SO2 • Endotoxin • Diesel Exhaust • ETS • Responses include: » IgE » PMNs » Eosinophils » Airway Reactivity 10 mean air air LPS mean LPS 1.0 2.0 4.0 8.0 16.0 32.0 64.0 128.0 256.0 512.0 1024.0 2048.0 PC20FEV1miteallergen (AU/ml) p<0.05 n=14
  11. 11. Airway Responses ofAirway Responses of Asthmatics to OzoneAsthmatics to Ozone
  12. 12. Copyright restrictions may apply. Daily Levels of Ozone (Both 1-Hour Average and 8-Hour Average), Particulate Matter of 2.5 {micro}m or Less (PM2.5), and Daily Maximum Temperature, With Daily Prevalence of Respiratory Symptoms for Users of Asthma Maintenance Medication (n = 130) for Southern New England, April 1 through September 30, 2001 Gent, J. F. et al. JAMA 2003;290:1859-1867
  13. 13. Granulocyte Response to OGranulocyte Response to O33
  14. 14. Effect of OEffect of O33 on IL-1on IL-1ββ and IL-6and IL-6 in Asthma and Normal Volunteersin Asthma and Normal Volunteers
  15. 15. Effect of OEffect of O33 on IL-8 and IL-10on IL-8 and IL-10 in Asthma and Normal Volunteersin Asthma and Normal Volunteers
  16. 16. Ozone Enhances Markers of Innate Immunity and AntigenOzone Enhances Markers of Innate Immunity and Antigen Presentation on Airway Monocytes in Healthy IndividualsPresentation on Airway Monocytes in Healthy Individuals J Allergy Clin Immunol. 2007 Sep;120(3):719-22J Allergy Clin Immunol. 2007 Sep;120(3):719-22
  17. 17. Ozone enhances response to inhaled allergens Effect of 0.16 ppm O3 on Immediate Bronchial Responses to Inhaled Allergen 500 250 125 64 32 16 8.0 4.0 500 250 125 64 32 16 8.0 4.0 Mean Air Ozone MeanMean Air Ozone Mean HDMConcentration(AU/ml)HDMConcentration(AU/ml) House Dust MiteHouse Dust Mite D-14 (Kehrl et al, 1999)(Kehrl et al, 1999) Effect of 0.4 ppm O3 on Nasal Allergen-Induced Eosinophil Influx 00 2525 5050 7575 Clean AirClean Air OzoneOzone 3-hr post allergen challenge3-hr post allergen challenge Eosinophils/mlNLF (x1000) Eosinophils/mlNLF (x1000) D-15 (Peden et al, 1995)(Peden et al, 1995) • Ozone exposure causes increased immediate allergic responses to house dust mite • Ozone causes increased eosinophil (allergy cell) influx to the airway • Experimentally demonstrated at levels as low as 0.12 ppm
  18. 18. SummarySummary • Epidemiological Studies clearly demonstrate an effect of ambient air ozone in asthma • Ozone causes an immediate decrease in lung function • Ozone induced airway inflammation » PMNs in all populations » Eosinophils-seen in asthmatics • Ozone results in changes in airway cell surface markers which likely modulate immune response • Ozone increases response to allergen
  19. 19. Climate Change, Pollutants andClimate Change, Pollutants and Environmental AllergensEnvironmental Allergens
  20. 20. Global temperature land-ocean anomaly (°C), 1880-2007, defined as the difference from theGlobal temperature land-ocean anomaly (°C), 1880-2007, defined as the difference from the average temperature of the base period (1951-1980). The 14 warmest years in the globalaverage temperature of the base period (1951-1980). The 14 warmest years in the global temperature record have all occurred since 1990. The blue points (annual means) in the boxtemperature record have all occurred since 1990. The blue points (annual means) in the box from 1990-2007 show the warmest years. Adapted from: NASA 2007from 1990-2007 show the warmest years. Adapted from: NASA 2007 20
