EDITORIALS levels and sepsis in the critically ill. Crit Care Med 2014;42: 97–107. 13. Quraishi SA, Camargo CA Jr. Vitamin D in acute stress and critical illness. Curr Opin Clin Nutr Metab Care 2012;15:625–634. 14. Kempker JA, Tangpricha V, Ziegler TR, Martin GS. Vitamin D in sepsis: from basic science to clinical impact. Crit Care 2012;16:316. 15. Holick MF. Vitamin D deficiency. N Engl J Med 2007;357:266–281. 16. Liu PT, Stenger S, Li H, Wenzel L, Tan BH, Krutzik SR, Ochoa MT, Schauber J, Wu K, Meinken C, et al. Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science 2006; 311:1770–1773. 17. Fabri M, Stenger S, Shin DM, Yuk JM, Liu PT, Realegeno S, Lee HM, Krutzik SR, Schenk M, Sieling PA, et al. Vitamin D is required for IFN-gamma-mediated antimicrobial activity of human macrophages. Sci Transl Med 2011;3:104ra102
18. Hewison M. Vitamin D and immune function: an overview. Proc Nutr Soc 2012;71:50–61. 19. Leaf DE, Raed A, Donnino MW, Ginde AA, Waikar SS. Randomized controlled trial of calcitriol in severe sepsis. Am J Respir Crit Care Med 2014;190:533–541. 20. Chen CIU, Schaller-Bals S, Paul KP, Wahn U, Bals R. Beta-defensins and LL-37 in bronchoalveolar lavage fluid of patients with cystic fibrosis. J Cyst Fibros 2004;3:45–50. 21. Chun RF, Liu NQ, Lee T, Schall JI, Denburg MR, Rutstein RM, Adams JS, Zemel BS, Stallings VA, Hewison M. Vitamin D supplementation and antibacterial immune responses in adolescents and young adults with HIV/AIDS. J Steroid Biochem Mol Biol [online ahead of print] 1 Aug 2014; DOI: 10.1016/j.jsbmb.2014.07.013.
Copyright © 2014 by the American Thoracic Society
Particulate Air Pollution and Lung Function In this issue of the Journal, Lepeule and colleagues (pp. 542–549) present remarkable additional evidence that exposure to air pollution adversely affects lung function and pulmonary health (1). Lung function measures (FVC and FEV1) from 858 elderly men who lived in the Boston area and were enrolled in the Normative Aging Study were evaluated. Concentrations of black carbon, a surrogate of exposure to traffic-related air pollution, were estimated for the geocoded participants’ addresses using data from 148 monitoring stations and a spatiotemporal land use regression model. Elevated pollution exposures were associated with significant reductions in baseline lung function levels as well as accelerated rates of lung function decline. The statistically robust results reported are remarkable, even surprising, for several reasons: air pollution levels in the Boston area are quite low (well within U.S. air quality standards), the study is not exceptionally large, and the statistical approach is quite ambitious by estimating joint effects on baseline lung function as well as rate of decline. Nevertheless, given the widespread nature of exposure, these results suggest measurable adverse respiratory health effects from traffic-source air pollution and have important public health and policy implications. This latest work augments an already substantial literature that demonstrates that breathing contaminants, especially combustionrelated particles, affects pulmonary function. It has long been known that cigarette smoking contributes to accelerated lung function decline in aging adults (2). There is also evidence that exposures to combustion-source particulate air pollution may have similar but smaller effects (3, 4). Daily time-series panel studies, mostly of children, provide evidence that short-term (one to a few days) elevated exposure to fine particulate matter is associated with small transient declines in lung function (5). A recent analysis of data from the Framingham Heart Study observed similar air pollution–related declines in lung function in adults (6). Lepeule and colleagues, also using the data from the Normative Aging Study, observed reduced lung function effects associated with 4 to 28 days of exposure to fine particulate matter and other measures of traffic-source air pollution (7). Results from the Southern California Children’s Health study indicate that chronic exposures
Editorials
