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Respiratory Burst in Alveolar Macrophages Exposed to Urban Particles Is Not a Predictor of Cytotoxicity

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Respiratory Burst in Alveolar Macrophages Exposed to Urban Particles Is Not a Predictor of Cytotoxicity Toxicology in Vitro 27 (2013) 1287–1297 Contents lists available at SciVerse ScienceDirect Toxicology in Vitro journal homepage: www.elsevier.com/locate/toxinvit Respiratory burst in alveolar macrophages exposed to urban particles is not a predictor of cytotoxicity Dalibor Breznan a, Patrick Goegan a, Vinita Chauhan a, Subramanian Karthikeyan a, Prem Kumarathasan b, ⇑ Sabit Cakmak c, Denis Nadeau d, Jeffrey R. Brook e, Renaud Vincent a, a Inhalation Toxicology Laboratory, Healthy Environments and Consumer Safety Branch, Health Canada, Ottawa, ON, Canada K1A 0K9 b Analytical Biochemistry and Proteomics Laboratory, Healthy Environments and Consumer Safety Branch, Health Canada, Ottawa, ON, Canada K1A 0K9 c Population Studies Division, Healthy Environments and Consumer Safety Branch, Health Canada, Ottawa, ON, Canada K1A 0K9 d Centre Hospitalier de l’Université Laval, Québec, QC, Canada G1V 4G2 e Atmospheric Environment Service, Environment Canada, Downsview, ON, Canada M3H 5T4 article info abstract Article history: We examined the utility of respiratory burst measurements in alveolar macrophages to assess adverse Received 27 November 2012 cellular changes following exposure to urban particles. Cells were obtained by bronchioalveolar lavage Accepted 21 February 2013 of Fisher 344 rats and exposed (0–100 lg/well) to urban particles (EHC-93, SRM-1648, SRM-1649, Available online 1 March 2013 PM2.5), the soluble (EHC-93sol) and insoluble (EHC-93insol) fractions of EHC-93 (EHC-93tot), mineral particles (TiO2, SiO2) and metal oxides (iron III oxide, iron II/III oxide, copper II oxide, nickel II oxide). Keywords: The particle-induced respiratory burst was measured by chemiluminescence for 2 h after the addition Alveolar macrophages of particles. The cells were then stimulated with phorbol 12-myristate 13-acetate (PMA), yeast Zymosan Oxidative stress fragments (Zymosan), or lipopolysaccharide plus interferon-gamma (LPS/IFN- ) and the stimulant- Particulate matter c Respiratory burst induced respiratory burst was measured. Independently of the potential of particles to induce directly Cytotoxicity a respiratory burst, exposure to most particles attenuated the subsequent stimulant-induced burst. The notable exception was SiO2, which produced a strong respiratory burst upon contact with the mac- rophages and enhanced the subsequent response to PMA or LPS/IFN-c. Based on the degree of inhibition of the stimulant-dependent respiratory burst, particles were clustered into groups of high (SRM-1649, iron III oxide), intermediate (EHC-93tot, EHC-93insol, SRM-1648, VERP, iron II/III oxide, copper II oxide), and low (EHC-93sol, SiO2, TiO2 and nickel II oxide) potency. Across these clusters, the potency of the par- ticles to inhibit the stimulant-dependent respiratory burst showed poor correlation with cytotoxicity determined by XTT reduction assay. Crown Copyright Ó 2013 Published by Elsevier Ltd. All rights reserved. 1. Introduction large body of in vitro and in vivo work shows the potential for heightened susceptibility to infections due to impaired phagocyto- Epidemiological studies have shown a positive correlation be- sis by macrophages and decreased ability of the lungs to clear tween exposure to ambient particulate matter and the develop- invading pathogens (Lundborg et al., 2006; Sigaud et al., 2007). ment and exacerbation of adverse respiratory and cardiovascular Alveolar macrophages play a critical role in the phagocytic re- outcome (Goldberg et al., 2001; Guaita et al., 2011). A specific con- moval of microbes as well as particulate matter from the airways sequence of exposure to high levels of particulate air pollution is and alveoli. Macrophages release reactive oxygen species in re- increased susceptibility to infections often leading to the hospital- sponse to an encounter with particles (Beck-Speier et al., 2005) ization of affected individuals (Lin et al., 2005; Gilmour, 2012). A and microbes (Gwinn and Vallyathan, 2006) in a process referred to as respiratory burst. For example, alveolar macrophages, ob- tained from humans or rodents, acutely exposed to ambient partic- Abbreviations: AU, absorbance units; BAL, bronchioalveolar lavage; LPS, lipo- ulate matter or minerals such as silicon dioxide (SiO2) and titanium polysaccharide; LU, luminescence units; PBS, phosphate-buffered saline; PM, dioxide (TiO2), have been shown to generate increased amounts of particulate matter; PMA, phorbol 12-myristate 13-acetate; PMS, phenazine methosulfate. oxidants (Becker et al., 2002; Goldsmith et al., 1997). ⇑ Corresponding author. Address: Inhalation Toxicology Laboratory, Environmen- High levels of oxidants are also released by macrophages in re- tal Health Centre, Health Canada, 0803C, Tunney’s Pasture, Ottawa, ON, Canada K1A sponse to biological materials such as lipopolysaccharide (LPS) and 0K9. Tel.: +1 613 941 3981; fax: +1 613 946 2600. yeast cell fragments (e.g. Zymosan), and other stimulants such as E-mail address: [email protected] (R. Vincent). 