  21. 21. Predicted increase in ambient OPredicted increase in ambient O33 by 2050by 2050 resulting from Climate Changeresulting from Climate Change 21Bell et al, Climatic Change (2007) 82:61–76 DOI 10.1007/s10584-006-9166-7
  22. 22. Predicted exceedance of the 1 and 8 hour OPredicted exceedance of the 1 and 8 hour O33 standardstandard by 2050 resulting from Climate Changeby 2050 resulting from Climate Change 22Bell et al, Climatic Change (2007) 82:61–76 DOI 10.1007/s10584-006-9166-7
  23. 23. Singer BD, Ziska LH, Frenz DA, Gebhard DE, Straka JG (2005) Increasing Amb a 1Singer BD, Ziska LH, Frenz DA, Gebhard DE, Straka JG (2005) Increasing Amb a 1 content in common ragweed (Ambrosia artemisiifolia) pollen as a function of risingcontent in common ragweed (Ambrosia artemisiifolia) pollen as a function of rising atmospheric CO2 concentration. Functional Plant Biology 32, 667–670.atmospheric CO2 concentration. Functional Plant Biology 32, 667–670. 23 Increased CO2 linked to increased Ragweed Pollen and increased Amb a 1 concentration/mg pollen
  24. 24. Effect of Urbanization on Ragweed growthEffect of Urbanization on Ragweed growth Ziska LH et al JACI, 2003Ziska LH et al JACI, 2003 24
  25. 25. Oxidant Stress and PollutantsOxidant Stress and Pollutants A unifying concept for the impact of pollutants in asthma
  26. 26. Oxidant stressOxidant stress is a common theme in theis a common theme in the action of a wide variety of air pollutants inaction of a wide variety of air pollutants in inflammatory processes.inflammatory processes. • Pollutants & oxidant stress: » Pollutants themselves • O3, metals » Products from pollutants • Polyaromatic hydrocarbons & quinones from DEP and ETS » Oxidants from macrophages and granulocytes • Singlet oxygen, H2O2, superoxide Cross, CE et al, American Journal of Respiratory and Critical Care Medicine Vol 166. pp. S44-S50, (2002)
  27. 27. GSTM1 polymorphisms and andGSTM1 polymorphisms and and lung disease in humanslung disease in humans ETS, DEP and O3
  28. 28. GSTM1GSTM1 • NRF2 nuclear transcription factor • GSTM1 Null » Associated with increased response to ozone » Associated with increased response to diesel exhaust » Associated with increased response to tobacco smoke
  29. 29. Effect of GSTM1 null genotype onEffect of GSTM1 null genotype on asthma relative to tobacco smokeasthma relative to tobacco smoke exposureexposure 0 0.5 1 1.5 2 2.5 3 3.5 4 Relative risk for ER visit for wheeze (Odds Ratio) GSTM1 + no smoking GSTM1- no smoking GSTM1+ smoking GSTM1- smoking • Effect of maternal smoking during pregnancy on asthma in GSTM1- children (panel to the left, Gilliland et al, AJRCCM 166:457-463, 2002) • GSTM1- children exposed to environmental tobacco smoke have a 5.5 odds ratio risk of current asthma relative to GSTM+ children (Kabesch et al, Thorax 59:569 2004)
  30. 30. DEP effect on the response to allergenDEP effect on the response to allergen stratified by GSTM1 genotypestratified by GSTM1 genotype Gilliland et al, Lancet. 2004 Jan 10;363(9403):119-25Gilliland et al, Lancet. 2004 Jan 10;363(9403):119-25 • Following DEP challenge, GSTM1 null individuals (vs. GSTM1+) have increased: » allergen-induced IgE (right) » histamine (not shown)
  31. 31. Effect of GSTM1 genotype and ozone inducedEffect of GSTM1 genotype and ozone induced decreases in FEF25-75 in asthmaticsdecreases in FEF25-75 in asthmatics Romieu et al, Thorax 2004;59:8-10Romieu et al, Thorax 2004;59:8-10 • GSTM1 null asthmatics have increased asthma symptoms with ozone exposure than do GSTM1 sufficient persons