to fine particulate and related air pollutants over a period of years were associated with deficits in rate of lung function growth and that exposures to traffic-related pollution as well as pollution from other sources have adverse effects on children’s lung function (8). Lepeule and colleagues correctly suggest that understanding how long-term air pollution exposures impact lung function in the elderly is important in understanding possible pathways for the mortality and morbidity associated with air pollution (1). This study provides important evidence that air pollution has adverse effects on lung function. Other studies indicate that air pollution, including traffic-related fine particulate pollution, contributes to chronic obstructive pulmonary disease and mortality (9). However, the simple mechanistic concept that air pollution induces accelerated decline in lung function, resulting in loss of reserve capacity, disability, and eventual death due to pulmonary disease, is clearly incomplete. Most of the particulate air pollution effects on mortality seem to be due to cardiovascular mortality (10), and a broad evaluation of the literature suggests that exposures to particulate air pollution are strongly associated with cardiovascular disease (11). Cardiovascular and pulmonary diseases have substantial common comorbidities, and deficit in lung function is a strong predictor of cardiovascular disease and mortality (12). Inflammation associated with pulmonary disease appears to contribute to cardiovascular risk (13). Lepeule and colleagues have also used data from the Normative Aging Study to explore epigenetic influences on inflammation, air pollution, and lung function (7, 14). The findings that traffic-related pollution is associated with deficits in lung function and accelerated rates of lung function decline are intriguing but leave important unanswered questions: How do deficits in lung function fit into a more comprehensive understanding of the biological pathways that link air pollution exposure to cardiopulmonary disease and death? What specific constituents or characteristics of the traffic-source pollution are really responsible for the adverse effects on lung function? Are the adverse health effects due to pollutants from gasoline combustion, diesel combustion, brake and/or tire wear, something else, or a combination of all? Are the effects due primarily to particulate
485
EDITORIALS pollution, or do gaseous pollutants such as CO and NO2 play a role? What is the role of ultrafine particles or primary versus secondary particles? Is it true that there remain significant and measurable health effects of air pollution, especially in metropolitan areas with relatively clean air that meets current air quality standards? If so, what can or should we do next? n Author disclosures are available with the text of this article at www.atsjournals.org. C. Arden Pope III, Ph.D. Department of Economics Brigham Young University Provo, Utah
References 1. Lepeule J, Litonjua AA, Coull B, Koutrakis P, Sparrow D, Vokonas PS, Schwartz J. Long-term effects of traffic particles on lung function decline in the elderly. Am J Respir Crit Care Med 2014;542–549. 2. Fletcher C, Peto R. The natural history of chronic airflow obstruction. BMJ 1977;1:1645–1648. 3. Holland WW, Reid DD. The urban factor in chronic bronchitis. Lancet 1965;1:445–448. 4. Tashkin DP, Detels R, Simmons M, Liu H, Coulson AH, Sayre J, Rokaw S. The UCLA population studies of chronic obstructive respiratory disease: XI. Impact of air pollution and smoking on annual change in forced expiratory volume in one second. Am J Respir Crit Care Med 1994;149:1209–1217. 5. Hoek G, Dockery DW, Pope A III, Neas L, Roemer W, Brunekreef B. Association between PM10 and decrements in peak expiratory flow rates in children: reanalysis of data from five panel studies. Eur Respir J 1998;11:1307–1311. 6. Rice MB, Ljungman PL, Wilker EH, Gold DR, Schwartz JD, Koutrakis P, Washko GR, O’Connor GT, Mittleman MA. Short-term exposure to air pollution and lung function in the Framingham Heart Study. Am J Respir Crit Care Med 2013;188:1351–1357.
