Effects of Air Pollution on the Defense System against Respiratory Tract Infections.

1. Effects of Air Pollution on the Defense System against Respiratory Tract Infections. Kevin S. Harrod, Ph.D. Infectious Diseases Program Lovelace Respiratory Res. Inst. Albuquerque, NM USA

2. Health Effects of Air Pollution Air pollution is increasing in both the industrialized and developing countries. Indoor air pollution is increasing recognized as potential health hazard, particularly to chronic or reoccurring disease. Increasing knowledge that respiratory infections often lead to exacerbation of chronic lung illness such as asthma or COPD. The effects of air pollution most likely impact the young and the elderly, corresponding to those ages that are the most susceptible to infectious disease.

3. Epidemiologic Evidence of the Impact of Air Pollution of Respiratory Infections. C.A. Pope, Circulation 109, 2004

4. Lung epithelial cell subpopulations and secretion of host defense proteins Immune cells Type I Type II upper lower alveoli

6. Mechanisms of environmental impact on lung disease. National Environmental Research Center Cancer Cardiovascular Inflammation Asthma Infection

7. Studies of diesel engine emissions in an experimental model of respiratory syncytial virus infection. Diesel engine emissions (30, 100, 300, 1000 mg/m3) 7 d exposure Susceptibility to infection Lung pathogenesis RSV (106 pfu)

8. Epidemiology of RSV disease. Common cause of respiratory infection in young children. Increasing importance in the elderly. Common pathogen of the small airways. Long-term immunity acquired only after repeated infections. Vaccine development has been hampered by enhanced disease in vaccinated individuals. Disease typically presents as an acute, self-limiting illness, however long term effects on lung function are well described.

9. 1000 mg/m3 DEE 300 mg/m3 DEE 30 mg/m3 DEE RSV persistence Air 4 7 10 Days post-infection DEE exposure reduces viral clearance and increases lung pathology to disease. 30 mg/m3 DEE 200 mg/m3 DEE Air M RSV-F Air + RSV Air RSV-G b-actin M= Gel marker 30 mg/m3 DEE + RSV 200 mg/m3 DEE + RSV

10. proximal mid-airway distal Air + RSV 30 mg/m3 DEE + RSV Air 30 mg/m3 200 mg/m3 200 mg/m3 DEE + RSV b-tubulin CCSP mucus Alveolar epithelium SP-A Altered epithelial changes to RSV by prior exposure to DEE. Airway epithelium Harrod et al AJRCMB 28, 2003

11. FA + RSV Lo + RSV Hi + RSV * * Dendritic cells (CD11c+) * * * * Ia+ CD80+ CD86+ Dendritic cell Activation Marker Lung dendritic cell activation is modulated by DEE.

12. Emissions reduction of particulate component of DEE reduces lung virus counts and lung disease after experimental infection. McDonald et al., Environ. Health Presp. 112 (2004)

13. Increased pathogenesis to respiratory viral infection by engine combustion exposure. DEE prolongs viral persistence. Lung pathogenesis to RSV is Increased by DEE. Adaptive immune mechanisms are altered by prior DEE exposure. The particulate component contributes to DEE-induced exacerbation of lung disease to RSV infection.

14. Environmental cigarette smoke increases lung viral load and reduces effector cytokines important in viral clearance. Phaybouth et al, AJP:Lung, 290(2) L222-231, 2006

15. Studies of diesel engine emissions in an experimental model of bacterial infection. Diesel engine emissions (30, 100, 300, 1000 mg/m3) 7 day or 6 month exposure Susceptibility to infection Lung pathogenesis Pseudomonas aeruginosa (108 cfu)

16. Decreased bacterial clearance and increased lung inflammation by prior exposure to diesel engine exhaust. Bacterial Clearance Lung histopathology Harrod, et al. Tox. Sci. 83 (2005)

17. DEE exacerbates changes in both large and small airways following P.a. infection. Harrod, et al. Tox. Sci. 83 (2005)

18. What effects does diesel engine emissions have on lung epithelial or immune mechanisms that lead to susceptibility or exacerbation of infection?

19. DEE particulate uptake by alveolar macrophages

20. GR1+ (PMN, Mf) Lung CD4+ CD8+ Lung DX5+ C11b+ Ia+ CD80+ Ia+ CD80+ Ia+ CD86+ Ia+ CD86+ Ia+ (MHC class II) LALN LANL Air DEE (300 mg/m3) DEE reduces lung immune cell populations

21. Clara cell morphology is altered by DEE exposure prior to infection. Harrod et al AJRCMB 28, 2003

22. RSV clearance is augmented by CCSP. Wang et al. J. Immunol. 171(2):1051-60, 2003

23. Microarray analysis indicates epithelial and innate immune mechanisms are attenuated by DEE prior to infection. “Low” DEE “High” DEE Gene Ontology Categories Antigen processing Signal transduction Immune function Mx1 Nalp4 Lypz Host defense Interferon mechanisms Reactive oxygen generation Growth and differentiation factors Decreased gene expression Increased gene expression

24. Increased pathogenesis to respiratory infection by air pollutant exposure. DEE can alter clearance of both viral and bacterial pathogens. Lung disease, particularly inflammation, are exacerbated. Genomic and cellular alterations can be induced by exposure alone. Despite differences in particulate and gaseous components, multiple sources of air pollution can yield effects in experimental models.

25. Harrod Laboratory

26. Funded by: NIH R01 HL66964 NIH R01 HL67790 NIH K02 HL71547 ALA Career Inv. Award Health Effects Institute NIEHS P-20-ES09781 and P-30-ES12072-01 Acknowledgements LRRI Jake McDonald Matthew Reed Joe Mauderly Andrew Gigliotti Matthew Campen Richard White Julie Wilder Scott Burchiel Collaborators Ralph Tripp, U. Georgia Mary Lipscomb, U. New Mexico Jeff Whitsett, Cincinnati Children’s