  32. 32. Effect of the GSTM1 null genotype on lung functionEffect of the GSTM1 null genotype on lung function and inflammatory response to 0.4 ppm ozoneand inflammatory response to 0.4 ppm ozone 32 Alexis et al, JACI 2009, available on line
  33. 33. Effect of the GSTM1 null genotype onEffect of the GSTM1 null genotype on airway cell function, IL-1airway cell function, IL-1ββ & IL-8 post& IL-8 post ozone challengeozone challenge 33 GSTM1 did impact cell function but not IL-1β or IL-8 Alexis et al, JACI 2009, available on line
  34. 34. GSTM1 and ozone summaryGSTM1 and ozone summary • GSTM1 does not determine lung function repsonse to ozone • GSTM1 null has a delayed PMN response to ozone • GSTM1 null vs.sufficient have different cell marker changes in airway monocytes
  35. 35. What to do about pollutant-What to do about pollutant- induced diseaseinduced disease Patient and societal interventions
  36. 36. Pollutant AvoidancePollutant Avoidance • Decrease tobacco use • Local Environmental Control • Live away from a roadway • Societal Changes (decrease traffic, better fuels)
  37. 37. Changes in Traffic PatternsChanges in Traffic Patterns 1996 Atlanta Olympics
  38. 38. Copyright restrictions may apply. Friedman, M. S. et al. JAMA 2001;285:897-905. Mean Levels of Major Pollutants Before, During, and After the 1996 Summer Olympic Games as a Percentage of the National Ambient Air Quality Standard (NAAQS)
  39. 39. Friedman, M. S. et al. JAMA 2001;285:897-905.
  40. 40. Inhaled SteroidsInhaled Steroids Effect on response to pollutants
  41. 41. Inhaled Corticosteroids andInhaled Corticosteroids and EndotoxinEndotoxin • Inhaled corticosteroids » Decreases baseline eosinophilic inflammation » Decreases CD14 expression on airway monocytes and macrophages » Decreases PMN influx to inhaled endotoxin 0 1000 2000 3000 steroid placebo * * significantly different than placebo (p = 0.04) PMN/mg 0 50 100 150 steroid placebo Neutrophils Monocytes Macrophages * significantly different from placebo (* p=0.001, ** p = 0.04) ** mCD14 (MFI)
  42. 42. 42
  43. 43. Antioxidants and Asthma Treatment Is this an option?
  44. 44. 44 Vitamin E + C supplementation protects asthmatics from OVitamin E + C supplementation protects asthmatics from O33-- induced changes in lung function and inflammation childreninduced changes in lung function and inflammation children with allergic asthmawith allergic asthma • Combination ascorbate and alpha tocopherol: » Decrease effect of ambient O3 exposure on FEF25-75 and PEFR » Decrease O3 related inflammation • Other reports: » Combination therapy decreased lung function response to O3 challenge in normal volunteers and asthmatics » Ascorbate may protect against exercise-induced asthma Romieu et al, AJRCCM Vol 166. pp. 703-709, (2002) Sienra-Monge et al, Clin & Exp Immunology 138 (2), 317-322. (2004)
  45. 45. AcknowledgementsAcknowledgements • Neil Alexis • Philip Bromberg • John Lay • Haibo Zhou • Michelle Hernandez • Carole Robinette • Martha Almond • Peg Herbst • Aline Kala • Lynne Newlin-Clapp • Sally Ivins • Heather Wells • Nolan Sweeney • Madeline Dillon • Jessica Wiser • Marlowe Eldridge • Robert Roubey • Dhaval Patel • Robert Devlin • David Diaz- Sanchez • Howard Kehrl • Martin Case • Steven Kleeberger 45

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