7. Lepeule J, Bind MA, Baccarelli AA, Koutrakis P, Tarantini L, Litonjua A, Sparrow D, Vokonas P, Schwartz JD. Epigenetic influences on associations between air pollutants and lung function in elderly men: the normative aging study. Environ Health Perspect 2014;122: 566–572. 8. Urman R, McConnell R, Islam T, Avol EL, Lurmann FW, Vora H, Linn WS, Rappaport EB, Gilliland FD, Gauderman WJ. Associations of children’s lung function with ambient air pollution: joint effects of regional and near-roadway pollutants. Thorax 2014;69:540–547. 9. Gan WQ, FitzGerald JM, Carlsten C, Sadatsafavi M, Brauer M. Associations of ambient air pollution with chronic obstructive pulmonary disease hospitalization and mortality. Am J Respir Crit Care Med 2013;187:721–727. 10. Pope CA III, Burnett RT, Thurston GD, Thun MJ, Calle EE, Krewski D, Godleski JJ. Cardiovascular mortality and long-term exposure to particulate air pollution: epidemiological evidence of general pathophysiological pathways of disease. Circulation 2004;109: 71–77. 11. Brook RD, Rajagopalan S, Pope CA III, Brook JR, Bhatnagar A, DiezRoux AV, Holguin F, Hong Y, Luepker RV, Mittleman MA, et al.; American Heart Association Council on Epidemiology and Prevention, Council on the Kidney in Cardiovascular Disease, and Council on Nutrition, Physical Activity and Metabolism. Particulate matter air pollution and cardiovascular disease: an update to the scientific statement from the American Heart Association. Circulation 2010;121:2331–2378. 12. Sin DD, Wu L, Man SFP. The relationship between reduced lung function and cardiovascular mortality: a population-based study and a systematic review of the literature. Chest 2005;127:1952–1959. 13. van Eeden SF, Yeung A, Quinlam K, Hogg JC. Systemic response to ambient particulate matter: relevance to chronic obstructive pulmonary disease. Proc Am Thorac Soc 2005;2:61–67. 14. Lepeule J, Baccarelli A, Motta V, Cantone L, Litonjua AA, Sparrow D, Vokonas PS, Schwartz J, Schwartz J. Gene promoter methylation is associated with lung function in the elderly: the Normative Aging Study. Epigenetics 2012;7:261–269.
Copyright © 2014 by the American Thoracic Society
Sleep Apnea, Continuous Positive Airway Pressure, and Renal Health Robust epidemiological evidence links obstructive sleep apnea (OSA) with a number of cardiovascular conditions. Based on population studies, OSA increases the risk of congestive heart failure, hypertension, stroke, and certain arrhythmias and worsens the prognosis of coronary artery disease (1–4). Salutary effects of continuous positive airway pressure (CPAP) therapy on cardiovascular conditions are also well known. Usage of CPAP by patients with OSA leads to a reduction in blood pressure (5), improvement of left ventricular function (6), and reduction of risk of cardiovascular events (3). Less well known is an equally important, bidirectional association between OSA and chronic kidney disease (CKD). While the prevalence of OSA rises as the severity of CKD worsens (to .50% in end-stage renal disease), the rate of glomerular filtration rate decline increases with worsening of nocturnal desaturations typical of sleep apnea (7, 8). Mechanisms of these deleterious effects of nocturnal hypoxemia are believed to involve generation of reactive oxygen species, direct activation of the sympathetic nervous system, and activation of the renin486
angiotensin system (RAS), resulting in an inflammatory response and endothelial cell dysfunction. On a functional level, these processes result in glomerular hyperfiltration, a correlate of proteinuria and glomerular filtration rate (GFR) decrease (9, 10). Usage of CPAP therapy may improve glomerular hyperfiltration (10). In this issue of the Journal, the article by Nicholl and colleagues (pp. 572–580) adds an important piece of information to our understanding of the role of renal RAS in mediating these beneficial changes of CPAP (11). The authors presented a novel observation that a compliant usage of CPAP improved hyperfiltration in a small group of 20 patients with at least moderate OSA and well-controlled hypertension. Compared with pretreatment values, CPAP therapy resulted in a significant decrease of GFR, a borderline increase of renal plasma flow, and, in consequence, a significant, beneficial decrease of the filtration fraction. Two additional positive effects—a significant drop in renal vascular resistance and a decrease in urinary albumin excretion—were also noted. An elevated response to angiotensin II challenge suggested that these positive effects were mediated by
