different from the culmination of the infection time course (Figure. 2b). Subsequently, the NETs became fragmented, and their num- bers decreased (Figure 2c).
Correspondence
1131 Figure 2. Immunohistochemical images from sputum collected from the patient presented in Case 2 (a, during the respiratory infection; b, after the initiation of antibiotic therapy; c, in the remission phase; d, at the time of recurrence of infection; e, during the second remission phase). (a) NETs were abundantly expressed in response to acute respiratory infection. (b) Even when clearance of bacteria was achieved by antibiotic therapy, NETs remained with extended fibers. (c) NETs eventually became fragmented. (d) The expression of NETs was up-regulated again with the recurrence of infection. (e) Expression of NETs was decreased after the suppression of the infection. Red: histone H1; blue: 49,6-diamidino-2phenylindole (DAPI); green: neutrophil elastase (N-E). Arrowheads indicate the triplestained area (NETs). Magnification: 3400.
different from the culmination of the infection time course (Figure 2b). Subsequently, the NETs became fragmented, and their numbers decreased (Figure 2c). Recurrence of infection again induced active expression of NETs (Figure 2d). The NETs then decomposed as the infection was suppressed (Figure 2e). The present reports suggest dynamic alteration of the expression of NETs in sputum collected from patients affected by acute respiratory infection (8). We reason that neutrophils carry out phagocytosis of the bacteria; then, they release NETs, and eventually, redundant NETs are degraded by enzymes such as DNase after elimination of the invading bacteria. Studies to further analyze the functional roles of NETs are warranted. Author disclosures are available with the text of this letter at www.atsjournals.org.
Tomoya Hirose, M.D.* Shigeto Hamaguchi, M.D.* Naoya Matsumoto, M.D., Ph.D. Taro Irisawa, M.D. Masafumi Seki, M.D., Ph.D. Osamu Tasaki, M.D., Ph.D. Hideo Hosotsubo, B.S. Kazunori Tomono, M.D., Ph.D. Takeshi Shimazu, M.D., Ph.D. Osaka University Graduate School of Medicine Osaka, Japan
References 1. Brinkmann V, Reichard U, Goosmann C, Fauler B, Uhlemann Y, Weiss DS, Weinrauch Y, Zychlinsky A. Neutrophil extracellular traps kill bacteria. Science 2004;303:1532–1535. 2. Fuchs TA, Abed U, Goosmann C, Hurwitz R, Schulze I, Wahn V, Weinrauch Y, Brinkmann V, Zychlinsky A. Novel cell death program leads to neutrophil extracellular traps. J Cell Biol 2007;176:231–241. * Equally contributing joint first authors.
3. Urban CF, Reichard U, Brinkmann V, Zychlinsky A. Neutrophil extracellular traps capture and kill Candida albicans yeast and hyphal forms. Cell Microbiol 2006;8:668–676. 4. Jaillon S, Peri G, Delneste Y, Fre´maux I, Doni A, Moalli F, Garlanda C, Romani L, Gascan H, Bellocchio S, et al. The humoral pattern recognition receptor PTX3 is stored in neutrophil granules and localizes in extracellular traps. J Exp Med 2007;204:793–804. 5. Curran CS, Demick KP, Mansfield JM. Lactoferrin activates macrophages via TLR4-dependent and -independent signaling pathways. Cell Immunol 2006;242:23–30. 6. Zhang LT, Yao YM, Lu JQ, Yan XJ, Yu Y, Sheng ZY. Recombinant bactericidal/permeability-increasing protein inhibits endotoxin-induced high mobility group box 1 protein gene expression in sepsis. Shock 2008;29:278–284. 7. Lo¨gters T, Margraf S, Altrichter J, Cinatl J, Mitzner S, Windolf J, Scholz M. The clinical value of neutrophil extracellular traps. Med Microbiol Immunol (Berl) 2009;198:211–219. 8. Remijsen Q, Kuijpers TW, Wirawan E, Lippens S, Vandenabeele P, Vanden Berghe T. Dying for a cause: NETosis, mechanisms behind an antimicrobial cell death modality. Cell Death Differ 2011;18:581–588. Copyright ª 2012 by the American Thoracic Society
Arsenic and Lung Cancer in Never-Smokers: Lessons from Chile To the Editor:
As recently highlighted by associations between long-term fine particulate matter (PM2.5) and lung cancer mortality (1), environmental agents pose significant lung cancer risks in lifelong neversmokers. Such effects are evidenced in Chile, where in Santiago, high levels of particulate matter (PM10/PM2.5) are strongly associated with elevated incidences of respiratory symptoms. However, in Northern Chile these issues are further compounded by an almost 15-year-long exposure to arsenic, a well-known human carcinogen for lung cancer (including never-smokers) (2). Over a year ago, this region gained worldwide attention when 33
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Chilean miners were rescued from half a mile beneath the earth’s surface. Today, in this same area, thousands of people—exposed to levels of arsenic as high as 10 times the acceptable thresholds (10 mg/L)—suffer alarming rates of lung cancer incidence and mortality (3). Worldwide, an estimated 160 million people (w2% of total human population) live in regions with elevated arsenic levels in drinking water, presenting an urgent health concern. Arsenic contamination was purported to cause “the largest mass poisoning of a population in history” when 77 million people in Bangladesh were exposed through drinking water (4). As the world’s demand for drinking water continues to grow, so too does the urgency with which these health issues must be addressed. Squamous cell carcinomas are some of the most common malignancies associated with chronic arsenic exposure, most frequently of the skin, bladder, liver, and lungs (3). Around the world, incidence of lung squamous cell carcinoma (SqCC)—a disease primarily associated with cigarette smoke—is decreasing. However, in Northern Chile, SqCC is rising—and increasingly in never-smokers (5). Intriguingly, this trend does not apply to similarly exposed indigenous populations of Northern Chile. Molecularly, arsenic-related lung SqCC tumors from never-smokers display distinct DNA copy-number alteration patterns relative to those from smokers, which may be reflective of distinct mechanisms of arsenicrelated tumorigenesis (6). Implementation of public policies and development of simple, cost-effective methods to detect and treat arsenic-contaminated water supplies are urgently needed around the world. Screening protocols based on biomarkers are necessary to reduce arsenicassociated cancer mortality. A greater understanding of molecular mechanisms driving arsenic-induced cancers are required to yield potentially translatable findings for treating arsenic-related lung cancers. Deep molecular characterization (at genetic/epigenetic
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level) of arsenic-related tumors and/or cell models may provide such insight. Author disclosures are available with the text of this letter at www.atsjournals.org.
Victor D. Martinez, Ph.D. Emily A. Vucic, Ph.D. Stephen Lam, M.D. Wan L. Lam, Ph.D. BC Cancer Research Centre Vancouver, British Columbia, Canada References 1. Turner MC, Krewski D, Pope CA III, Chen Y, Gapstur SM, Thun MJ. Long-term ambient fine particulate matter air pollution and lung cancer in a large cohort of never-smokers. Am J Respir Crit Care Med 2011;184:1374–1381. 2. Sun S, Schiller JH, Gazdar AF. Lung cancer in never smokers–a different disease. Nat Rev Cancer 2007;7:778–790. 3. International Agency for Research on Cancer (IARC). Some drinkingwater disinfectants and contaminants, including arsenic. Monographs on chloramine, chloral and chloral hydrate, dichloroacetic acid, trichloroacetic acid and 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5h)furanone. IARC Monogr Eval Carcinog Risks Hum 2004;84:41–156. 4. Argos M, Kalra T, Rathouz PJ, Chen Y, Pierce B, Parvez F, Islam T, Ahmed A, Rakibuz-Zaman M, Hasan R, et al. Arsenic exposure from drinking water, and all-cause and chronic-disease mortalities in Bangladesh (HEALS): a prospective cohort study. Lancet 2010;376:252–258. 5. Ferreccio C, Gonzalez C, Milosavjlevic V, Marshall G, Sancha AM, Smith AH. Lung cancer and arsenic concentrations in drinking water in Chile. Epidemiology 2000;11:673–679. 6. Martinez VD, Buys TP, Adonis M, Benitez H, Gallegos I, Lam S, Lam WL, Gil L. Arsenic-related DNA copy-number alterations in lung squamous cell carcinomas. Br J Cancer 2010;103:1277–1283. Copyright ª 2012 by the American Thoracic Society