0887-2333/$ - see front matter Crown Copyright Ó 2013 Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tiv.2013.02.014 1288 D. Breznan et al. / Toxicology in Vitro 27 (2013) 1287–1297 phorbol 12-myristate 13-acetate (PMA) (Zughaier et al., 2005). The Table 1 phorbol ester PMA is a soluble chemical mitogen that acts through Occupational exposure limits for airborne contaminants. a protein kinase C cell signaling pathway (Babior, 1992) and acti- Material TWAa Ontario and TWAb NIOSH TWA/TLVc vates reduced nicotinamide adenine dinucleotide phosphate Québec (mg/m3) (mg/m3) ACGIH (mg/m3) (NADPH) oxidase (Dusi and Rossi, 1993). In contrast, Zymosan is SiO2 0.05 0.05 0.05 an insoluble cell wall polysaccharide of Saccharomyces cerevisiae Cu II oxide 0.2 0.1 0.2 that activates macrophages via Toll-like receptor 2, and that is rec- Ni II oxide 0.1 0.015 0.2 Fe II/III oxide 5 5 5 ognized by macrophages and dendritic cells by dectin-1, a pattern Fe III oxide 5 5 5 recognition receptor important in antifungal innate immunity d TiO2 10 15 (OSHA) 10 (Brown et al., 2003). Furthermore, Zymosan activates NADPH oxi- a dase through the cell membrane receptors type 3 complement Time-weighted average for Ontario and Québec. b Time-weighted average for National Institute for Occupational Safety and receptor and mannosyl-fucosyl receptor (Ezekowitz et al., 1985). Health. The cell wall component of Gram-negative bacteria, LPS primes c Time-weighted average/threshold limit value for the American Conference of macrophages through a receptor-dependent mechanism that in- Governmental Industrial Hygienists. d volves acute-phase plasma protein, LPS binding protein, CD14 cell Occupational Safety and Health Administration. surface receptor, and transmembrane receptor Toll-like receptor 4 (Ulevitch, 1999; Wright et al., 1990). Stimulation of alveolar mac- rophages with LPS has also been linked to mitogen-activated pro- Institute of Standards and Technology (Gaithersburg, MD, USA) tein kinase signaling pathways, including c-Jun N-terminal and used as supplied, except for TiO2, which was subjected to three kinase, extracellular signal-regulated kinase, and p38 (Carter washes with methanol, followed by three washes with phosphate et al., 1999; Monick et al., 1999). The kinases affect apoptosis, che- buffered saline (Vincent et al., 1997). Fine particulate matter from motaxis, cytoskeletal rearrangement, cytokine gene expression, Vermillion, Ohio (VERP), with an aerodynamic size cut-off of degranulation and respiratory burst (Davis, 1993). 2.5 lm (PM2.5) collected on hi-vol filters in 1992 was recovered Whereas particles can induce respiratory burst in phagocytic by sonication and lyophilization (Vincent et al., 1997). The metal cells, the oxidant response of cells to other stimuli such as mi- oxides, iron II/III oxide (<5 lm diameter; 98% purity), iron III oxide crobes or microbial components is diminished by exposure to par- (<5 lm; 99+%), copper II oxide (<5 lm; 99+%) and nickel II oxide ticulate matter. For instance, particle exposures have resulted in a (<10 lm; 76–77%), were obtained from Sigma–Aldrich Co., St. decreased release of reactive oxygen species in alveolar macro- Louis, MO, USA. The particulates including metal oxides were se- phages induced with oxidant-generating stimuli such as phorbol lected given that they cover a wide range of occupational limits esters, or opsonized yeast (Becker and Soukup, 1998; Fabiani for airborne exposures (ACGIH, 2010; NIOSH, 2007; Ontario Minis- et al., 1997). Another study has shown that insoluble components try of Labour, 2010; OSHA, 2006; Québec Gazette Officielle, 2009; of urban air particles play a role in the inhibition of oxidant release Table 1). and phagocytosis in activated alveolar macrophages (Soukup and Becker, 2001). 2.2. EHC-93 fractions It remains unclear whether particle-related reduction of respi- ratory burst is attributed to cytotoxic events. Past studies have For aqueous extraction, one g of EHC-93 was suspended in 5 ml shown that exposures of macrophage cells to air pollution particles of deionized sterile water (>16 MOhms resistivity), sonicated on (Imrich et al., 1999; Soukup et al., 2000), metals (Benson et al., ice for 20 min, and centrifuged at 500g, 10 min. The extract was 1988; Riley et al., 2005) or minerals (Costantini et al., 2011; Fubini collected and the insoluble material was resuspended in 5 ml of and Hubbard, 2003) may result in cytotoxicity often leading to water. This process was repeated twice and pooled supernatant apoptotic or necrotic cell death. In contrast, extracts of airborne was centrifuged at 900g for 3.5 h. The pellet was combined with particulates from industrialized Rhine-Ruhr area have been shown the previous insoluble fraction. The aqueous extract was further to inhibit phagocytosis in human peripheral blood macrophages filtered through a 0.2 lm nylon filter. The filtrate was eluted with without apparent effect on cell viability (Hadnagy and Seemayer, 5 ml of methanol and the eluate was pooled with the aqueous ex- 1994). tract. The aqueous extract and the water-insoluble pellet were sub- The present study aimed to assess the relationship between sequently frozen at À80 °C and lyophilized.
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