American Journal of Respiratory and Critical Care Medicine Volume 190 Number 5 | September 1 2014
18. Hewison M. Vitamin D and immune function: an overview. Proc Nutr Soc 2012;71:50–61. 19. Leaf DE, Raed A, Donnino MW, Ginde AA, Waikar SS. Randomized controlled trial of calcitriol in severe sepsis. Am J Respir Crit Care Med 2014;190:533–541. 20. Chen CIU, Schaller-Bals S, Paul KP, Wahn U, Bals R. Beta-defensins and LL-37 in bronchoalveolar lavage fluid of patients with cystic fibrosis. J Cyst Fibros 2004;3:45–50. 21. Chun RF, Liu NQ, Lee T, Schall JI, Denburg MR, Rutstein RM, Adams JS, Zemel BS, Stallings VA, Hewison M. Vitamin D supplementation and antibacterial immune responses in adolescents and young adults with HIV/AIDS. J Steroid Biochem Mol Biol [online ahead of print] 1 Aug 2014; DOI: 10.1016/j.jsbmb.2014.07.013.
Copyright © 2014 by the American Thoracic Society
Particulate Air Pollution and Lung Function In this issue of the Journal, Lepeule and colleagues (pp. 542–549) present remarkable additional evidence that exposure to air pollution adversely affects lung function and pulmonary health (1). Lung function measures (FVC and FEV1) from 858 elderly men who lived in the Boston area and were enrolled in the Normative Aging Study were evaluated. Concentrations of black carbon, a surrogate of exposure to traffic-related air pollution, were estimated for the geocoded participants’ addresses using data from 148 monitoring stations and a spatiotemporal land use regression model. Elevated pollution exposures were associated with significant reductions in baseline lung function levels as well as accelerated rates of lung function decline. The statistically robust results reported are remarkable, even surprising, for several reasons: air pollution levels in the Boston area are quite low (well within U.S. air quality standards), the study is not exceptionally large, and the statistical approach is quite ambitious by estimating joint effects on baseline lung function as well as rate of decline. Nevertheless, given the widespread nature of exposure, these results suggest measurable adverse respiratory health effects from traffic-source air pollution and have important public health and policy implications. This latest work augments an already substantial literature that demonstrates that breathing contaminants, especially combustionrelated particles, affects pulmonary function. It has long been known that cigarette smoking contributes to accelerated lung function decline in aging adults (2). There is also evidence that exposures to combustion-source particulate air pollution may have similar but smaller effects (3, 4). Daily time-series panel studies, mostly of children, provide evidence that short-term (one to a few days) elevated exposure to fine particulate matter is associated with small transient declines in lung function (5). A recent analysis of data from the Framingham Heart Study observed similar air pollution–related declines in lung function in adults (6). Lepeule and colleagues, also using the data from the Normative Aging Study, observed reduced lung function effects associated with 4 to 28 days of exposure to fine particulate matter and other measures of traffic-source air pollution (7). Results from the Southern California Children’s Health study indicate that chronic exposures
Editorials
