STEP Summer Seminar 2017 - Mark Miller, University of Edinburgh - Health Effects of Nanoparticles
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STEP Summer Seminar 2017 - Mark Miller, University of Edinburgh - Health Effects of Nanoparticles
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STEP Summer Seminar 2017 - Mark Miller, University of Edinburgh - Health Effects of Nanoparticles
- 1. From Car to Coronary: How nanoparticles in air pollution damage the heart and blood vessels Dr Mark R. Miller Centre for Cardiovascular Science University of Edinburgh mark.miller@ed.ac.uk STEP Summer Seminar Edinburgh, 7th June 2017
- 2. From Car to Coronary: How nanoparticles in air pollution damage the heart and blood vessels Dr Mark R. Miller Centre for Cardiovascular Science University of Edinburgh mark.miller@ed.ac.uk STEP Summer Seminar Edinburgh, 7th June 2017
- 3. The Great Smog of London Deathsregistered
- 4. Air pollution is still a major problem World-wide: 3 - 7 million deaths per year Responsible for 6% of all deaths globally UK: 29,000 – 52,000 deaths per year Associated with £54 billion cost to UK economy annually Reduces average life expectancy by 8 months Europe: 400,000 premature deaths per year Exposure to airborne particles reduce life expectancy by 1 year
- 5. Lim et al. 2013. Lancet 380: 2224-2260 Cardiovascular disease Air pollution is responsible for millions of deaths every year The world-wide effects of air pollution are considerable MORTALITY: 800,000 - 7 million deaths per year MORBIDITY loss of more 5 million work days per year
- 6. Air pollution and the cardiovascular system - How does pollution cause cardiovascular effects? - Which components of air pollution are responsible? • Underlying cause for link unknown. • Long term exposure to air pollution linked to heart disease • Short term exposure to air pollution linked to heart attacks
- 7. What is air pollution? Particles Gases Volatile Liquids organic species reactive metals The link between air pollution and cardiovascular disease is greatest for the particles in air pollution
- 8. Particle size 0.5 μm diameter (μm) Coarse: PM10 2.5 – 10.0 Fine: PM2.5 0.1 – 2.5 Ultrafine PM (nanoparticles) < 0.1
- 9. 20μg/m3130μg/m3 Typical particles black smoke now1950 Traffic derived nanoparticles Trends in particulate air pollution Vehicles on UK roads 2 million 28 million
- 10. Nanoparticles 10 nm100 nm1 µm10 µm100 µm 50 µm 0.05 µm0.5 µm5 µm MoleculesvirusBacteriaRBC Mononuclear CellPollenHair Limit of human vision combustion- derived nanoparticles • Diesel engine exhaust rich in nanoparticles • Mass vs surface area • Believed to be especially harmful
- 11. Controlled exposure to dilute diesel exhaust
- 12. Exposure to diesel exhaust has widespread actions throughout the cardiovascular system Blood Heart Vessels
- 14. Biological mechanisms for the cardiovascular effects of air pollution Air pollution lungs cardiovascular disease
- 15. air spaces of the lung “Particle translocation” blood vessels in the lung lung tissue
- 16. Investigating particle translocation Difficulties • Small size of particles • Low levels of particles that translocate • Large volume of blood in the body • Labels for tracking can come off particles • Detection of soot-based particles confounded by levels of carbon in cells
- 17. gold nanoparticles Why use gold? • Size similar to particles in urban air pollution • Non-harmful • Specialised techniques to measure very low levels 50 nm Gold nanoparticles Citrate Buffer
- 18. Gold inhalation • 2-hour inhalation of gold nanoparticles during intermittent exercise • Blood samples from 15 min – 24h & 3 months • 24-h urine collection
- 19. Gold in blood and urine Miller & Raftis et al. (2017). ACS Nano
