title: The role of free radicals in the toxic and inflammatory effects of four different ultrafine particle types.
abstract: PM10 contains an ultrafine component, which is generally derived from combustion processes. This ultrafine fraction may be a factor in the increases in exacerbations of respiratory disease and deaths from cardiorespiratory causes associated with transient increases in levels of PM10. By using four different ultrafine particles (carbon black, cobalt, nickel, and titanium dioxide), we set out to determine the attributes of the ultrafine particle (surface area, chemical composition, particle number, or surface reactivity) that contribute most to its toxicity and proinflammatory effects both in vivo and in vitro. Instillation of 125 micro g ultrafine carbon black (UFCB) and ultrafine cobalt (UFCo) particles induced a significant influx of neutrophils at both 4 and 18 h postinstillation. Accompanying the influx of neutrophils was an increase in macrophage inflammatory protein-2 (MIP-2) (at 4 h) and an increase in gamma-glutamyl transpeptidase (at 18 h) in bronchoalveolar lavage fluid (BAL). Ultrafine nickel (UFNi) did not induce a significant increase in neutrophil influx until 18 h postinstillation. The increase in neutrophils induced by UFNi at this timepoint was comparable to that induced by UFCo and UFCB. UFTi did not induce a significant increase in neutrophils following instillation into the rat lung. The levels of MIP-2 observed at 4 h and neutrophil influx at 18 h induced by the particle samples were consistent with the pattern of surface free radical generation (as measured by the plasmid scission assay) whereby UFCo, UFCB, and UFNi all cause significant increases in inflammatory markers, as well as inducing a significant depletion of supercoiled plasmid DNA, indicative of hydroxyl radical generation. A role for free radicals and reactive oxygen species (ROS) in mediating ultrafine inflammation is further strengthened by the ability of the antioxidants N-acetylcysteine (NAC) and glutathione monoethyl ester (GSHme) to block the particle induced release of tumour necrosis factor-alpha (TNF-alpha) from alveolar macrophages in vitro. The ultrafine particles in PM10 may cause adverse effects via oxidative stress, and this could have implications for susceptible individuals. Susceptible individuals, such as those with COPD or asthma, already exhibit preexisting oxidative stress and hence are in a primed state for further oxidative stress induced by occupational or environmental particles.
authors.affiliation: School of Health and Life Sciences, Napier University, Edinburgh, United Kingdom. colin.dick@scottish-biomedical.com
authors.forename: Colin A J
authors.initials: CA
authors.lastname: Dick
authors.forename: David M
authors.initials: DM
authors.lastname: Brown
authors.forename: Ken
authors.initials: K
authors.lastname: Donaldson
authors.forename: Vicki
authors.initials: V
authors.lastname: Stone
mesh_terms: D000393:Air Pollutants / Q000633:toxicity*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D002244:Carbon / Q000633:toxicity*; D002452:Cell Count; D054426:Chemokine CXCL2; D003035:Cobalt / Q000633:toxicity*; D005609:Free Radicals / Q000378:metabolism; D066298:In Vitro Techniques; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism*; D019570:Inhalation Exposure; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D016676:Macrophages, Alveolar / Q000378:metabolism; D008297:Male; D015846:Monokines / Q000032:analysis; D009532:Nickel / Q000633:toxicity*; D010316:Particle Size; D051381:Rats; D017208:Rats, Wistar; D014025:Titanium / Q000633:toxicity*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D005723:gamma-Glutamyltransferase / Q000032:analysis
chemical_list: D000393:Air Pollutants; D000975:Antioxidants; D054426:Chemokine CXCL2; D005609:Free Radicals; D015846:Monokines; D014409:Tumor Necrosis Factor-alpha; C009495:titanium dioxide; D003035:Cobalt; D002244:Carbon; D009532:Nickel; D014025:Titanium; D005723:gamma-Glutamyltransferase