to fine particulate and related air pollutants over a period of years were associated with deficits in rate of lung function growth and that exposures to traffic-related pollution as well as pollution from other sources have adverse effects on children’s lung function (8). Lepeule and colleagues correctly suggest that understanding how long-term air pollution exposures impact lung function in the elderly is important in understanding possible pathways for the mortality and morbidity associated with air pollution (1). This study provides important evidence that air pollution has adverse effects on lung function. Other studies indicate that air pollution, including traffic-related fine particulate pollution, contributes to chronic obstructive pulmonary disease and mortality (9). However, the simple mechanistic concept that air pollution induces accelerated decline in lung function, resulting in loss of reserve capacity, disability, and eventual death due to pulmonary disease, is clearly incomplete. Most of the particulate air pollution effects on mortality seem to be due to cardiovascular mortality (10), and a broad evaluation of the literature suggests that exposures to particulate air pollution are strongly associated with cardiovascular disease (11). Cardiovascular and pulmonary diseases have substantial common comorbidities, and deficit in lung function is a strong predictor of cardiovascular disease and mortality (12). Inflammation associated with pulmonary disease appears to contribute to cardiovascular risk (13). Lepeule and colleagues have also used data from the Normative Aging Study to explore epigenetic influences on inflammation, air pollution, and lung function (7, 14). The findings that traffic-related pollution is associated with deficits in lung function and accelerated rates of lung function decline are intriguing but leave important unanswered questions: How do deficits in lung function fit into a more comprehensive understanding of the biological pathways that link air pollution exposure to cardiopulmonary disease and death? What specific constituents or characteristics of the traffic-source pollution are really responsible for the adverse effects on lung function? Are the adverse health effects due to pollutants from gasoline combustion, diesel combustion, brake and/or tire wear, something else, or a combination of all? Are the effects due primarily to particulate
485
EDITORIALS pollution, or do gaseous pollutants such as CO and NO2 play a role? What is the role of ultrafine particles or primary versus secondary particles? Is it true that there remain significant and measurable health effects of air pollution, especially in metropolitan areas with relatively clean air that meets current air quality standards? If so, what can or should we do next? n Author disclosures are available with the text of this article at www.atsjournals.org. C. Arden Pope III, Ph.D. Department of Economics Brigham Young University Provo, Utah
References 1. Lepeule J, Litonjua AA, Coull B, Koutrakis P, Sparrow D, Vokonas PS, Schwartz J. Long-term effects of traffic particles on lung function decline in the elderly. Am J Respir Crit Care Med 2014;542–549. 2. Fletcher C, Peto R. The natural history of chronic airflow obstruction. BMJ 1977;1:1645–1648. 3. Holland WW, Reid DD. The urban factor in chronic bronchitis. Lancet 1965;1:445–448. 4. Tashkin DP, Detels R, Simmons M, Liu H, Coulson AH, Sayre J, Rokaw S. The UCLA population studies of chronic obstructive respiratory disease: XI. Impact of air pollution and smoking on annual change in forced expiratory volume in one second. Am J Respir Crit Care Med 1994;149:1209–1217. 5. Hoek G, Dockery DW, Pope A III, Neas L, Roemer W, Brunekreef B. Association between PM10 and decrements in peak expiratory flow rates in children: reanalysis of data from five panel studies. Eur Respir J 1998;11:1307–1311. 6. Rice MB, Ljungman PL, Wilker EH, Gold DR, Schwartz JD, Koutrakis P, Washko GR, O’Connor GT, Mittleman MA. Short-term exposure to air pollution and lung function in the Framingham Heart Study. Am J Respir Crit Care Med 2013;188:1351–1357.
