Article

Comparison of the Pro-Oxidative and Proinflammatory Effects of Organic Diesel Exhaust Particle Chemicals in Bronchial Epithelial Cells and Macrophages

Department of Pathology and Laboratory Medicine, University of Wisconsin–Madison, Madison, Wisconsin, United States
The Journal of Immunology (Impact Factor: 4.92). 11/2002; 169(8):4531-41. DOI: 10.4049/jimmunol.169.8.4531
Source: PubMed

ABSTRACT

Inhaled diesel exhaust particles (DEP) exert proinflammatory effects in the respiratory tract. This effect is related to the particle content of redox cycling chemicals and is involved in the adjuvant effects of DEP in atopic sensitization. We demonstrate that organic chemicals extracted from DEP induce oxidative stress in normal and transformed bronchial epithelial cells, leading to the expression of heme oxygenase 1, activation of the c-Jun N-terminal kinase cascade, IL-8 production, as well as induction of cytotoxicity. Among these effects, heme oxygenase 1 expression is the most sensitive marker for oxidative stress, while c-Jun N-terminal kinase activation and induction of apoptosis-necrosis require incremental amounts of the organic chemicals and increased levels of oxidative stress. While a macrophage cell line (THP-1) responded in similar fashion, epithelial cells produced more superoxide radicals and were more susceptible to cytotoxic effects than macrophages. Cytotoxicity is the result of mitochondrial damage, which manifests as ultramicroscopic changes in organelle morphology, a decrease in the mitochondrial membrane potential, superoxide production, and ATP depletion. Epithelial cells also differ from macrophages in not being protected by a thiol antioxidant, N-acetylcysteine, which effectively protects macrophages against cytotoxic DEP chemicals. These findings show that epithelial cells exhibit a hierarchical oxidative stress response that differs from that of macrophages by more rapid transition from cytoprotective to cytotoxic responses. Moreover, epithelial cells are not able to convert N-acetylcysteine to cytoprotective glutathione.

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    • "After the particles or pathogens have eluded or overwhelmed the epithelial barrier of the upper airways, they come into contact with the dedicated antigen presenting dendritic cells (DCs) (e.g. Steinman and Cohn, 1973; Nicod, 1997; Lipscomb and Masten, 2002; Holt, 2005) which are highly phagocytic (Dreher et al., 2001; Kiama et al., 2001, 2006; Walter et al., 2001). If they reach the alveolar surface, they are dealt with by the PSMs (e.g. "

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    • "While activation of p38 MAPK was analyzed 2 and 4 h after the addition of OE, COX-2 protein was determined at the 16-h time point [16] [21] [27]. Cell lysate preparation, protein assay and western blot were performed as previously described [15] [27] [28]. HO-1, phosphorylated p38, total p38, COX- 2, and ␤-actin proteins were detected using respective primary Abs (1:1000) followed by horseradish peroxidaseconjugated secondary Abs (1:1000). "
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    ABSTRACT: Commercial charbroiling emissions are a significant source of ambient particulate matter (PM) in urban settings. The objective of this study was to determine whether organic extract of PM emissions from commercial charbroiling meat operations could induce an inflammatory response in human bronchial epithelial cells and whether this effect was mediated by oxidative stress. PM samples were collected during cooking hamburgers on a commercial-grade under-fired charbroiler and sequentially extracted with water and methanol to obtain the aqueous PM suspension (AqPM) and organic extract (OE). The pro-oxidative and pro-inflammatory effects of OE were assessed using human bronchial epithelial cell line BEAS-2B. While AqPM did not have any effect, OE effectively induced the expression of heme oxygennase-1 and cyclooxygenase-2 in BEAS-2B cells. OE also up-regulated the levels of IL-6, IL-8, and prostaglandin E2. OE-induced cellular inflammatory response could be effectively suppressed by the antioxidant N-acetyl cysteine, nuclear factor (erythroid-derived 2)-like 2 activator sulforaphane and p38 MAPK inhibitor SB203580. In conclusion, organic chemicals emitted from commercial charbroiling meat operations could induce an inflammatory response in human bronchial epithelial cells, which was mediated by oxidative stress and p38 MAPK.
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    • "Oxidative stress in response to DE has been demonstrated in vitro (Hashimoto et al., 2000; Koike et al., 2004; Li et al., 2002) and may be reversible with the anti-oxidant N-acetylcysteine (Koike et al., 2004). An endogenous anti-oxidant response to DE has also been shown in human bronchial epithelial cells in vitro (Li et al., 2002; Xiao et al., 2003) and a controlled human exposure model has shown increases in glutathione in bronchial wash at 6 h and in bronchoalveolar lavage at 18 h following exposure to DE (Behndig et al., 20062006). Finally, in asthmatics exposed to DE, there is a drop in the pH of exhaled breath condensate (McCreanor et al., 2007), suggestive of oxidative stress. "
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    ABSTRACT: Background: Inhalation of diesel exhaust (DE) at moderate concentrations causes increased airway responsiveness in asthmatics and increased airway resistance in both healthy and asthmatic subjects, but the effect of baseline airway responsiveness and anti-oxidant supplementation on this dynamic is unknown. Objectives: We aimed to determine if changes in airway responsiveness due to DE are attenuated by thiol anti-oxidant supplementation, particularly in those with underlying airway hyper-responsiveness. Methods: Participants took N-acetylcysteine (600 mg) or placebo capsules three times daily for 6 days. On the last of these 6 days, participants were exposed for 2 h to either filtered air (FA) or DE (300 μg/m(3) of particulate matter smaller than 2.5 microns). Twenty-six non-smokers were studied under each of three experimental conditions (filtered air with placebo, diesel exhaust with placebo, and diesel exhaust with N-acetylcysteine) using a randomized, double-blind, crossover design, with a 2-week washout between conditions. Methacholine challenge was performed pre-exposure (baseline airway responsiveness) and post-exposure (effect of exposure). Results: Anti-oxidant supplementation reduced baseline airway responsiveness in hyper-responsive individuals by 20% (p = 0.001). In hyper-responsive individuals, airway responsiveness increased 42% following DE compared with FA (p = 0.03) and this increase was abrogated with anti-oxidant supplementation (diesel exhaust with N-acetylcysteine vs. filtered air with placebo, p = 0.85). Conclusions: Anti-oxidant (N-acetylcysteine) supplementation protects against increased airway responsiveness associated with DE inhalation and reduces need for supplement bronchodilators in those with baseline airway hyper-responsiveness. Individuals with variants in genes of oxidative stress metabolism when exposed to DE are protected from increases in airway responsiveness if taking anti-oxidant supplementation.
    Preview · Article · Jun 2014 · Toxicological Sciences
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