- 20. Gold nanoparticles accumulate at areas of vascular disease Aortic arch region – heavily diseased artery Descending Aorta – artery with little disease untreated animal untreated animal
- 21. Gold nanoparticles accumulate at areas of vascular disease 50 µm Non-exposed Gold-exposed
- 22. Summary • Air pollution is associated with cardiovascular disease • The small particles in air pollution are especially harmful • The biology underlying this needs further investigation Using gold as model, we show that: • Inhaled nanoparticles get into our blood • These particles preferentially accumulate in areas of disease
- 23. Key messages • Ultrafine particles in air pollution may enter the blood and accumulate in vascular plaques • Accumulation of reactive environmental particles at sites of disease could have serious consequences for health • More effort is needed to reduce air pollution • Interventions that reduce nanoparticles in the air could reduce cardiovascular disease
- 24. Acknowledgements Centre for Cardiovascular Science Centre for Inflammation Research Steven McLean Katie Shaw Jeremy Langrish Eileen Miller Shea Connell Ian Smith Annalisa Gastaldello Callam Davidson Caroline Tabor Stephen Borthwick Kate Leyland James Russell Danny McClure Sarah Robertson Gillian Gray Edwin Carter Keith Fox Nick Boon Paddy Hadoke Nick Mills Dave Newby Jen Raftis Ken Donaldson Bill MacNee Rodger Duffin Umea University, Sweden Jenny Bosson Thomas Sandstrom Anders Blomberg Royal Holloway, London, UK Steve Smith Department of Chemistry Colin Campbell Pawitrabhorn Samutrtau VU University, Netherlands Petra Krystek mark.miller@ed.ac.uk UCLA, USA Jesus Araujo Akeem Lawal RIVM, Netherlands Flemming Cassee John Boere Paul Fokkens Dan Leseman Western Univ’ Health Sci, USA Arezoo Campbell Government of the Netherlands
- 26. Air pollution is a topical issue
- 27. Air pollution – facts and figures World-wide: 3 - 7 million deaths per year Responsible for 6% of all deaths globally Loss of more 5 million work days per year Scotland: 2,100 – 3,500 deaths per year Responsible for 3.9% of deaths of people over the ages of 25 Cost of £1.6 billion to Scottish economy per year UK: 29,000 – 52,000 deaths per year Associated with £54 billion cost to UK economy annually Reduces average life expectancy by 8 months Europe: 400,000 premature deaths per year Exposure to airborne particles reduce life expectancy by 1 year
- 28. Lim et al. 2013. Lancet 380: 2224-2260 Air pollution as a risk factor for all-cause disease Lim et al. 2013. Lancet 380: 2224-2260
- 29. Air pollution and vascular disease healthy heart aortic arch descending thoracic aorta diaphragm vascular disease: saline 1 mm vascular disease: diesel particles healthy: saline vascular disease: saline vascular disease: diesel particles healthy: diesel particles
- 30. Lab tests to look at particle toxicology 3330 3340 3350 3360 3370 3380 Magnetic wavelength blank filter diesel filter Diesel exhaust particle O2 CO2 T Free radical generation Blood vessel relaxation
- 31. Diesel exhaust particle constituents
- 32. Diesel exhaust particles are complex Steve Smith, Royal Holloway, London
- 33. ‘Cleaning’ DEP with aqueous solutions Direct addition of particulate to isolated rat aorta Pulmonary administration of particulate to ApoE-/- mice Atherosclerotic burden organics aqueous soluble components metals ‘whole’ DEP ‘aqueous-washed DEP’ Aqueous wash
- 34. Air pollution is still a major problem World-wide: 3 - 7 million deaths per year Responsible for 6% of all deaths globally UK: 29,000 – 52,000 deaths per year Associated with £54 billion cost to UK economy annually Reduces average life expectancy by 8 months Europe: 400,000 premature deaths per year Exposure to airborne particles reduce life expectancy by 1 year
- 35. Diesel Exposure Chamber, Umeå, Sweden