7. Lepeule J, Bind MA, Baccarelli AA, Koutrakis P, Tarantini L, Litonjua A, Sparrow D, Vokonas P, Schwartz JD. Epigenetic influences on associations between air pollutants and lung function in elderly men: the normative aging study. Environ Health Perspect 2014;122: 566–572. 8. Urman R, McConnell R, Islam T, Avol EL, Lurmann FW, Vora H, Linn WS, Rappaport EB, Gilliland FD, Gauderman WJ. Associations of children’s lung function with ambient air pollution: joint effects of regional and near-roadway pollutants. Thorax 2014;69:540–547. 9. Gan WQ, FitzGerald JM, Carlsten C, Sadatsafavi M, Brauer M. Associations of ambient air pollution with chronic obstructive pulmonary disease hospitalization and mortality. Am J Respir Crit Care Med 2013;187:721–727. 10. Pope CA III, Burnett RT, Thurston GD, Thun MJ, Calle EE, Krewski D, Godleski JJ. Cardiovascular mortality and long-term exposure to particulate air pollution: epidemiological evidence of general pathophysiological pathways of disease. Circulation 2004;109: 71–77. 11. Brook RD, Rajagopalan S, Pope CA III, Brook JR, Bhatnagar A, DiezRoux AV, Holguin F, Hong Y, Luepker RV, Mittleman MA, et al.; American Heart Association Council on Epidemiology and Prevention, Council on the Kidney in Cardiovascular Disease, and Council on Nutrition, Physical Activity and Metabolism. Particulate matter air pollution and cardiovascular disease: an update to the scientific statement from the American Heart Association. Circulation 2010;121:2331–2378. 12. Sin DD, Wu L, Man SFP. The relationship between reduced lung function and cardiovascular mortality: a population-based study and a systematic review of the literature. Chest 2005;127:1952–1959. 13. van Eeden SF, Yeung A, Quinlam K, Hogg JC. Systemic response to ambient particulate matter: relevance to chronic obstructive pulmonary disease. Proc Am Thorac Soc 2005;2:61–67. 14. Lepeule J, Baccarelli A, Motta V, Cantone L, Litonjua AA, Sparrow D, Vokonas PS, Schwartz J, Schwartz J. Gene promoter methylation is associated with lung function in the elderly: the Normative Aging Study. Epigenetics 2012;7:261–269.
Copyright © 2014 by the American Thoracic Society
Sleep Apnea, Continuous Positive Airway Pressure, and Renal Health Robust epidemiological evidence links obstructive sleep apnea (OSA) with a number of cardiovascular conditions. Based on population studies, OSA increases the risk of congestive heart failure, hypertension, stroke, and certain arrhythmias and worsens the prognosis of coronary artery disease (1–4). Salutary effects of continuous positive airway pressure (CPAP) therapy on cardiovascular conditions are also well known. Usage of CPAP by patients with OSA leads to a reduction in blood pressure (5), improvement of left ventricular function (6), and reduction of risk of cardiovascular events (3). Less well known is an equally important, bidirectional association between OSA and chronic kidney disease (CKD). While the prevalence of OSA rises as the severity of CKD worsens (to .50% in end-stage renal disease), the rate of glomerular filtration rate decline increases with worsening of nocturnal desaturations typical of sleep apnea (7, 8). Mechanisms of these deleterious effects of nocturnal hypoxemia are believed to involve generation of reactive oxygen species, direct activation of the sympathetic nervous system, and activation of the renin486
angiotensin system (RAS), resulting in an inflammatory response and endothelial cell dysfunction. On a functional level, these processes result in glomerular hyperfiltration, a correlate of proteinuria and glomerular filtration rate (GFR) decrease (9, 10). Usage of CPAP therapy may improve glomerular hyperfiltration (10). In this issue of the Journal, the article by Nicholl and colleagues (pp. 572–580) adds an important piece of information to our understanding of the role of renal RAS in mediating these beneficial changes of CPAP (11). The authors presented a novel observation that a compliant usage of CPAP improved hyperfiltration in a small group of 20 patients with at least moderate OSA and well-controlled hypertension. Compared with pretreatment values, CPAP therapy resulted in a significant decrease of GFR, a borderline increase of renal plasma flow, and, in consequence, a significant, beneficial decrease of the filtration fraction. Two additional positive effects—a significant drop in renal vascular resistance and a decrease in urinary albumin excretion—were also noted. An elevated response to angiotensin II challenge suggested that these positive effects were mediated by
American Journal of Respiratory and Critical Care Medicine Volume 190 Number 5 | September 1 2014