- 36. Air pollution impairs forearm blood flow responses Cuff inflated Cuff deflated non-infused arm vasodilator infusion 10 30 100 0 5 10 15 20 25 30 Verapamil, µg/min P=ns ForearmBloodFlow (ml/100mloftissue/min) verapamil 2 4 8 0 5 10 15 20 25 30 SNP,µg/min P<0.001 ForearmBloodFlow (ml/100mloftissue/min) nitroprusside 2h after exposure infused arm ● diesel exhaust non-infused arm ● filtered air Mills et al. Circulation 2005 100 300 1000 0 5 10 15 20 25 30 Bradykinin, pmol/min ForearmBloodFlow (ml/100mloftissue/min) P<0.05 bradykinin 5 10 20 0 5 10 15 20 25 30 Acetylcholine, µg/min P<0.05 ForearmBloodFlow (ml/100mloftissue/min) acetylcholine
- 37. Blood Clotting • High shear chamber mimics moderately diseased coronary arteries • Low shear chamber mimics flow conditions within healthy coronary arteries • Well established ex vivo model of thrombogenecity • Passes human blood over a piece of damaged artery under flowing conditions
- 38. Porcine aortic strips from chamber AIR DIESEL
- 39. Air pollution impairs fibrinolytic function Mills NL et al. Circulation 2005 100 300 1000 0 30 60 90 120 150 180 Bradykinin, pmol/min Netreleaseoft-PAantigen (ng/100mLoftissue/min) Air Diesel *
- 40. Cardiac Ischaemia BASELIN E J POINT J POINT + 60ms ST-SEGMENT DEPRESSION Worsening cardiac ischaemia clean air exposure diesel exhaust exposure
- 41. Summary of Clinical Studies Acute exposure to dilute diesel exhaust: => Impairs the ability of arteries to relax => Promotes excessive blood clotting => Prevents the body from breaking down blood clots => Makes the heart more prone to the lack of oxygen • The time course of effects • If ambient particles in the air produce similar effects • If diesel exhaust increases the rigidity of arteries • The biological messengers involved in the effects • The components in diesel exhaust that are harmful • Comparison of a city-cycling engine versus idling engines • Particle traps on exhaust • Benefits of wearing a facemask in a city with high air pollution • If air pollution is associated with heart failure and stroke Subsequent clinical studies investigated:
- 42. The three hypotheses for the cardiovascular effects of inhaled particles Combustion Derived Nanoparticles Lungs Inflammatory mediators 1. Lung Inflammation Cardiovascular Impairment 3. Autonomic Regulation Regulation of parasympathetic: sympathetic balance Direct vascular interaction 2. Particle Translocation
- 43. Oxidative stress and cytotoxicity necrosis apoptosis DNA mutation O2 -. oxidative stressparticles healthy cell O2 -. O2 -. O2 -. O2 -.
- 44. How could particles harm cells? necrosis apoptosis DNA mutation O2 -. particles healthy cell
- 45. Oxygen free radicals oxygen +electron O2 -. superoxide age smoking radiation illness Antioxidants e.g. vitamins air pollution particles ?
- 46. Air pollution is a systemic problem • exacerbates kidney disease • irritates the gastrointestinal system • Alters stem cells & the body’s regeneration? • Promotes the rejection of lung transplants • Air pollution harms the lung: promotes asthma, respiratory infections, chronic obstructive pulmonary disease… lung cancer?
- 47. Conclusions • Inhalation of diesel exhaust has many harmful effects on the cardiovascular system • Chronic exposure to diesel exhaust particles worsens vascular disease • Inhaled nanoparticles get into our blood and preferentially accumulate in areas of disease
- 48. Key messages • Interventions that reduce nanoparticles in the air could reduce cardiovascular disease • Current measures of particles in air pollution do not adequately measure nanoparticles from vehicle exhaust • Understanding how air pollution affects the body will inform: - which parts of air pollution are most harmful - which people are likely to be most susceptible - the strategies which best reduce the health effects of pollution • Everyone can play their part, but more effort is needed at a regulatory level